Introduction Merged

UNIT-1
PHARMACEUTICAL QUALITY AUDIT

SYLLABUS
 INTRODUCTION
 OBJECTIVES
 MANAGMENT OF AUDIT
 RESPONSIBILITES
 PLANNING PROCESS
 INFORMATION GATHERING
 ADMINISTRATION
 CLASSIFICATION OF DEFICIENCIES
INTRODUCTION
 International organization for standardization (ISO) defines the audits as
"Systematic, independent and documented process for obtaining audit evidence
and evaluating them objectively to determine the degree to which the verification
criteria are met”.
 In the pharmaceutical industry, audits are virtual means for assessing
compliance with the established objectives defined in the quality system and thus
paving the way for the continuous improvement program by providing feedback
to management.
INTRODUCTION...
 A company that produces drugs today must be able to demonstrate that it does so
with absolute reliability, in optimal conditions and with extreme uniformity that
allows accurate reproduction.
 Audits are conducted to ascertain the validity and reliability of the information;
also to provide an assessment of the internal control of a system.
 It provides management with information on the efficiency with which the
company controls the quality of its processes and products.
 The audit in simple terms could be defined as the inspection of a process or a
system to ensure that it meets the requirements of its intended use.
INTRODUCTION...
 Instead of considering the audit as an intrusive and potentially threatening

review, pharmacies should consider the audit as a quality control mechanism.
 The results of the audit and the resulting corrective actions ensure all the
involved parties that a program works in accordance with established rules of
practice.
 Pharmaceutical audit experience includes the drafting and revision of validation
policies, guidelines and standard operating procedures (SOP) from project
qualification to performance evaluation phases.
TYPES OF AUDITS
 Quality audits are performed to verify the effectiveness of a quality management
system. The quality audit system mainly classified in three different categories:
1.Internal Audits
2.External Audits
3.Regulatory Audits
 Regulatory authority for quality audits:
ISO standards ,
Code of federal regulations [CFR] , ICH Q10,USFDA ,GMP
INTERNAL AUDITS
 This type of audit is also known as First-Party Audit or self-audit. Those auditing
and those being audited all belong to the same organization.
 Internal audit is a professional activity that consists of advising organizations on

how to achieve their goals in a better way.
 The internal audit involves the use of a systematic methodology to analyze

business processes or organizational problems and recommend solutions.
EXTERNAL AUDITS
 This type of audit is also known as Second-Party Audit. It refers to a customer
conducting an audit on a supplier or contractor.
 Although there are no strict legal requirements for this control.
 It is always advisable to evaluate the competence of the contractors in which we

produce our products or carry out the analysis of our products or any other
activity according to GMP.
REGULATORY AUDITS
 This type of audit is also known as Third-Party Audit. Neither customer nor
supplier conducts this type of audit. A regulatory agency or independent body
conducts a third party audit for compliance or certification or registration
purposes.
 International regulatory bodies such as MHRA,UK, USFDA, Therapeutic goods

administration (TGA), Australia, Medicines control council (MCC), South Africa
,etc. are responsible for carrying out these checks.
 There is a team to perform the audit, it must be composed of audit inspectors

and multidisciplinary company team.
OBJECTIVES
OBJECTIVES...
 Evaluating conformity of requirements to ISO 9001.
 Evaluating conformity of documentation to ISO 9001.
 Judging conformity of implementation to documentation.

 Determining effectiveness in meeting requirements
and objectives.
 Meeting any contractual or regulatory requirements for auditing.

 Providing an opportunity to improve the quality
management system.
 Permitting registration and inclusion in a list of registered companies.

OBJECTIVES...
 Qualifying potential suppliers.
 To determine the conformity or non-conformity of the quality system in meeting

the specified requirements.
 To determine the effectiveness of the implemented

quality in meeting the specified Quality objectives.
 To provide the Audit team with an opportunity to improve the Quality system.
 To meet the regulatory requirement .
 To permit listing of the audited organizations Quality systems in a register.

MANAGEMENT OF AUDIT
 An audit program may include one or more audits, depending on the size, nature,
and complexity of the organization to be audited.
 These audits may have a variety of objectives and may also include joint
(multiple auditing organizations) or combined (Quality management and
Environmental management systems) audits.
 Management of an audit program includes all the activities necessary for

planning and organizing the types and number of audits, and for providing
resources for conducting them effectively and efficiently within the specified time
frames.
MANAGEMENT OF AUDIT...
 The organization’s top management should grant the authority for managing
the audit program. Those assigned the responsibility for managing the audit
program should:
1. Plan, establish, implement, monitor, review and improve the audit

program.
2. Identify the necessary resources and ensure they are provided.
 The simple goal of this complex process is to evaluate existing activities and
documentation and determine if they meet the established standards.
MANAGEMENT OF AUDIT...
RESPONSIBILITIES
 An audit will evaluate the strengths and weaknesses of quality control and quality
assurance processes, the results of which will help us to improve processes and
build a better system for the benefit of the company.
 Every product manufactured by a pharmaceutical company has characteristics

that must be quantified or qualified by laboratory tests.
 Quality control and quality assurance are the necessary processes that play the
role of control and balance system in pharmaceutical industry.
RESPONSIBILITIES...
The auditor has the following responsibilities:
 Assist in the selection of the team and inform the team.
 Responsibility to plan and manage all phases of the audit.

 Represent the audit team with the auditee.
 Control conflicts and manage difficult situations.
 Direct and control all meetings with the team and the
auditee.
 Make decisions about audit issues and the quality system.

 Report the results of the audit without delay.
 Report the main obstacles encountered.
 Report critical non-conformances immediately.
 Possesses effective communication skills.
PLANNING PROCESS
 In order to conduct an audit effectively and efficiently, the work needs to
be planned and controlled.
 The form and nature of the planning required for an audit will be affected by the
size and complexity of the enterprise, the commercial environment in which it
operates, the methods of processing transactions and the reporting requirements
to which it is subjected.
 Audit planning is the formulation of the general strategy for audit which sets the
direction for the audit, describes the expected scope and conduct of the audit and
provides guidance for the development of the audit program.
PLANNING PROCESS...
Adequate planning of an audit work aims at:
 Establishing the intended means of achieving the objectives of the audit.
 Assisting in the direction and control of the work.
 Helping to ensure that attention is devoted to

critical aspects of the audit work.
 Ensuring that the work is completed expeditiously.
 Facilitating review of the audit work.
 Helping to assign the proper tasks to members of

the audit team and coordinates outside experts.
PLANNING PROCESS...
The steps in planning an audit include:
 Basic discussions with the client about the nature of the practices by
sampling, reviewing the law and testing internal rules and practices for
reasonableness.
Engagement are performed first, and the auditor meets the key employees or
new employees of a continuing client. The overall audit strategy or the timing
of the audit may also be discussed.
 Ask about recent developments in the company such as mergers and new
product lines which will cause the audit to differ from earlier years.
PLANNING PROCESS...
 Ask about recent developments in the company such as mergers and new
product lines which will cause the audit to differ from earlier years.
 Interim financial statements are analyzed to identify accounts and

transactions that differ from expectations (based on factors such as budgets or
prior periods).
The performance of such analytical procedures is mandatory in the planning of an

audit to identify accounts that may be misstated and that deserve special
emphasis in the audit program.
PLANNING PROCESS...
 Timing of the various audit procedures should be determined.
 Outside assistance needs should be determined, including the use of a

specialist as required and the determination of the extent of involvement of the
internal auditors of the client.
 Pronouncements on accounting principles and audit guides should be read or

reviewed to assist in the development of complete audit programs fitting the
unique needs of the industry.
 Scheduling with the client is needed to coordinate activities.

PLANNING PROCESS...
 Non-audit personnel of the accounting firm who have provided services (such
as tax preparation) to the client should be identified and consulted to learn
more about the client.
 Staffing for the audit should be determined and a meeting held to discuss the
engagement.
The purpose of all this is to ensure that the risk of performing a poor quality
audit (and ultimately giving an inappropriate audit opinion) is reduced to an
acceptable level.
INFORMATION GATHERING
 Information is simply the facts or knowledge provided or learned. It can be
tacit, in people's heads, or explicit, in documents-electronic or hard copy.
 During the audit, information relevant to the objectives, scope and criteria,
including information on interfaces between functions, activities and processes,
should be collected by appropriate sampling and should be verified.
 Only verifiable information can be audit evidence which must be recorded.

INFORMATION GATHERING...
Audit evidence:
 It is any information used by the auditor to determine if the audited information

is in accordance with the established criteria and to arrive at the conclusions on
which the audit opinion is based. Internal Audit Evidence includes any data,
information, process flows, vouchers, bills, memos, contracts or transactions.
Methods of gathering audit information:There are six basic methods of
gathering information during an audit. Depending on the type of information
that needs to be obtained, the Internal Auditor will need to determine which
method, or combination of methods, should be used.
Interviews:
 Interviewing is a powerful data collection technique, which works well on its

own and is often used to support other techniques, such as observation.
 The interviewee’s insights can guide the Internal Auditor’s decisions about
what to observe.
 The most important thing to remember when interviewing is to always talk to

the right person, as it can save a lot of time and confusion.
Inspections:
 When inspecting something, it is good practice to start with general
observations and then proceeding to the more specific elements.
 First, the Internal Auditor will have a good overall look around the facility and
then examine specific items more closely, noting anything that does not seem
quite right.
 It is important to ask questions throughout the inspection. If a problem is
found, the Internal Auditor must investigate (dig deeper) to explore the extent
of the finding.
Reviewing documents:
 Documents should be clear regardless of who reads them. Details vary but, in
general, every document should carry a title, an owner and a revision status. If
any of this information is missing, the Internal Auditor should ask why.
 The revisions noted should be checked against the master record. Changes must
be authorized, signed and dated by an authorized person.
 However, one sample taken in one given period of time is usually not enough to
form accurate conclusions. Another important aspect of record keeping is
clarity.
Observations:
 The simplest way to check how a process works is to observe it in action.
 Observing a routine activity for a couple of hours can give the Internal Auditor
the opportunity to see how something is done under normal circumstances.
 He or she should ask questions about what they see, making sure at all times not
to interfere with the processes they are observing, as that may cause the
personnel not to carry out their tasks as they usually do.
Vertical tracking:
 This method is also referred to as “vertical auditing” and consists of following a

specific development from the beginning until the end, simultaneously checking
all the records that are produced in the process.
 Applying the vertical tracking technique can lead the Internal Auditor to areas
that were not initially part of the scope, but it does facilitate a bigger picture
view, as this allows the Internal Auditor to see how the various parts of a given
program work together.
Exercises:
 The aim of an exercise is to test something that is usually done at the facility as
part of the routine. However, the Internal Auditor gets to pick the time and the
circumstances for the test.
 The subject of testing can be the personnel, the program, or the equipment. An
Internal Auditor should not run an exercise without the knowledge and
cooperation of the auditee.
 Doing so is likely to have negative consequences as unannounced actions may

breach certain facility specific rules or regulations which the Internal Auditor is
unaware of.
ADMINISTRATION
Administration:
 The internal audit team must have the confidence and trust of the key
stakeholders it works with and be seen as a credible source of assurance and
advice.
 This confidence should not be assumed and can only be established and
maintained by having an effective working relationship, by delivering high
quality and timely advice and internal audit reports that are seen to be
contributing directly to assisting the organisation to meet its responsibilities.
ADMINISTRATION...
The key stakeholders of internal audit are:

1.Chief Executive
2.Board of Directors
3.Audit Committee
4.Senior management
5.External auditor
6.Other reviewers
ADMINISTRATION...
Chief executive:
 While internal audit reports functionally to the Audit Committee, it is important

that the Head of Internal Audit has direct access, as and when required, to the
Chief Executive.
 Organisations today, recognize the advantages in making the Head of Internal

Audit directly accountable to the Chief Executive. This not only sends a clear
signal about the importance of the internal audit function, it also facilitates
regular contact between the Chief Executive and internal audit.
ADMINISTRATION...
 This contact should be used as an opportunity to gain insights into new and
emerging risks and issues facing the organisation and to discuss the role the
Chief Executive expects internal audit to fulfill in the company.
Board of directors:
 The Head of Internal Audit may formally report to the Board of Directors on the
effectiveness of the internal audit function in order to exchange views and ideas.
ADMINISTRATION...
 As the Audit Committee is usually a sub-committee of the Board, this
responsibility is often delegated to the Audit Committee.
 As a minimum, it is important that the Head of Internal Audit has direct access
to the Chair of the Board and the Chief Executive, as and when required.
Audit committee:
 Audit Committees play an integral role in the governance framework of

organizations. It assists Chief Executives and Boards to understand whether key
controls are appropriate and operating effectively.
ADMINISTRATION...
 In this respect, the relationship between internal audit and the Audit Committee
is crucial and has a number of dimensions which are mentioned below:
a. Advise the Chief Executive about the internal audit plans of the organisation.
b.Direct or coordinate work programs relating to internal and external audits.
c. Review the adequacy of responses to reports of internal and external audits.
d.Utilize the internal audit function to undertake secretariat compliance.

ADMINISTRATION...
Senior management:
 To effectively fulfill its responsibilities, it is important that internal audit has a

professional and constructive relationship with senior management of the
organization.
 Internal auditors should interact on a regular basis with members of the senior
management team, and through the delivery of practical, business-focused and
useful reports and advice, build a relationship that is based on cooperation,
collaboration and mutual respect.
ADMINISTRATION...
 These meetings should also be used to obtain informal feedback about the
performance of internal audit and to assist in identifying ways that internal
audit can best assist organization management.
External auditors:
 External auditors too must help in developing internal audit strategy and
internal audit work plan.
 Both audit teams need to address the key financial and business systems
underpinning the company's financial statements and to avoid duplication of
compliance and assurance.
ADMINISTRATION...
 To avoid such duplication, the external auditor must evaluate the work of the
internal audit function to determine its adequacy for external audit purposes.
 The Internal audit function can be made responsible for liaising with external
auditor on behalf of the organization. Such a role can be a useful way for an
internal audit team to be aware of planned and actual external audit coverage.
 Thus, a constructive relationship between both sets

of auditors assists in the conduct of external audits.
ADMINISTRATION...
 Such a role can only be fulfilled when there is healthy communication between
teams which can be achieved by establish meetings to allow for a routine
exchange of information.
Other reviewers:
 Internal audit is one of a number of internal and external review and assurance
activities that exist as part of an organization’s governance arrangements.
 The company shall benefit when all these activities, such as those performed by
the Ombudsman and regulators, operate in a coordinated and complementary
manner to the greatest extent possible.
ADMINISTRATION...
 This requires regular formal and informal contact between review bodies to
minimize duplication and overlap.
 Some organisations see a benefit in protocols being formalised for such activities:
providing, for example, for the regular exchange of views and information and
for the reporting of the results of work undertaken in a coordinated manner.
 Protocols can be particularly important in situations where internal audit needs

to work closely with other entities as a result of inter-agency or other agreements.
CLASSIFICATION OF DEFICIENCIES…
Nonconformities or deficiencies:
As the audit proceeds, there might arise some situations where the facts
indicate there is a failure, either partially or wholly, of the quality management
system, such a situation is called nonconformity”.
What is nonconformity?
 a condition adverse to Quality.
 The non-fulfillment of a requirement.
The number of nonconformities that can arise during an audit can be

numerous. Following types of defects are identified during an internal audit and
these are helpful in regulatory compliance:
Critical defect:
 Critical defects have a high probability of resulting in a product recall or in an

adverse physiological response by the consumer.
 Critical deficiencies found in internal audits that usually produce significant

effects on the strength, identity, safety, and purity of the product that will be
considered during regulatory compliance.The possible source of a critical defect
are:
 Cross-contamination of materials of the product.
 Incorrect labeling.
 Active ingredients outside of specifications.
 Product manufactured according to obsolete or unapproved procedures.

 Open sterile products located in a non-aseptic area.
 Untrained operators working in the sterile filling area.
 Contaminated purified water or water for injection system.

Major defect
Major defects found during the internal audit can reduce the usability or
stability of a product, but without causing harm to the consumer.The possible
source of a major defect are:
 Major equipment not calibrated or out of calibration.
 Inadequate segregation of quarantine components.
 Inadequate evaluation of production process outside of action levels.
 Process deviations not properly documented or investigated.
 Operator not trained in or familiar with the standard operating procedures.
 Preventive maintenance on a critical water system not conducted according to

schedule.
 Lack of standard operating procedures for cleaning equipment.
 Audits of a contract manufacturer not conducted.
Minor defect
Minor defects have a low probability of affecting the quality or usability of

the product which can help in regulatory compliance.Possible source of the
minor defect are:
 Failure to complete all batch record entries.
 Warehouse not cleaned according to schedule

 Cracks in wall surfaces.
 Failures to correct documentation errors properly.
 Operator uniform not properly worn.
 Standard operating procedure review is overdue.
 Adhesive tape used on manufacturing equipment.
 Laboratory buffer solutions are obsolete.

CONCLUSION
 Audits to be conducted at planned intervals to evaluate effective implementation
and maintenance of the quality system and to determine if processes and products
meet established parameters and specifications.
 An audit performed by a well trained and thoroughly prepared auditor

can be highly beneficial by identifying areas for genuine improvement.
 Auditing in the pharmaceutical sector serves two different categories: regulatory

compliance and business needs.
REFERENCE
1. Review on“Pharmaceutical quality audits” by princy agarwal & amul misra ,
Nnovare;2018.
2. Vedanabhlata S, Gupta VN. “A review on audits and compliance management”.

Asian J Pharm Clin Res 2013;6:43-5.
3. Kaur J. Quality audit: Introduction, types and procedure [Internet].Pharma

Pathway; 2017. http://pharmapathway.com/quality-audit- introduction-
types-and-procedure/.
4. Chartered Institute of Internal Auditors. How to gather and evaluate

information;2017. https://www.iia.org.uk/resources/delivering- internal-
audit/how-/.
UNIT-2
ROLE OF QUALITY SYSTEM AND
AUDITS IN PHARMACEUTICAL
MANUFACTURING ENVIRONMENT
Syllabus: cGMP Regulations, Quality assurance functions, Quality systems approach,
Management responsibilities, Resource, Manufacturing operations, Evaluation
activities, Transitioning to quality system approach, Audit checklist for drug industries.
ROLE
• This Chapter describes outlines and discusses the regulations applicable to the
QA function and unit, structure, , charter, and application of the unit in the
pharmaceutical manufacturing environment.
• By regulation
• Appropriate practice
• Common sense
• Quality assurance (QA) is a critical function in the pharmaceutical manufacturing
environment. The need for an independent unit to audit and comment on the
appropriate application of standard operating procedures, master batch records,
procedures approved in product applications.
• This helps assure that products are manufactured reliably, with adherence to approved
specifications, and that current good manufacturing practices (cGMP) are maintained in
conformance to regulation, both in the facility in general and the microenvironment of
each product’s manufacturing sequence.
•Quality assurance personnel must have the appropriate training, experience,
familiarization with the manufacturing facility and products and the ability to review
adherence to procedures, policies, This helps to provide both an environment and a
manufactured product that can withstand Food and Drug Administration (FDA) inspection
and support a firm’s reputation for quality products.
•The cGMP regulations establish requirements that are intended to provide a high level of
assurance that the pharmaceutical products produced satisfy the strength, purity, potency,
and other quality requirements established for the finished product to assure that it is fit
for its intended use.
cGMP REGULATION
• The cGMP regulations for the manufacture of pharmaceutical products are contained in Parts
210 and 211 of Title 21 of the Code of Federal Regulations (CFR)
• Part 210 specifies the scope and applicability of the cGMP regulations and defines terms
used in the regulations. Part 210 also indicates that the regulations establish “minimum”
cGMP requirements and that products that are not manufactured under cGMP are
adulterated. Adulterated products and the persons responsible for the adulteration are
subject to regulatory action by the FDA.
• Part 211 contains specific good manufacturing practice requirements for finished
pharmaceuticals and is divided into Subparts A–K as follows:
• A. Scope
• B. Organization and Personnel
• C. Buildings and Facilities
• D. Equipment
• E. Control of Components and Drug Product Containers and Closures
• F. Production and Process Controls
• G. Packaging and Labeling Control
• H. Holding and Distribution
• I. Laboratory Controls
• J. Records and Reports
• K. Returned and Salvaged Drug Products
• The cGMP regulations are written to address the primary potential sources of product
variability.
• Subpart B establishes the quality control unit and the duties of that unit, establishes personnel
requirements and addresses personnel practices (e.g. sanitation) intended to reduce the
likelihood of product contamination.
• Sub- parts C and D establish requirements for buildings and facilities and equipment used
in the manufacture, processing, packing, or holding of a drug product.
• Subparts E through H establish controls over the major processes associated with the
production of a finished and packaged drug product that is ready to be shipped for
distribution to users.
• Subpart I requires the appropriate specifications, standards, sampling plans, and test
procedures; requires instrument specifications and calibration
• Subpart J establishes documentation requirements including master and batch
records
• Subpart K addresses the control and disposition of returned drug products and places
limitations on the salvage of drug products that have been subjected to improper
storage conditions (e.g., smoke, heat, fire, moisture).
Duties of Quality Control Unit under cGMP Regulations
• The cGMP regulations assign specific duties to the quality control unit. The unit is required to
have the responsibility and authority to approve or reject all components, drug product
containers, closures, in-process materials, packaging material, labeling, and drug products
• The organization must assure that the quality control unit has adequate laboratory facilities for
the testing and approval (or rejection) of components, drug product containers, closures,
packaging materials, in-process materials, and drug products.
• In addition to duties associated with the approval of materials and finished products, the unit
is also responsible for approving or rejecting all procedures or specifications for identity,
strength, quality, and purity of the drug product.
Quality Assurance Function
• The term quality is used in many industries and in everyday life and can have various meanings
depending on context.
• Quality mean the product requirements or attributes that have requirements.
• Quality assurance activities are those processes and activities conducted to assure that a
product or service consistently satisfies its requirements and is fit for its intended use.
• In the pharmaceutical manufacturing environment, this means the activities conducted to
assure that the pharmaceutical product’s identity,strength, purity, potency, and other quality
attributes conform
• A management commitment to quality that is communicated throughout the organization
• Identifying quality requirements using risk management and other methods as appropriate
• Developing a quality policy, plan, objectives
• Establishing an organizational structure with identified responsibilities and authorities that allows
quality objectives to be met
• Providing the resources needed to meet quality objectives
• Developing the required systems and processes
• Establishing methods for the ongoing objective evaluation of the performance of systems and
processes including quality auditing
• Initiating corrective and preventive actions as needed to assure that quality objectives are consistently
and reliably met
• The use of risk management techniques in identifying product requirements,
establishing processes and process control and monitoring methods, evaluating
quality data, identifying appropriate corrective and preventive actions to address
quality problems, and for other quality-related activities can increase the overall
efficiency and effectiveness of the quality system
• In a modern quality system, the organizational unit responsible for quality related
activities within the organization generally has a central role in the development and
management of the overall quality system.
• These activities can include quality control, quality assurance, quality planning, and
quality improvement.
• The cGMP regulations do not define or employ these terms, But the activities the
regulations assign to the quality control unit
• Current quality system models involve quality-related activities and terms that are
not included in the cGMP regulations.
• important for organizations adopting a quality systems approach to
unambiguously define the terms and quality concepts they will be using
• include these definitions as appropriate in training all staff in the organization who will be
involved in quality-related activities.
• This will help assure effective communication throughout the organization and
with vendors and others
FDA guidance on the quality systems approach the following definitions:
• QualityAssurance (QA) Proactive and retrospective activities that provide confidence that requirements are fulfilled.
• Quality Control (QC) The steps taken during the generation of a product or service to ensure that it meets requirements and
that the product or service is reproducible.
• Quality Management (QM) Accountability for the successful implementation of the quality system.
• Quality System (QS) Formalized business practices that define management responsibilities for organizational
structure, processes, procedures, and resources needed to fulfill product/service requirements, customer
satisfaction, and continual improvement.
• Quality Unit (QU) A group organized within an organization to promote quality in general practice.
Other cGMP-assigned responsibilities of the QU that are consistent with modern
quality system approaches include the following:
• Ensuring that controls are implemented and completed satisfactorily during
manufacturing operations
• Ensuring that developed procedures and specifications are appropriate and
followed, including those used by a firm under contract to the manufacturer
• Approving or rejecting incoming materials, in-process materials, and drug products
• Reviewing production records and investigating any unexplained discrepancies
FDA has designed and implemented quality system
can do the following
• Reduce the number of (or prevent) recalls, returned or salvaged products, and defective products entering the
marketplace
• Harmonize the cGMP regulations to the extent possible with other widely used quality management
systems, which is desirable because of the globalization of pharmaceutical manufacturing,
• When the use of effective risk management practices, handle many types of changes to facilities,
equipment, and processes without the need for prior approval regulatory submissions
• Potentially result in shorter and fewer FDA inspections by lowering the risk of manufacturing problems
• Provide the necessary framework for implementing quality by design , continual improvement, and risk
management in the drug manufacturing process
Quality Systems Approach
The major elements of the quality system model described in the FDA’s pharmaceutical
QS guidance document,These elements are as follows:
• Management responsibilities
• Resources
• Manufacturing operations
• Evaluation activities
Management responsibilities
Current quality system models assign management a major role in operation of a successful quality system
• Provide leadership ,communicated throughout the organization
• Create an organizational structure with clearly defined responsibilities and authorities to perform quality
functions associated with achieving quality objectives
• Building and documenting a quality system to meet specified quality and regulatory requirements and
achieve quality objectives
• Establishing a quality policy and objectives, and quality plans and communicate this throughout the
organization
• Assure that appropriate corrective and preventive actions are taken in response to quality problems using
effective change control procedures and documented
• Under a comprehensive quality system the QU can expect an expanded and more visible role
within the organization with greater accountability to and interaction with upper
management.
• the QU should be structured to reflect management’s strong commitment to quality and
to facilitate achieving quality objectives.
• The structure (e.g., organizational relationship to other organizational units, reporting
relationships) should provide clear lines of responsibility and authority that support the
production, quality, and management activities necessary to achieve quality objectives.
• The cGMP regulations require quality-related activities to be conducted during all
phases of manufacturing from the acceptance of raw materials through batch release,
packaging, and labeling.
• the role of quality personnel can be significantly expanded to include internal
quality auditing, expanded review and analysis of quality data, investigation of
nonconformance, root cause analysis, risk analysis, and other quality-related
activities.
• Quality staff should have sufficient scientific and technical knowledge and training
(e.g., statistical methods, risk analysis)
Resources
• Inadequate staffing, training, manufacturing equipment and facilities,

environmental controls, analytical equipment, and other resources can be
sources of variability leading to the production of product that does not meet
specified requirements
• Modern quality system standards specifically address the issue of resources by
requiring the organization to determine and provide the human, infrastructure,
and work environment resources necessary for the quality system.
• The cGMP regulations address the resource issue in the adequacy of
personnel (including consultants), manufacturing facilities including
contract facilities, equipment, and laboratory facilities. The QU has
significant responsibility in this regard.
• The FDA, in its pharmaceutical QS guidance document, discusses the need
for adequate resources in developing, implementing, and managing a
quality system that complies with the cGMP regulations.
• Management is responsible for identifying resource requirements and providing
resources accordingly, including providing training that is appropriate to the
assigned activities
• Personnel should understand the impact of their activities on their assigned duties and
be familiar with cGMP requirements and the organization’s quality system.
• Management should establish a working environment that encourages problem
solving and communication in identifying and acting upon quality-related issues.
• the QU and other organizational units should be involved in the
identification of the resources required to achieve quality objectives,
including regulatory compliance, evaluating the effect of personnel, facility,
product, process, regulatory
• The FDA notes that the cGMP regulations place as much emphasis on
processing equipment as testing equipment and contain specific
requirements for the qualification, calibration, cleaning, and maintenance of
production equipments
• the specification of facility and equipment requirements may be performed
by technical experts (e.g., engineers)
• The cGMP regulations require the QU to be responsible for reviewing and
approving all initial design criteria and procedures pertaining to facilities
and equipment and any subsequent changes
• A requirement of both the cGMP and current quality system models is that
such review and approval be conducted by persons who are qualified by
education, training and experience to do so.
• the control of outsourced operations, the cGMP regulations require that the
QU approve or reject products or services provided under a contract.
• Under current quality system models, the organization must follow a formal
vendor qualification process to qualify outsource providers and verify
through inspection or other To comply with the regulation, these operations
should be conducted by the QU
MANUFACTURING OPERATIONS :
This requirements contained in current quality system models

such as ISO 9001-2000 and the GMP regulation requirements for
manufacturing.
The FDA has identified four major elements of QS approach to

manufacturing operations.
CFR cGMP REGULATIONS RELATED TO
MANUFATURING OPERATIONS
Design, Develop and document product and process
In a modern quality system manufacturing environment, the significant characteristics of the
product being manufactured should be defined and verified as meeting requirements from design
to delivery, and control should be exercised over all changes.
This is consist of the cGMP regulations.

That require quality and manufacturing process and procedures, and changes to
them to be defined approved and controlled.

Document is required and can include the following
Resource and facilities used
Procedures to carry out the process
Identifications of the process owner who will maintain and
update the process as needed
Identification and control of important variables

Quality control measures, necessary data collection, monitoring,
and appropriate controls for the product and process
Any validation activities, including operations acceptance
criteria ranges and
Effect on related process, functions, or personnel

 labling controls.
 So packaging and labelling requirements, process and controls should
be included in a QS based approach to product and process design
and development.
 The FDA acknowledges that the reluctance to pursue potentially
innovative changes in pharmaceutical manufacturing can be
undesirable from a public health perspective and has published a
process analytical (PAT)guidance document.
This guidance is intended to address this by promoting the use of
analytical tools to gain process understanding and meet regulatory
requirements for validating and controlling manufacturing process.
The FDA has published the guidance document and other

pertinent PAT information on its website at www.fda.gov.
companies interested in PAT methods should contact the FDA.
FDA internal implementation of PAT include the following:
A PAT team approach of CMC review and cGMP inspections
Joint training and certification of FDA PAT review, inspection,
and compliance staff
Scientific and technical support for the PAT review, inspection,
and compliance staff

EVALUATION ACTIVITIES :
The evaluation component of a QMS is intended to provide
objective information and data that allow the organization to assess
the conformity of the product, evaluate the performance of its quality
system, and maintain and improve its effectiveness.

CFR cGMP REGULATIONS RELATED TO
EVALUATION ACTIVITIES
TREND ANALYSIS
 Trend analysis is one statistical tool specifically recommended by the FDA in
its pharmaceutical QS guidance document.
That can be very valuable monitoring process and quality system performance to
identify emerging problems and to assess the effectiveness of improvement efforts.
Traditional statistical process control and other methods also provide valuable
support in the objective and ongoing analysis of quality data and can be helpful in
implementing real-time quality assurance practices as recommended by the FDA.

CONDUCT INTERNAL AUDITS
Internal audit is not specifically required by the cGMP regulations,
but manufacturers have traditionally used internal audits as a self-
assessment tool and to prepare for FDA inspections.
International standards provide guidance on auditing.

Audits procedures should be developed and documented to ensure that the
planned audit scheduled takes into account the relative risks of the quality system
activities.
Factors that can incorporated into a risk-based approach to
planning audit frequency and scope include the following :
Exiting legal requirements (e.g., cGMPs)
Overall compliance status and history of the company or facility
Robustness of a company’s quality risk management activities
Complexity of the site
Complexity of the manufacturing process
Complexity of the product and its therapeutic significance
Number and significations of quality defects (e.g., recall)
Result of previous audits/inspections that can include prior internal audit
results as well as regulatory (e.g., state, federal, or other regulatory agencies)
and third-party audits.
Major changes of building, equipment, process and key personnel
Experience with manufacturing of a product (e.g., frequency, volume,
number of batches )
Test results of official control laboratories
Different audit approaches may be applied depending on the
intended purpose and scope of the audit.
A top-down approaches first evaluates the overall structure of the

quality system and its subsystem.
Subsystem may be chosen for review.
Systems identified and developed by the FDA in a SIX-
SYSTEM inspection model for the inspection of drug
manufacturers.
 Overall quality system
 Facilities and equipment
 Materials system
 Production system
 Packaging system
 Laboratory controls
Quality Risk Management
A formal risk management process consists of several components:
Risk assessment
• Risk identification
• Risk analysis
• Risk evaluation
Risk control
• Risk reduction
• Risk acceptance
Risk communication
Risk review
CORRECTIVE AND PREVENTIVE ACTION
A corrective and preventive action may be initiated based on
reviewed and analysis of quality data from a verity of sources
including adverse experiences, product complaints, quality audits,
FDA inspection, third-party inspections, nonconforming materials
reports, process control information, trend analyses, and other
sources.
A firm's CAPA system and process should be designed to analyse
and respond to quality issues in a systematic way that is
commensurate with the risk.
The system should provide for the verification or validation of
corrective and preventive actions to assure their effectiveness and
to assure that actions do not adversely affect the finished product.
The system should also assure that pertinent CAPA information is
appropriately disseminated throughout the organization as
necessary to assure the effective operation of the quality system
and for management review.
Promote Improvement
Continual improvement is a requirement of existing quality system models such as
ISO 9001 - 2000 in which the organization is required to continually improve the
effectiveness of the quality management system through the use of the quality policy,
quality objectives, audit results, analysis of data, corrective and preventive actions, and
management review. In adapting the ISO 9001 - 2000 standard to serve as a regulatory
standard for medical device quality management systems, drafters of the ISO 13485 standard
altered the requirement slightly to require the organization to “ identify and implement any
changes necessary to ensure and maintain the continued suitability and effectiveness of the
quality management system through the use of the quality policy, quality objectives, audit
results, analysis of data, corrective and preventive actions, and management review. ”
TRANSITIONIG TO QUALITY SYSTEM
APROCH
The GMP regulations assign significant responsibilities to the
organizational unit responsible for quality-related activities.
Organizations implementing a quality system model will be
responsible for additional quality-related activities including but
not necessarily limited to, conducting quality audits, analysis of
quality data, risk assessment, and preventive actions based on
review and analysis of quality data to prevent the occurrence of
product nonconformities.
Some points to consider in planning the
transition :-
Create a transition team: A cross functional team should be
developed involving key managers and staff from throughout the
organization to plan and execute the transition.
The transition team should have a clear understanding of its
mission and the organizational objectives associated with the
transition.
 Train the transition team: management should assure that all individuals on
the transition team receive proper training on quality systems requirements,
risk management, and FDA ‘s recommended approach to quality system.
 Develop a transition plan: a transition plan, based on clearly defined
objectives, should be developed by the transition team.
Identify staffing requirements: The transition will likely affect individual job
descriptions and create additional duties that will have to be addressed
through the reassignment of staff, and providing necessary training to all
affected staff.
Define roles and responsibilities: The plan should clearly define the roles
and responsibilities of those responsible for development and execution of
the plan for quality system implementation as well as staff roles and
responsibilities under the quality system.
consider organizational structure requirements: In order to function
properly, person responsible for quality-related activities must have the
responsibilities and associate authority defined and appropriately
communicated within the organization.
 Consider benchmarking: If possible, arrange with other organizations
that have successfully made the transition to meet with them, review their
system , and discuss transition issues and how they were solved.
Communicate regularly: clear and ongoing communication within the
transition team and with management is essential to effectively coordinate
plan activities, report progress, resolve issues, and identify evolving resource
needs
 validate the system
 Maintain regulatory compliance.
AUDIT CHECKLIST FOR DRUG INDUSTRY
• The checklist provided in Table is intended to aid in the systematic
GMP audit of a facility that manufactures drug components or finished
products.
• The adequacy of any procedures is subject to the interpretation of the
auditor.
• Therefore, the author accepts no liability for any subsequent regulatory
observations or actions stemming from the use of this audit checklist.
Instructions for Using Audit Checklist
• Before starting an on - site audit, plan the audit. Review past audits,
note indications of possible problem areas and items, if any, that were
identified for corrective action in a previous audit.
• If you are not already familiar with this facility, learn the type of
product produced and how it is organized by personnel and function.
• What does your “ customer, ” that is, your superior or senior facility
management, expect to learn from this audit?
1. The checklist is to be used with a notebook into which detailed entries can
be made during the audit.
2. While the checklist is to guide the auditor, it is not intended to be a
substitute for knowledge of the GMP regulations.
3. Although a single question may be included about any requirement, the
answer will usually be a multipart one since the auditor should determine the
audit trail for several products that may use many different components.
Enter details in you notebook and cross reference your comments with the
questions.
4. At least three production batches should be selected for thorough analysis
to include: (a) traceability of all components or materials used in the subject
batches, (b) documentation of raw material or component, in - process, and
finished goods testing for the subject product batches, and (c) warehousing
and distribution records as they would relate to a possible recall.
5. Responses entered on the checklist should be consistent. “ X ” is
recommended for “ No ” ; a checkmark for “ Yes ” ; “ N/A ” for not applicable to
questions that do not apply. An asterisk and notebook page number should be
entered on the checklist to identify where relevant comments or questions are
recorded in your notebook.
6. The notebook used should be a laboratory - type notebook with bound pages.
The notebook should be clearly labeled as to the audit type, date, and auditor(s).
Many auditors prefer to use a notebook for a single audit so it may be fi led with
the checklist and the final report.
REFERENCE :-
• Active Pharmaceutical Ingredients Committee (APIC). Auditing guide; 2016.
Available from:
http://apic.cefic.org/pub/Auditing/APIC_CEFIC_AuditingGuideAugust2016.
pdf. [Last accessed 19 Mar 2018] Place Unknown: Word Press; 2008.
Available from: https://drpotdar.wordpress.com/2008/04/30/audit/.
• BSI standards publication: European committee for standardization.
Guidelines for auditing management systems; 2011. Available from:
http://qic-eg.com/wp-content/uploads/2015/08/BS-EN-ISO-19011-2011.pdf.
• Roger CPA Review Blog.The 10 steps in planning an audit; 2009. Available
from: https://www.rogercpareview.com/ blog/10-steps-planning-audit.
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)
SUPPLIER QUALIFICATION &

MANAGEMENT GUIDELINE
December 2009
Content
1. Introduction
2. Chapter 1: Supplier Selection
3. Chapter 2: Due Diligence
4. Chapter 3: Quality Assessment
5. Chapter 4: Change Control + Production Assessment
6. Chapter 5: Supply Chain Security
7. Chapter 6: Ongoing Monitoring and Evaluation
8. Appendices
Appendix 1: Examples of Critical/ non Critical Raw Materials
Appendix 2: Supplier Selection Check List
Appendix 3: Due Diligence Check List
Appendix 4: Supplier Questionnaires
Appendix 5: Check list for Change Control Assessment
2
INTRODUCTION
Manufacture of Medicinal Products and the Active Pharmaceutical Ingredients (APIs)

used as starting materials in the production of these products is subject to strict good
manufacturing practice regulations that are designed to ensure their quality, safety and
efficacy. This ensures that patients worldwide and at any time can have confidence in the
quality, safety and efficacy of medicines.
The cGMP regulations for final medicinal products are clearly defined in each country
and region. The content of the regulations may vary but the objectives are the same:
- To deliver high quality, safe medicines manufactured and distributed following

controlled procedures to treat diseases and
- To prevent deaths, serious illnesses, adverse events or product recalls resulting from
deficiencies in the manufacturing and distribution processes.
While in the vast majority of cases, the pharmaceutical industry, under the oversight of
the Regulatory Authorities and inspectorates consistently applies appropriate cGMP
practices, there are many cases known where the standards expected from manufacturing
companies have not been maintained. Some of these cases had very serious consequences
e.g.:-
The heparin case in 2008, causing around 150 fatalities in the U.S. due to
deliberate contamination of the API with a bogus substance (oversulphated
chondroitin sulphate)
The many scandals involving the contamination of glycerine with diethylene
glycol that led amongst others to 107 deaths in the USA (1937), around 300
deaths in Bangladesh (1990), 88 deaths (young children) in Haiti (1996), and 138
deaths in Panama (2006), due to lack of controls in the distribution networks of
glycerine and in the medicinal product manufacturing sites involved
The gentamicin sulphate case in which unknown contaminants caused in total
around 65 deaths in the USA in 1994 and 1999 respectively
Other cases of counterfeit medicines, falsified APIs and medicinal product recalls
due to adulteration of medicines or APIs released to the market underline the
potential magnitude of the risk to patients if the supply chain for medicines is not
properly qualified.
In some cases business pressures to reduce costs results in sourcing APIs and the raw
materials used in their manufacturing process at the lowest cost. While this practice, in
and of itself, does not create non-compliance, it does create an opportunity for
unscrupulous suppliers to insert themselves into the supply chain and introduce
substandard materials. This situation also highlights the need for clarity regarding
expectations and requirements for supplier quality and assurance of the full supply chain.
3
The scope of this guidance document is to share the best practices of APIC member
companies on systems to be implemented to adequately manage suppliers through the
complete life cycle of the product, including
Supplier Selection Process based on definition of the User’s Requirements for a
material with as a minimum a specification
o Sample evaluation including where necessary laboratory and /or
production trials
Due Diligence process of potential suppliers of critical raw materials, registered

intermediates and APIs
Quality Assessment of all suppliers
Change control and production assessment as necessary
Supply chain security
Ongoing monitoring and evaluation
The target audience for the guidance document is primarily API Manufacturers while it
may also be used by medicinal product manufacturers who are primarily responsible to
qualify their suppliers / manufacturers of APIs used as Starting Materials in the
manufacture of medicinal products.
We have classified the materials into the following four categories based on quality
criticality to the API manufacturing process and on risk related to potential for harm to
the patients:-
Non-critical raw materials
Critical raw materials (including API Starting Materials)
Registered intermediates
APIs
4
The quantity of materials in each category is likely to decrease as the criticality increases
as indicated in the following triangle:
Non critical Raw Materials
Critical Raw Materials
Increasing Levels of GMP

Registered Intermediates
Intermediates
APIs
In terms of defining the categories of materials we recommend that companies review the
use of the material based on the ICH Q7 definition of Critical:-
“Critical describes a process step, process condition, test requirement, or other relevant
parameter or item that must be controlled within predetermined criteria to ensure that
the API meets its specification”.
For an API manufacturing process involving multiple-step synthesis, raw materials used
in the early steps are likely to be less critical than those used in the final API step given
that accurate specifications will be defined for all raw materials.
To assess the risk to patients related to the material we recommend that companies follow
ICH Q9 for their Quality Risk Management process and use the ICH Q9 definition of
Risk:-
“Risk is the combination of the probability of occurrence of harm and the severity of the
harm to the patient or consumer”.
For example the risk of particulate or microbiological contamination from a reagent,

solvent, water system, utility or primary packaging material that are in direct contact with
an API will or greater than materials used earlier in the process.
We recommend that suppliers of all the materials should be approved using the
Company’s Change Control Procedures and / or Supplier Approval Procedures. Change
5
control requirements would also be more stringent for critical raw materials (including
API Starting Materials), registered Intermediates and API and should include a
Regulatory Assessment.
Definitions:
Raw materials can be sub-categorised into three different classes:
a. Those that are widely commercially available and are used in multiple industries, for
example acids, bases, solvents, filter aids, petroleum based raw materials, naturally
occurring raw materials, packaging materials, water systems or utilities in contact with
the API such as nitrogen or compressed air.
b. Those that are commercially available for use in the API Industry such as catalysts,
enzymes, chemical (including chiral) building blocks.
c. API Starting Materials. These may be generally available or involve custom synthesis
or specific process development by the supplier before becoming available on an
industrial scale.
Registered intermediates usually involve custom synthesis or process development

by the supplier.
APIs will be manufactured under custom synthesis or contract manufacture or will be

generally available if used in the manufacture of off-patent medicinal products.
Further examples of types of materials covered by the scope of this guidance

document and guidance on criticality are given in Appendix 1.
Guidance:
The quality system requirements to identify, select, approve and qualify suppliers of all
materials used in the manufacture of APIs and medicinal products are clearly defined in
the GMP Guidelines.
Manufacturers of medicinal products, APIs and registered intermediates for APIs are
responsible for approving and qualifying their suppliers and to monitor on an ongoing
basis the performance of their critical suppliers.
The Regulatory Agencies will and do inspect the supplier qualification procedures used
by medicinal product manufacturers and expect that they periodically audit their API
supplier / manufacturer. As part of this audit, the medicinal product manufacturer should
ensure that the API supplier / manufacturer also has supplier qualification procedures in
place for their suppliers of critical and non-critical raw materials, API Starting Materials,
Registered Intermediates and APIs (in the case of contract manufacturers). In relation to
critical raw materials the Authorities will also expect a monitoring programme to be in
6
place and for the manufacture to have clear oversight of the changes with possible quality
impact made by their suppliers.
Inspectors will also expect that the distribution and supply chains have also been
evaluated and that controls are in place to ensure there is adequate Supply Chain
Security, to avoid possible fraudulent practices and to ensure that appropriate
transportation conditions (i.e. temperature and humidity) are applied during distribution
where this is required based on the properties of the materials.
The pre-requisites for approval of suppliers of all materials including non critical raw
materials are that the material meets the specification defined by the customer confirmed
by 1) sample evaluation (QC testing) and that 2) there is an evaluation of the quality
system in place designed to assure and control the manufacture, testing, release and
distribution of the material.
The expected Product Quality Standard and the depth of the quality assessment will vary
depending on the type of material but these two pre-requisites should always be there and
would be considered as the basic requirement for approval of a non-critical raw material
supplier.
For critical raw materials, intermediates and API’s, it is recommended there should be a
due diligence assessment, a more detailed assessment of the quality system and material
evaluation should involve laboratory or plant trials prior to full production assessment.
A purchasing contract that defines quality requirements should be in place for suppliers
of all materials and a Quality Agreement should be in place for suppliers of registered
intermediates and APIs.
Any changes to the material specification, analytical methods and/or manufacturing

process that may affect the quality of the material supplied and/or the down stream
products should be informed in advance (and prior to implementation) to evaluate the
impact on down stream production/product.
Our guidance covers supplier management over the entire product lifecycle as described
in the Vendor Management Flow Chart below:
7
Vendor Management Across The Life Cycle
Identification of
Potential Suppliers
based on Specs
Data Collection
Short List Supplier Selection from the suppliers
Process
Sample Evaluation
Go/No Go on
(if sample is
Short List
available)
Technical Due Diligence Cross Functional

Review Process Visit
Recommendations
Sample Evaluation
Go/No GO
Quality Assessment
Remediation and Assessment of the

Remediation
Quality/Contract
Agreement
Development
Signed Quality/
Approval under Contract
change control Agreements
Yes/No
Change Control
Evaluation
API & Reg

Intermediates and
Critical Raw
Production & Materials based on
Validation Risk Assessment
Key to Colour
Assessment
Codes
All materials
Supplier
Approval/
Qualification
Yes/No
Supply Chain
Security
Ongoing
Monitoring &
Evaluation
8
The main steps of Supplier Management are described in each chapter including the
elements relevant for non critical or critical raw materials, registered intermediates or
API’s.
We are also referring to existing APIC guidance documents whenever applicable to

further clarify expectations and provide consistency to the processes. e.g.:
- Quality Agreements
- Auditing Guide,
- APIC Audit Programme
- APIC Quick Guide for API Sourcing
- APIC ICHQ7 How to do Document
- APIC Quality Management System Guide for API manufacturers
Those documents are available on the APIC website: WWW. APIC.CEFIC.ORG
In the appendices we also provide specific assessment documents as examples to help

with supplier evaluation based on best practice sharing by the Task Force members listed
below:
- Bryson Lynn (JOHNSON MATTHEY MACFARLAN SMITH)

- Buggy Tom (DSM ANTI-INFECTIVES)
- Stilgenbauer-Voigt Ingrid (BASF)
- Chekatt Habiba (DSM NUTRITIONAL PRODUCTS)
- Hamrin Pia (DSM NUTRITIONAL PRODUCTS)
- Vandeweyer François (JANSSEN PHARMACEUTICA)
- Stampfli Claudia (LONZA)
- Cox Robert (LONZA)
- Counihan Eileen, Chair (MERCK SHARP & DOHME)
- Vandenbossche Claude (AJINOMOTO OMNICHEM)
- Storey Anthony (PFIZER)
We have had a lot of fun and enjoyed working together and sharing best practice in the
creation of this document. We hope you will find it useful in the serious business of
supplier management and the assurance of safe APIs and medicines for the health, safety
and quality of life of our patients worldwide.
If you have any comments or suggestions for improvement please contact the APIC
Secretary at:
CEFIC
Active Pharmaceutical Ingredients Committee (APIC)
Av. E. Van Nieuwenhuyse 4 / box 2
B - 1160 Brussels
Tel : +32 2 676 72 02 or +32 2 676 72 44 - Fax : + 32 2 676 73 59
E-mail : pvd@cefic.be or abo@cefic.be
For further details on APIC and for other APIC Guidances see: www.apic.cefic.org
9
CHAPTER 1. SUPPLIER SELECTION
The purpose of this step is to define a set of criteria that can be taken into consideration in
the selection process of a supplier. If a supply need is identified purchasing is contacted
for the identification of (a) potential supplier(s). The supplier selection process starts with
the definition of the user requirements for the materials(s) within scope.
The user requirement specifications provided to purchasing should contain as a minimum
the following information:
• Name of the product (including formulae and CAS number when available)
• Material specifications
• Quantity required
The materials within scope of this guidance have been classified as follows:
• Non-critical raw materials,
• Critical raw materials (including API starting materials);
• Registered intermediates;
• APIs
For the raw material group a sub-categorisation into three different classes is proposed.
• Those that are widely commercially available and are used in multiple industries, for
example acids, bases, solvents, filter aids, petroleum based raw materials, naturally
occurring raw materials, packaging materials, water systems or utilities in contact with
the API such as nitrogen or compressed air.
• Those that are commercially available but are for use in the API Industry such as
catalysts, enzymes, chemical (including chiral) building blocks.
• API Starting Materials. These may be generally available or involve custom synthesis
or specific process development by the supplier before becoming available on an
industrial scale.
The quality system evaluation may be less or more elaborate in function of the identified
material classes and follows a documented process. The following information from the
supplier should be requested as part of the Suppliers Questionnaire (As per Appendix 4) :
- Specifications
- Manufacturing/packaging/labelling details
- Materials Safety Data Sheets
- Logistic information (lead time to produce, delivery time, etc)
- Certificates regarding Quality system, residual solvents, etc...
- BSE/TSE evaluation
-Analytical test method
It is a pre-requisite to demonstrate that the material provided by the potential supplier

meets the specification as defined, and compliance to the specifications should be
verified by analytical testing of a sample. The sample (representative of commercial
production) can be pre-shipment sample(s) (with appropriate controls) or the release
sample of the first delivery.
10
For critical raw materials, intermediates and APIs it is likely that the data to be requested
and collected from the potential suppliers will be more elaborate comprehensive than for
raw materials.
For critical raw materials, registered intermediates and APIs key selection criteria have
been identified and categorised.
Following different dimensions could be assessed:

- Assurance of Supply,
- Quality & Regulatory compliance;
- Cost/Procurement aspects;
- Technical/Innovation;
- Communication capabilities & responsiveness
The Supplier Selection Checklist (Appendix 2) contains a non-exhaustive list of areas to

address which must be requested from the supplier. The Supplier selection checklist
should be seen as an example and should be adopted in function of the company’s need.
Some of the identified criteria can also be considered in the selection process for non-
critical raw materials. A suggestion of topics to be checked for non critical raw materials
is provided in Appendix 2.
Each different criteria is discussed in more detail below:
1. Assurance of Supply
Assurance of supply is an essential element in order to guarantee appropriate supply

chain management in the organisation. To obtain a picture as complete as possible
following aspects should be taken into consideration:
 Capacity (Scale equipment, batch size, chemistry experience, etc.…)
 Safety/Health/Environmental Risk
 Inventory management
 Financial solvency/business stability
 REACH requirements
 Delivery performance
 Supply chain management of the material in question
2. Quality & Regulatory Compliance
In the selection process it is essential to take the quality and regulatory track record
history into account. To obtain a comprehensive picture of the supplier's compliance
status, the following aspects should be taken into consideration:
 cGMP Compliance & regulatory track record
 Recalls & Complaints
 Change/Deviation Management
 Materials management controls
11
 Quality Management Systems
 Quality Agreement
 Quality Culture
 Production Facilities & Equipment
 Product Quality Review
 Process Validation approach:
 QOTIF % (On time in Full)
 Documentation standard
3. Procurement/Cost
Next to the price of the material within scope there are other aspects related to cost and
procurement that should be taken into consideration:
 Cost Management (Cost visibility)
 Presence in Low Cost Countries (Emerging markets)
 Ability to achieve the target price
4. Innovation/Technical
In order to generate a better understanding of the technical competences and innovative

profile of the supplier, following aspects should be taken into consideration:
o Technology specialism
o Plant capabilities
o Laboratory capabilities
o Business problems resolving capabilities
o Technical skills/ Staff Qualifications
o Control systems
o Development capability
o Process development expertise
o Project management
o Willingness to innovate
o Intellectual property
5. Responsiveness & Communication
In order to generate a better view on the responsiveness and communication capabilities,

following aspects should be taken into consideration:
o Rapidity project assessment

o Resource availability
o Flexibility (Attitude)
o Functional contacts definition
o Openness
o Ease of communication (understanding of English)
o Pro-activeness
12
For critical raw materials, registered intermediates and APIs all data collated from the
potential suppliers is assessed thoroughly ideally by a multidisciplinary team. This
assessment should result in a shortlist of potential suppliers. In case material samples
were received the analytical test results generated are used to support the GO/NO GO
decision to pursue the supplier qualification process of the identified supplier. The next
step is to initiate the due diligence procedure. This will allow the company to compile
documented evidence of the supplier's suitability. Further guidance on the due diligence
procedure is provided in Chapter 2.
For non critical raw materials meeting the defined user requirements a quality assessment
is started to determine the suitability of the supplier. A positive outcome of the quality
assessment is required to continue progressing with the supplier. Further guidance on
how to conduct the Quality Assessment is provided in Chapter 3.
13
CHAPTER 2. DUE DILIGENCE
Purpose:
This chapter is not applicable for non-critical raw materials.

For Critical Raw Materials including API Starting Materials the necessity to
perform a due diligence can be based on a risk assessment according to ICH Q9.
This chapter will define and provide detail to assure that the appropriate due
diligence is conducted prior to contracting with the supplier. Documented
evidence will be assembled to support the Go/No Go decision process.
The possibility of establishing a long term business relationship with the supplier
will be evaluated.
The implemented systems and existing facility will be assessed and challenged in
order to evaluate the capability of the supplier to comply with the customer’s
requirements.
The potential to supply where process is not yet established and samples /
production batches are not available/ produced will also be assessed based on
capabilities for example:
o process equipment ,
o facility containment,
o quality of utilities,
o analytical equipment availability including stability chambers
o potential for process and analytical method development and validation
o ability / demonstrated performance of preparing regulatory submissions
1. Selection of cross functional team:
Depending on a criticality evaluation a cross functional team will be formed.

Representatives of the Project Management, Procurement and the Quality Unit will
always be part of the due diligence team. Resulting from the criticality evaluation the
team can be extended with representatives from other areas such as:
- Engineering,
- Regulatory,
- Environmental/ Health / Safety,
- Technical Experts e.g. Chemical/Biological Process Engineer(s) and QBD
experts,
-Procurement,
Each member of the due diligence team documents the collected information and
formulates a decision and/or action proposal related to his/her expertise field. The
combined information is presented to the Senior Management in the form of a
recommendation.
14
2. Areas to be challenged:
2.1. General Material Information:
The general material information to be challenged can be based on sample evaluation

results where available, possible impurity profile issues, quality system pre-assessment
and/or supply chain assurance. Examples to verify are:
Sufficient capacity to assure supply chain,
Anti Counterfeiting measurements,
Audit sustainability (qualification of the total supply chain),
The most important items to challenge related to the general material information are
listed in Appendix 3 Due Diligence Check List.
2.2. Quality Systems:
ICH Q7 must be used as basis to evaluate the implemented quality systems for Registered
Intermediates and API’s.
If for Critical Raw Materials including API Starting Materials, the outcome of a risk
assessment according to ICH Q9 indicates the necessity to perform a due diligence, the
focus of the evaluation of the quality systems implemented can be reduced according to
the requirements indicated by the risk assessment.
If ICH Q7 is not applicable the General Quality System in place (example ISO 9001)
should be challenged.
Additional to compliance to ICH Q7 other topics can be challenged. Examples are:
Use of Quality By Design,
Implementation of systems to assure Continuous Quality Improvement,
Implementation and use of Risk Management
2. 3. Plant Tour / Organization
A plant tour contributes to the evaluation of the ability and willingness of the
management to support facility and equipment maintenance and
contamination prevention.
Examples of items to be challenged during the plant tour are:
Contamination prevention,
Utilities: Water system, HVAC, Nitrogen, Steam, Cool media,
Equipment calibration and maintenance (production and QC),
Laboratory controls and product release procedures
Warehouse controls
15
2.4. Documentation / Organization
The documentation review contributes to the evaluation of capability of the organization

to demonstrate traceability, compliance to the manufacturing process and compliance to
ICH Q7 and/or the General Quality System in place.
Examples of documentation that can be challenged during review are:
master records, batch production records, laboratory records
Training and personnel qualification,
Quality systems (product release, change control, deviation handling, failure
investigations, stability program, etc.).
2.5. Process
Evaluation of the process and equipment availability contributes to the evaluation of the
capability of the company to manufacture material of consistent quality and compliant to
ICH Q7 if applicable (examples: API and registered intermediates) or compliant to the
General Quality System in place.
2.5.1. Chemical Synthesis.
Examples of items that can be assessed are:

Critical process parameters and their associated critical quality attributes
identified,
Chemical development history/report,
2.5.2. Bio Chemical Synthesis.

Cultivation Process,
Purification Process,
Cell bank maintenance,
2.5.3. Manufacturing process (Chemical and Biological):

Process trending (Yield, Quality, etc.),
Rework / Reprocess
Validation protocols and reports,
2. 6. Physical Properties of the material
Evaluation of the consistency of the Physical Chemistry of the material contributes to the
evaluation of the manufacturability of the material in next process steps.
16
Examples of Physical properties can be assessed are:
Solubility profile,
Polymorphism, documentation on most stable polymorph,
Particle size
Degradates
2. 7. Analytics & Stability
Evaluation of the analytical and stability results contributes to the evaluation of the
consistency of the quality of the material, its quality profile and accuracy of implemented
storage conditions.
Stability indicating methods,
Analytical methods validated
Pharmacopeia methods are verified,
Specifications and technical justification,
Product Quality Reviews
2. 8. Regulatory:
Evaluation of the regulatory status and documentation contributes to the evaluation of the
compliance status of the material for all intended countries.
2.9. Economics:
Evaluation of the economic contribution to the decision process related to the location of
the manufacturing site, supply chain, and business continuity assurance:
2.10. Intellectual Property
Evaluation of the patent situation, as well for the production process as the manufacturing
technologies used contributes to the decision process.
2.11. Safety, Environment & Health
Evaluation of the safety, environment & health systems implemented contributes to the
evaluation of the ability and willingness of the management to assure compliance to local
authorities' requirements and people health protection as part of the decision process.
Examples of items that can be challenged are:
Industrial Hygiene aspects,
Child labour
Synthesis steps with extreme conditions (temperature, pressure, reagents),
Waste Management Licences and SHE Quality Systems such as ISO 14001
17
3. Conclusion/Outcome:
An overall report will be issued by the team. The combined information must be used to
formulate a final recommendation to Senior Management.
If critical issues (Quality, Safety, Health, Environment, Regulatory, Business continuity)

are identified and do not have a clearly defined actions for remediation, this information
must be escalated to Senior Management.
If Critical Quality and GMP issues are identified an accurate and approved mitigation
plan must be available before the Quality Audit will be executed.
Senior Management is responsible for the final Go/No-Go decision.
18
CHAPTER 3. QUALITY ASSESSMENT
A summary of the quality assessment procedure is outlined in table 1 for the three
categories of materials.
Table 1: Summary of Quality Assessment Procedure

Requirement Non Critical Raw Critical Raw Registered
material material Intermediate/
API
TSE/BSE Assessment √ √ √
Tanker Cleaning Assessment

√ √ √
Supplier/Manufactures
Questionnaire √ √ √
Manufacturer Audit
**√ √
Historical Performance*
**√ √ √
cGMP Compliance History **√
√
rd
3 party certification*
**√ **√ √
Contract Agreement
√ √ √
Quality Agreement
**√ √
*(if available)
√- Required
**√ - Dependant on risk assessment performed on material being purchased.
1. Format of the Quality Assessment
The format of the quality assessment is dependant on the criticality of the raw material
being purchased and the outcome of risk assessment being performed on the material.

For non-critical materials the quality assessment may be limited to a core section of the
supplier questionnaire as outlined in Appendix 4 and/or the provision of an ISO
9001:2008 or equivalent certificate and/or satisfactory past performance by the supplier.
The level of assessment is ultimately a decision based on a documented risk assessment.
19
Critical Raw Materials
The level of quality assessment is based on risk assessment which will take into account
the level of in house analysis the customer intends to perform.
In some circumstances, depending on the supply relationship, the customer can use the
suppliers evaluation procedures for the manufacturer, as long as this is documented as
part of their (the customers) supplier evaluation procedure.
If the customer intends to implement reduced testing of the material it is recommended

that the quality assessment takes the form of a manufacturer questionnaire or for
“critical” raw materials a manufacturer audit. This decision is again risk based. An
example of a full scope of a manufacturer questionnaire is outlined in Appendix 4.
Registered Intermediates and API’s

For registered intermediates and API’s a quality audit of the manufacturer is
recommended as a key part of the quality assessment.
2. General Considerations
The following must be addressed in the quality assessment of all raw materials/ registered
intermediates and API’s:
TSE/BSE Assessment
The supplier must be able to certify that all raw materials/ source materials and any other
materials (i.e. cleaning agents) used at any stage of the production process comply with
the “Note for guidance on minimising the risk of Transmitting Animal Spongiform
Encephalopathy Agents via Medicinal Products”- EMEA/410/01 (TSE Guideline).
Materials delivered in tankers

When dealing with material which is to be delivered in tankers the quality assessment
must address if the tanker is dedicated to one material and if not, cleaning verification
procedures must be considered as part of the assessment. This may be in the form of
cleaning certificates, testing for trace impurities or if necessary an audit of the tanker
cleaning procedure.
20
3. Timeline

The quality assessment for non-critical raw materials can be concurrent with the
production assessment as long as TSE and tanker cleaning certification are in place
before the material is accepted for use in production, following usual raw material
acceptance criteria i.e. testing to specification.
Critical raw materials

The quality assessments for critical raw materials should be initiated as early as possible
in the procurement process, refer to flow chart. It may not always be possible to have a
manufacturer questionnaire response or manufacturer audit performed prior to the
production assessment process. The requirement for theses being in place prior to
production assessment should be considered as part of the risk assessment for the raw
material. At a minimum TSE and tanker cleaning certification must be in place and full
testing to specification must be performed prior to the production assessment going
ahead, with the manufacturer questionnaire having been sent ( if previously deemed
necessary). In some cases the risk may be such that the production assessment does not
go ahead until the manufacturer questionnaire / audit have been performed and
satisfactory responses have been obtained.
The customer cannot implement reduced testing until the manufacturer evaluation has
been completed as per in house SOPs and the requirements of ICHQ7 section 7.3 have
been met.

It is to be remembered that the quality assessment must be completed, with satisfactory
outcomes before any production can be scheduled. Therefore planning is vital, ensuring
data can be gathered, assessments made and remediation performed, if necessary, without
risking the integrity of the assessment or project due to time constraints.
The time line should cover items such as:
The preparation and sending of a pre-audit questionnaire, allowing suitable time for
response.
The development of the agenda with the company and allowance of time to obtain
any up front information.
The actual scheduling of the audit and its performance, at a time convenient to not
only the project but also when the supplier has an available slot in their schedule.
Submission of the audit report/ receipt of response.
Remediation- if necessary.
Close out of the audit, once remediation is successful and if necessary re-audit/
assessment.
Agreeing and signing the quality agreement by both parties
21
It should also be noted that flexibility has to be built into the time line as all supplier
quality assessments will be different, dependant on the scope of the project and the level
of compliance of the supplier.
4. Roles and Responsibilities
The quality assessment is under the complete control of the Quality unit. The Quality
Unit can ask for assistance from other departments which may be able to provide
specialist knowledge however ownership cannot be delegated. The Quality unit is
responsible for carrying out the assessment and making the Go/No Go decision based on
the quality assessment independently.
When an audit is being performed, the lead auditor should be a certified/ experienced
auditor who is either internal to the company purchasing the material or from a 3rd party,
with relevant experience in the field being audited.
5. Manufacturer Questionnaire
Each manufacturer questionnaire should be tailored to the raw material being purchased.
The format of the questionnaire can mimic that of a pre-audit questionnaire, as outlined
in the APIC auditing guide or refer to an example questionnaire, Appendix 4. It should be
remembered that manufacturers of critical raw materials do not always work to cGMP
and as such an appropriate standard suitable for the manufacture of the material should be
applied where available.
6. Audit Standard
The audit should be tailored to the particular type of material being manufactured and it’s
mode of manufacture i.e. critical raw materials, API’s derived from plant sources, sterile
liquids, and biotechnological processes.

Critical raw materials are not always manufactured to cGMP. The manufacturer may be
registered to an alternative quality standard or no quality standard at all. Therefore the
audit must be performed taking into account the manufacturers quality system and the
customers requirements from the manufacturer i.e. does the manufacturer have full
traceability from raw material to final product, final product testing etc.
22
ICHQ7 will be the preferred standard for auditing however depending on the market
source consideration should be given to other standards. The audit must be performed
with consideration to the potential sales region of the finished goods and potential
expansion of sales in the future. Is the market for the finished goods world wide or local?
Is particular regulatory approval to be sought? Will the finished material be BP, USP etc?
Knowledge of where the finished goods are to be sold will define the audit standard i.e.
ICH Q7 guidelines and it will also aid in determining the predefined audit acceptance
criteria. The acceptance criteria must be defined prior to the audit taking place.
7. Performance of Audit
For guidance on how to perform a supplier audit refer to APIC Auditing Guide. When
auditing the following should also be considered:
Depending on the country being audited and the written and spoken language of the
supplier/ manufacturer, an interpreter may be a vital member of the audit team. The
interpreter will aid in an overview of documentation and communicating questions and
answers. The preferred option is that the interpreter is independent of the company being
audited and is employed by auditing company.
The performance of this audit would be for the proposed manufacture of the intended
drug / material but should also facilitate expansion of scope. Does the manufacturer being
audited have the potential to supply to a different regulatory standard, if it is required in
the future? Does this supplier have the potential to be a long term partner?
Depending on the complexity of the supply chain the scope of the audit may need to be
expanded and the decision should be risk based.
8. Audit Report
The audit report should be issued in a timely manner and a response, with timelines for
remediation, should be requested from the supplier. Personnel with the authority to action
the remediation must be identified in the report response by the manufacturer.
The report should state whether the pre-determined acceptance criteria have been met and
if not, what points require remediation. The levels of deficiencies should be assessed as
per the APIC auditing guide as the criticality of the deficiencies will define the next stage
in the process.

If critical or major deficiencies have been identified in the audit, then a risk assessment
must be performed on whether the deficiencies are such that the customer's product may
be at risk from the raw material supplied. At this stage the customer must maintain full
23
testing of the raw material. The manufacturer must agree that a need for remediation has
been identified and a commitment made to remediate with a time line. A re-audit may be
performed if the deficiencies warrant it.
If there is a deficiency that is deemed other then the assessment can proceed as long as
remediation has been identified and a commitment made to remediate.
If remediation is not required then the quality assessment can be completed.

If critical or major deficiencies have been identified in the audit, then the assessment
process cannot be completed until these have been satisfactorily addressed in the view of
the auditor.
If there is a deficiency that is deemed other then the assessment can proceed as long as
remediation has been identified and a commitment made to remediate.
If remediation is not required then the quality assessment can be completed along with
Quality Agreement being signed (if the assessment outcome is GO).
Registered Intermediates and API’s Remediation
If remediation is required, then it must be agreed between the Quality unit of the auditing
company and supplier in advance, with a timeline for completion (taking into account the
project schedule, as no manufacturing can occur until all critical/ major points have been
addressed).
The auditor should also decide in advance what level of checks are required post
remediation i.e. re-audit or supply of documented evidence. This will be dependant on the
criticality of the deficiencies previously identified and this should be scheduled into the
project timeline.
The cycle of remediation and re-check is continued until the auditor is satisfied with the
remediation outcome and the pre-determined audit acceptance criteria have either been
met or only other actions are outstanding.
If satisfactory remediation cannot be agreed and the deficiencies are critical/ major to the
project then the quality assessment is ended as a NO GO.
9. Completion of Quality Assessment
All the data of the quality assessment should be collated and reviewed; this will vary
depending on the category of raw material however may include satisfactory QC testing
of the material to specification, tanker cleaning certification, TSE certification, historical
performance, response to the questionnaire , manufacturer questionnaire, audit data and
completion, compliance history, reputation, 3rd party certification and successful
24
authority inspections. Much of this data will have been previously collated and reviewed
earlier in the supplier assessment i.e. during due diligence; however it still forms part of
the quality assessment. This review is independent and the final decision is the Quality
Units alone. If the review of all the data, (not only the result of the audit), is un-
satisfactory then a decision must be made on whether further remediation is to be
considered or the quality assessment is a NO GO.

If the quality assessment is satisfactory then the decision is GO

If the quality assessment is satisfactory then the decision is GO. If the customer wishes to
consider reduced testing then the criteria outlined in ICHQ7 section 7.3 must also be met

If the quality assessment is satisfactory then the decision is GO, on the signing of the
Quality Agreement.
10. Quality Contract/ Agreement

A purchasing contract will suffice for non-critical raw materials, this may include any
specific quality issues that need to be addressed i.e. compliance to pre-agreed
specification etc.

A quality/ purchasing contract is required for critical raw materials. This can be
supplemented with a quality agreement, if the customer feels the quality of the material
supplied is at risk by not having one.

A quality agreement should be drawn up- e.g. refer to the APIC Quality Agreement
Template. This should be forwarded to the supplier, when the rest of the quality
assessment process is ongoing. The Quality agreement must be approved and signed by
both parties before any manufacturing takes place. The Quality Agreement should
address the need for 1) notification of any potential changes that may impact the quality
of the product and 2) no changes to be made without prior approval.
25
CHAPTER 4. CHANGE CONTROL AND PRODUCTION ASSESSMENT
The change control and production assessment process follows five main steps, Initiation
of Change, Execution of Change, Evaluation of Change, Closure of the Temporary
Change Control Package and Preparation for Ongoing Monitoring as follows.
1. Initiation of Change
The execution of changes to the process are managed by a cross functional team
according to the following principles
All changes that have the potential to impact product quality (identity, strength,
purity, bioavailability, regulatory filings) must be evaluated. The types of changes
requiring notification should be defined and agreed to by both the firm and the
supplier.
The system for Change Control is overseen by the Quality organisation, but may be
managed by another function
All changes are assessed from a Technical, Quality, Regulatory, Stability, Safety,
Environmental and business standpoint with the appropriate personnel involved in the
review.
The impact of the change to the affected areas, processes and systems is evaluated
and communicated
All changes requiring a change to the filed process will be communicated to the
appropriate agencies
For non critical raw materials the process may be streamlined to assess the change as
there is no regulatory impact and the impact may be minor to the process.
2. Mechanism for Review of Change
2.1 Non Critical Raw Materials:

2.1.1. The mechanism for review is as follows. A temporary change request (this can also
be covered under the Vendor Approval Process) is issued by the assigned coordinating
function (usually technical) to all appropriate other functions together with the supporting
justification. This request should consider the following points,
Tracking number
Detailed description of change
Specification for the material based on User Requirements
Defined number of batches that will be impacted if known
Products impacted (name and identification code)
The reason for the change
Acceptance Criteria
Supporting documentation – if required by the evaluation of the change
o Outline of changes to master batch records
o Financial impact
o Impact on current testing
26
o Analytical test results of samples preferably from typical industrial scale
batches
o Results of use test of material and the follow on product evaluation (if
applicable)
2.1.3. The resulting temporary change request must be approved, at a minimum by the
Technical function and Quality units.
For changes to non critical raw materials the change control may be approved and closed
at this point depending on the assessment outcome. This process must be documented in
an SOP and at a minimum the approval must be completed by the Technical function and
Quality unit.
2.2 For Critical Raw Materials and API Intermediates

2.2.1. The mechanism for review is as follows. A temporary change request is issued by
the assigned coordinating function (usually technical) to all appropriate other functions
together with the supporting justification. This request may include, but is not limited to,
Tracking number
Detailed description of change
Specification for the material based on User Requirements
Defined number of batch that will be impacted
Products impacted (name and identification code)
The reason for the change
Acceptance Criteria
Supporting documentation
o Outline of changes to master batch records
o Financial impact
o Impact on current testing
o Validation impact
o Results of use test of material and the follow on product evaluation
2.2.2. Each of the supporting functions (Quality, Regulatory, Stability, Safety,

Environmental and business) then reviews the package and the change is again assessed
as per Appendix 5
The reviews may take place in parallel by all functions for additional impact. The results
of the assessment are communicated to the coordinating function and the findings are
consolidated and the final package is complied approval.
2.2.3. The resulting temporary change request must be approved, at a minimum by the
Technical function and Quality unit. All prior to release and prior to implementation
requirements must be consolidated and placed in the appropriate sites system.
2.2.4. Amendments to the temporary change is allowed, but only if the original intent is
not changed. This can be managed through the addition of an amendment to the change
request and this must be approved by the original approvers (Technical and Quality unit).
27
2.2.5. The material to be used is assessed on delivery. This assessment may include, but
is not limited to, the following
For each batch, routine testing is assigned to this material (sampling level may be
tightened)
Extra testing that may be appropriate to the evaluation
Use test of the material
2.2.6. If there is a process validation impact this is documented using the site system and
a Process Validation Protocol is developed and approved.
3. Execution of Change:
Following approval of the temporary change request by the appropriate functions and the
completion of all actions required for the change the process is executed using the new
material. Depending on the regulatory impact assessment the resulting material may need
to be segregated and controlled to ensure compliance.
4. Evaluation of Change:
The evaluation of the change is performed at a number of levels as follows
4.1. The resulting material produced as part of the temporary change is then evaluated by
Routine testing of the material for all materials
Use tests to produce the final product for critical materials and API Intermediates
Extra testing to evaluate the material produced and ensure that it is within
expectations for critical materials and API Intermediates
4.2. The validation completion report is drafted and approved as per the normal site
procedure.
4.3. All prior to release and prior to implementation requirements are assessed and
tracked to closure as per the site systems.
5. Closure of the Temporary Change Control Package:
5.1. A closure memo is prepared by the assigned coordinating function that verified and
shows evidence that all requirements of the temporary change request have been met.
This may include but is not limited to the following
Evaluation of the material received

Evaluation of the product by testing (routine and extra)
Approval of the validation completion report
28
Confirmation that all prior to release and prior to implementation requirements are
fulfilled. If there are some requirements that will remain pending after closure then
this will be highlighted and are managed by other site systems.
The final document is approved by the original approvers of the change Technical,
Quality unit and Business areas.
5.2. Material may be released following approval of the change.
For any regulatory requirement that remain pending, the appropriate control of the
material and documentation should be maintained.
5.3. If the change does not perform as expected then the temporary change request will be
discontinued and cancelled and the resulting material destroyed.
5.4. The change request remains temporary until all the appropriate regulatory agencies
approval is received. The change then progresses through the site system and the change
can be made permanent.
6. Preparation for Ongoing Monitoring:
To assist ongoing monitoring and evaluation of the material and the supplier, the
company must identify KPIs (Key Performance Indicators) at this stage in the process.
Examples of KPIs are chosen based on the criticality of the material and the following
examples could be included
No agency observation leading to supply impact
Number of observations from agency inspections
No significant investigations
Number of atypical investigations and OOSs on the material
No market action as a result of an investigation or customer complaint
Number of Customer complaints
Response time to customer complaints and atypical investigations
No of rejected batches in the year
On time delivery performance in full
Percentage on time completion of audit observations
Percentage on time completion of Corrective Action
29
CHAPTER 5. SUPPLY CHAIN SECURITY
The previous chapters preliminarily focused on the supplier qualification and

management activities in a direct interaction between the customer and the manufacturer
of the material. However, this is not always the case as agents, brokers, distributors,
repackers, relabelers may be involved (in addition) apart from transport companies. As a
general principle it should always be considered that the shorter the supply chain, the
more secure it will be.
In the light of an increasing presence of counterfeit and sub-standard products this aspect
gains even more importance. This development is also reflected by the fact that various
initiatives have been taken such as the founding of the FDA Counterfeit Drug Task
Force, the European Commission’s “Public consultation in preparation of a legal proposal
to combat counterfeit medicines for human use” (adaptation of directive 2001/83 EC) and
the WHO Program “IMPACT” (International Medical Products Anti-Counterfeiting
Taskforce). The “APIC Quick Guide for API Sourcing” provides some specific guidance
on this topic especially related to the interaction between the API manufacturer and the
medicinal product manufacturer and provides possible measures that may be taken by
both partners in order to ensure only non-rogue APIs are used in the manufacture of
medicinal products
The entire supply chain from the manufacturer of an API, registered intermediates or
critical raw material to the customer should be assessed and qualified from a quality
perspective by applying the same principles as described in the previous sections of this
guide, mainly related quality system, transportation, storage and related conditions as
well as traceability of the material.
For temperature/ humidity sensitive materials, the use of data loggers should be
considered in order to have documented evidence that the product was stored at the
required conditions during transportation.
As any changes on the original container – e.g. by repackaging, relabeling – are

considered as an additional risk for alteration or contamination, these should, whenever
possible, be avoided.
Apart from the supplier qualification and management activities the following measures
related to packaging can be considered and may increase the supply chain security for
APIs, registered intermediates and critical raw materials:
Use of tamper-resistant packaging closure by the manufacturer, a manufacturer-

specific design of the seal is recommended to be used; the use of unique seals
may be considered. The communication of the type of seal, by the manufacturer
to the customer, is needed.
Evaluation of the label by the customer: the label on the material matches the
reference label provided by the manufacturer. The labels need to be in line with
ICH Q7, 9.42/43 for APIs & registered intermediates hence also need to indicate
30
the name, address of the manufacturer and special storage/transport conditions
apart from the name or identification code of the product, batch number, quantity
of contents and the expiry date. In case of a retest date, this may be indicated on
the CoA.
Assessment of the CoA against an authentic manufacturers CoA.
For non critical raw materials, the activities as described in chapter 1, 3, 4 and 6 of this
guide are applied to qualify and manage the supplier.
31
CHAPTER 6. ONGOING MONITORING AND EVALUATION
After the approval of a new supplier, a periodic evaluation should be performed. For this
evaluation different elements should be considered. The following chapter will define the
activities for the ongoing evaluation and finally define the status of the qualification.
1. Responsibilities
The evaluation should be under the control of the Quality Unit but completed as part of a
muti-displinary team evaluating all aspects of supply. The Quality Unit is responsible for
the ongoing evaluation and the re-approval of the supplier. Other departments should
give their input to ensure that all relevant aspects are taken into account.
2. Elements of monitoring and rating
Ongoing monitoring
Each supplied batch should be assessed according to defined criteria. These criteria
should be a result of the risk assessment. At least the following aspects should be taken
into consideration:
o Specification (results on certificate of analysis and own results)
o Statistical Evaluation of Quality Control data for critical parameters (if
applicable) to identify any adverse trends
o Packaging, sealing
o Labelling
o Delivery dates and quantities
o Certificates and other documents
o Other aspects
All deviations should be monitored and managed according to the company’s complaint
procedure.
Periodic evaluation
Regular, typically on an annual basis, the supplier’s performance should be assessed. For
non-critical raw materials a periodical evaluation may not be required.
Depending on the type of material the following data should be evaluated:
o Periodic full testing of material

o Quality – for example number of not right first-time deliveries
o Complaint situation
o Product Quality Review (registered intermediates and APIs)
o Results of SQC/SPC analysis (if applicable)
o Assessment of changes (critical materials, registered intermediates and APIs)
o Reaction on audit and remediation plan (if audit had taken place)
o Response times for complaints and questions
o Reaction time if e.g. regulatory requirements change (critical materials,
registered intermediates and APIs)
32
o Regulatory or cGMP/compliance issues (critical materials, registered
intermediates and APIs)
o Predefined KPIs with examples in Chapter 4 (registered intermediates and
APIs)
The result of the evaluation should be summarised in a report which is the basis for the
rating and the Review.
Rating (classification of supplier)
After the periodic evaluation the supplier should be classified according to an objective
rating system. This rating system gives an indication about performance and satisfaction.
The following categories are an example for a rating system:
o Completely satisfactory: approval
o Mainly satisfactory: limited approval (ongoing supply)
o Partially satisfactory: conditional approval (no supply until corrective actions
are in place)
o Not satisfactory: Supplier disqualified until actions are taken
The result of the rating has an important impact on the frequency of re-audits, re-
evaluation, extent of sampling and testing.
Review with supplier
In order to develop a trustful relationship and take all opportunities to maintain and
improve the quality of the service, the results of the periodic evaluation should be shared
with the supplier. This should be mandatory for critical materials, registered
intermediates and APIs.
Depending on results and need for an exchange of information this could be either in
person or in written form.
In this review the monitoring results should be presented and, if necessary, discussed. If
there is a need for corrective actions they should be defined and timelines for
improvement agreed.
In addition to that a meeting should also be used for general discussions and exchanges of
experience.
Re-audit
The decision for auditing/re-auditing suppliers of critical raw materials should be risk
based. In this regular risk assessment the performance of the supplier, regulatory
requirements and criticality of the material should be considered. The result of the
assessment should be documented.
The supplier of registered intermediates and APIs should be audited on a regular basis.
33
The GMP standard for the re-audit should be the same as the initial audit. Further
developments in the guidelines should be considered.
The frequency of the re-audit should by dynamic and depending on the rating.
Example:
o Completely satisfactory: 5 years
o Mainly satisfactory: 3 years.
o Partially satisfactory: 1 year
The frequency should be maintained until the performance is on a higher level. If the
supplier shows a low performance for more than one year, the approval should be
reconsidered.
For APIs the recommended period for re-audit is 2 to 3 years as defined in the EMEA
document “Compilation of Community Procedures on Inspections and Exchange of
Information”
In the case of serious complaints, unsatisfactory response on remediation plans or any

doubts regarding GMP compliance an unscheduled audit can be performed.
Re-Evaluation
In parallel with the re-audit the supplier should be re-evaluated. As a result of the
outcome the Quality Agreement and other contracts should be reviewed and updated as
necessary.
3. Reduced testing
Testing of non critical, critical raw materials and registered intermediates may be reduced
depending on the rating and the performance of the supplier over a period of time and the
criticality of the material. The approach also needs to be in line with ICHQ7 chapter 7.3.
************
34
24579 IPEC cover CX2:113114_IPEC Cover 4-1 PGS 10/3/08 12:46 PM Page 1
INTERNATIONAL PHARMACEUTICAL EXCIPIENTS COUNCIL
Qualification of
Excipients for
Use in
Pharmaceuticals
Printed in the USA by IPEC-Americas

1655 N. Ft. Myer Drive, Suite 700 Copyright © 2008 International Pharmaceutical Excipients Council
Arlington, VA 22209
QUALIFICATION OF EXCIPIENTS FOR USE IN
PHARMACEUTICALS
FOREWORD
IPEC is an international industry association formed in 1991 by manufacturers and users of excipients. It is an
association comprising three regional pharmaceutical excipient industry associations covering the United
States, Europe, and Japan (which are known respectively as IPEC-Americas, IPEC Europe, and JPEC). IPEC’s
objective is to contribute to the development and harmonization of international excipient standards, the
introduction of useful new excipients to the marketplace and the development of best practice and guidance
concerning excipients.
IPEC has three major stakeholder groups;

1. Excipient manufacturers and distributors, who are considered suppliers in this document,
2. Pharmaceutical manufacturers, who are called users, and
3. Regulatory authorities who regulate medicines.
Suppliers Users
IPEC
Regulatory
Authorities
This document offers best practice and guidance in the establishment of an effective relationship between an
excipient supplier and excipient users. The excipient supplier may be a manufacturer or a distributor (or both).
It concentrates on the issues that the two parties are likely to encounter and offers advice and best practice as to
how to address them, thereby ensuring a smoother relationship and easier use of the excipient by the user and
in their dealings with the regulatory authorities.
Because excipients are diverse and often have uses other than in pharmaceutical applications, a supplier may
discover that their product is being used by the pharmaceutical industry as an excipient. This document will be
especially valuable in such situations because many of the issues described will be new to the supplier.
Copyright © 2008 The International Pharmaceutical Excipients Council Page. ii

Excipient
Qualification
Suppliers Users
IPEC
Regulatory
Authorities
Thus any material used in the pharmaceutical drug product will be required to be manufactured under
appropriate Good Manufacturing Practices (GMP) and supplied under Good Distribution Practices (GDP). The
exact definition of GMP or GDP will depend on the material in question (e.g. excipient, active pharmaceutical
ingredient, packaging etc) and legislation where the excipient is supplied or sold. Within this guide the terms
GMP and GDP are used to encompass all of these various definitions.
Like all guides this document is not meant to be proscriptive, and suppliers and users may follow the guideline
as written or find their own manner to address the subjects highlighted. The guide is intended to be
comprehensive and covers the essential aspects of the supplier-user relationship. In this regard not every topic
may be appropriate for all relationships.
To facilitate reading, the excipient qualification process has been presented in flow charts as a means of linking
the activities and steps in a logical manner. This aids comprehension and places these steps into context.
There is no specific requirement to follow the exact sequences of actions as detailed in the flowcharts although
users will find these helpful to ensure all aspects are considered.
Although excipient qualification does not directly involve the regulatory authorities, they set many of the
conditions that have to be satisfied if a user is to employ an excipient in their medicine.
This document describes the three phases of the excipient qualification process. The layout and content are as
follows:
Section 1 Introduction: describes the scope, purpose, and layout of this guide.
Phase 1 The Excipient Supplier’s Process
Section 2 General Guidance: provides background concerning excipient manufacture,
regulation, and controls.
Section 3 Excipient Development and Specification Process: provides guidance to
excipient suppliers on the development of an excipient and its specifications.
Phase 2 The User’s Process
Copyright © 2008 The International Pharmaceutical Excipients Council Page. iii

Section 4 Excipient User Assessment, Selection, and Specification Process: provides
guidance on how users should assess the excipients for inclusion in their
formulations.
Phase 3 The Negotiation Process
Section 5 Excipient Supplier-User Negotiation Process: provides guidance on the
development of an agreement between the excipient supplier and
pharmaceutical user to define excipient quality requirements.
Glossary Terms defined in the glossary appear in bold the first time they are used in
this document.
Appendices Flow diagrams that illustrate the development of a material for sale as an
excipient, the approval of the use of an excipient in a dosage form, the
negotiation process used to determine the appropriateness of the requirements,
and the specific requirements for the excipient.
Each Phase of the process is also described by a flowchart illustrating the process:
Phase One- The Excipient supplier’s Process shows the steps a chemical manufacturer may take to evaluate
the market and regulatory requirements for the proposed excipient and the steps leading up to the
market launch,
Phase Two- The User’s Process illustrates the path a pharmaceutical company ordinarily follows in
evaluating the excipient and its manufacturer for use in a formulation, and
Phase Three- The Negotiation Process shows the process by which the supplier and user interact to reach a
mutual agreement on quality requirements.
As an international guidance document, the guide cannot specify all national legal requirements or cover in
detail the particular characteristics of excipient qualification in all territories. Although the details in this
document highlight European and United States issues, the principles can be applied to any excipient supplier
– excipient user relationship worldwide.
By setting out all the stages in excipient qualification both suppliers and users will be better placed to use the
tools in ICH Q9 Quality Risk Managementi to better assess which steps in this guide are most appropriate and
necessary for their particular situation.
i
ICH Q9, Quality Risk Management, http://www.ich.org/LOB/media/MEDIA1957.pdf
Copyright © 2008 The International Pharmaceutical Excipients Council Page. iv

TABLE OF CONTENTS
FOREWORD ii
ACKNOWLEDGEMENTS vii
1. INTRODUCTION 1
1.1 Purpose 1
1.2 Scope 1
1.3 Principles Adopted 1
1.4 Layout 1
2. GENERAL GUIDANCE 2
2.1 Differentiation of Excipient Manufacture 2
2.1.1 Reference Documents 3
2.2 Preliminary Excipient Marketing Decision 3
2.2.1 Determination of the Intended Target Market and Route of Administration 3
2.3 Regulatory Assessment 4
2.3.1 Safety, Toxicological, and Precedence of Use Issues 4
2.3.2 New (Novel) Excipients 5
2.3.3 Compendial Requirements 6
General Comments 6
United States Pharmacopeia 7
European Pharmacopeia 8
Japanese Pharmacopeia 8
New and Novel Excipients not listed in a Pharmacopoeia 8
Other regulatory requirements 10
2.3.4 Desired Properties for Intended Use 10
2.3.5 Excipient Master Files and Other Filings 10
United States Drug Master Files 10
European Certificates of Suitability (CEP) 11
Japanese Drug Master Files 12
2.3.6 International Conference on Harmonisation (ICH) 12
2.3.7 Specific Safety Issues 13
2.3.8 Concluding Comments on the Regulatory Assessment 14
2.4 Manufacturing and Packaging 14
2.4.1 Process Capability and Validation 15
2.4.2 Test Methods and Validation 16
2.5 Excipient Specifications 17
2.5.1 Excipient Stability 17
3. EXCIPIENT DEVELOPMENT AND SPECIFICATION PROCESS 18
3.1 Excipient Consistency and Control 18
3.2 Performance Indicators 19
3.3 Production Specification and Master Batch Record 19
3.4 Marketing Materials 20
3.4.1 Sampling Guidelines 21
3.5 Customer Feedback 22
3.6 Post Product Launch 22
3.7 Confidential Information 22
4. ASSESSMENT, SELECTION AND SPECIFICATION PROCESS 24
Copyright © 2008 The International Pharmaceutical Excipients Council Page. v

4.1 Project Initiation 24
4.2 New Formulation Development Projects 24
4.2.1 Selecting the Excipient 25
4.2.2 Selecting the Supplier 26
4.2.3 Regulatory Assessment 28
4.2.4 Refining the Excipient List 29
4.2.5 Formulation Design, Development, and Optimization 30
4.3 Alternative Excipient Source Projects 31
4.4 Negotiation Process Impact 33
5. NEGOTIATION PROCESS 34
5.1 Review of Excipient User Requirements 34
5.2 Quality Agreement 36
5.3 Modification of Requirements 37
5.4 Identification of Potential Solutions 37
5.4.1 Lot Selection 38
5.4.2 Manufacture to Order 41
5.5 Other Approaches 41
5.5.1 In-House Processing 41
5.5.2 Reformulate 41
5.5.3 Supplier Custom Manufacture 42
5.6 Concluding Agreements 42
APPENDIX A: FLOW DIAGRAMS 43
APPENDIX B: DEFINITIONS AND GLOSSARY 51
APPENDIX C: BIBLIOGRAPHY 55
Copyright © 2008 The International Pharmaceutical Excipients Council Page. vi

ACKNOWLEDGEMENTS
This Guide was developed by representatives of many of the member companies of the International
Pharmaceutical Excipients Council (IPEC), an industry association whose members consist of excipient
manufacturers, distributors, and pharmaceutical users. The company representatives who worked on this Guide
are listed below:
IPEC-AMERICAS
William F. Busch, Dow Wolff Cellulosics
Dale Carter, J.M. Huber Engineered Materials
Raymond Croes, SPI Pharma, Inc.
Sidney A. Goode, Pharm.D, The Dow Chemical Company
Maria Guazzaroni Jacobs, Ph.D., Pfizer, Inc.
Diana Hickey, EMD Chemicals Inc.
David B. Klug, M.S., sanofi-aventis U.S. LLC
Cindy Libonati, C.P.M., Purdue Pharma L.P.
Brian McCarter, EMD Chemicals Inc.
Philip H. Merrell, Ph.D., Jost Chemical Co.
Ann Van Meter, The Dow Chemical Co.
R. Christian Moreton, Ph.D., FinnBrit Consulting
Frank H. Murphy, Dow Chemical
Londa L. Ritchey, M.S., Wyeth
David R. Schoneker, M.S., Colorcon, Inc.
Alexa Smith, Colorcon, Inc.
Bob Sulouff, Hercules/Aqualon
Katherine L. Ulman, Dow Corning Corporation
Robert E. Wiens, Eli Lilly Incorporated
Priscilla Zawislak, Hercules Incorporated
IPEC EUROPE
Iain Moore, Ph.D., Croda Europe Ltd
Ariane Etoc, Dow Corning
Doris Wangel, Flamel Technologies
IPEC EUROPE QA TEAM
Karen Hudson, Eli Lilly
Adrian Bone, Eli Lilly
EX OFFICIO CONTRIBUTORS
Irwin B. Silverstein, Ph.D., IBS Consulting in Quality LLC
Copyright © 2008 The International Pharmaceutical Excipients Council Page. vii

1. INTRODUCTION
1.1 Purpose
This document is meant as a guide for the qualification of excipient ingredients by excipient
suppliers and pharmaceutical users. Its goal is to establish the information needed to support the
introduction of a material for marketing as an excipient to the pharmaceutical industry as well as
to indicate the steps used to establish the requirements for use of an excipient by a pharmaceutical
company.
1.2 Scope
This guide is applicable to all excipients used in pharmaceutical dosage forms.
1.3 Principles Adopted

When considering how to use this guide, each excipient supplier must consider how it may apply
to their material and processes. In addition pharmaceutical formulators should consider the proper
use of the excipient in their formulation. Although the steps are laid out in a specific sequence in
this guide, supplier and users are not required to follow that route through the excipient
qualification process nor indeed cover every aspect described. The diversity of excipients means
that some principles of the guide may not be applicable to certain materials and processes. The
terminology “should” and “it is recommended” do not necessarily mean “must”.
1.4 Layout
Flow diagrams are a pictorial display of the process described in detail in this document. They
outline a logical path with sequential steps and appropriate decision points that should be
evaluated in the excipient development and qualification process. Decision points show what the
next phase of the evaluation would be, dependent upon the decision reached.
The reference number contained in the boxes of the flow diagram refers the reader to the
corresponding section in this guide where further information is provided. The box number
appears as bold text between the chevrons (<number>) in the text.
Copyright © 2008 The International Pharmaceutical Excipients Council Page 1

PHASE ONE: THE EXCIPIENT SUPPLIER’S PROCESS
2. GENERAL GUIDANCE
2.1 Differentiation of Excipient Manufacture

Many materials used as excipients have applications other than in pharmaceuticals, such as food
additives, cosmetics, or industrial products. Thus, environmental conditions, equipment, and
operational techniques employed in excipient manufacture are often those of the chemical
industry rather than those of the pharmaceutical industry. The excipient starting materials may not
be required to be manufactured in accordance with Good Manufacturing Practice (GMP)
requirements for excipients (for example as in the IPEC-PQG GMP Guide1) because these other
uses of the material do not demand the adoption of GMP. Excipients may be manufactured
through significant chemical change, physical modification, blending, or purification which
causes many of the other components present in the starting materials to be removed or reduced.
The effectiveness of these steps is confirmed by chemical, biological, or physical testing of the
excipient. Once synthesized or isolated, excipients normally undergo additional purification. Thus
while materials manufactured by the chemical industry, primarily for other applications can be
used as pharmaceutical excipients, in these cases the principles of GMP will need to be applied
when the material is intended for use in the pharmaceutical industry.
For distributors the same principles apply in that the purity, integrity, and suitability of the
excipient for use in pharmaceutical products needs to be assured. In these cases the IPEC Good
Distribution Practice (GDP) Guide2 is an appropriate starting point for defining the quality
assurance standards and systems required.
The finished dosage formulator is highly dependent on the excipient manufacturer to provide
materials that are uniform in chemical and physical characteristics. This is particularly important
in the context of the pharmaceutical product approval process where bioequivalence comparisons
are made between pivotal, clinical trial batch ("biobatch") production and commercial scale-up
lots. The excipient used to manufacture commercial lots should not differ significantly from those
used in biobatches to provide adequate assurance of finished product performance. Therefore, it is
important to minimize variation between the different batches of excipient, as well as within the
excipient batch itself. However if significant differences do occur between excipient lots used in
clinical and commercial drug product lots, additional testing by the finished dosage manufacturer
may be required to establish the bioequivalence of the drug product.
The user of the excipient typically does not significantly alter the chemical and/or physical
properties of the excipient prior to use. Consequently, other components present in the excipient
are likely to be present in the drug product. Excipients frequently function because they are not
“pure”. That is to say that there may be concomitant components that are necessary for the
correct functioning of the excipient. These concomitant components should not be confused with
“impurities”.3
Although dosage form manufacturers may have some limited control over excipient quality
through specifications, the excipient manufacturer must be considered to have greater control
over physical characteristics, quality, and the presence of other components in the excipient they
produce. Control over other components in the excipient should not be taken to mean minimizing
or even eliminating concomitant components from the excipient. The presence of concomitant
components in the excipient often has a beneficial effect on excipient performance, but control is
needed to assure that the presence of concomitant components is at a consistent level and other
1
The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006
2
The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, 2006
3
IPEC Excipient Composition Guide (in development)
Phase 1 Copyright © 2008 The International Pharmaceutical Excipients Council Page 2

components are kept to a minimum. It is important to remember however that it is the
responsibility of the pharmaceutical dosage form manufacturer to ensure the safety of their drug
product and the excipients used in the formulation.
Excipients are frequently used in different types of drug products where physical characteristics,
such as particle size, may be important. While the pharmaceutical formulator is primarily
responsible for identifying the particular physical characteristics needed, it is the responsibility of
the excipient manufacturer to adequately control the excipient manufacturing process to assure
consistent excipient conformance to the agreed specifications.
2.1.1 Reference Documents

Several sources have been used for reference information in the development of this
guideline and are listed in Appendix C-Bibliography. IPEC has issued several guidelines
that are referred to in this document. In addition, the pharmacopoeias have pertinent
information in their general chapters that are applicable. Finally, several ICH4 documents
are referenced in various sections of this guideline (and are also included in Appendix C-
Bibliography).
2.2 Preliminary Excipient Marketing Decision

The original manufacturer begins the process of offering a chemical to the pharmaceutical
market as a substance suitable for use as an excipient in a drug product <1.1>. It is not
appropriate for a distributor to make the determination to use a non-pharmaceutical grade as a
drug component.
Alternatively, a pharmaceutical customer may approach the excipient supplier and indicate a
desire to utilize their product as an excipient (see Section 4-Phase 2). In either instance the
decision to provide the material as an excipient should be made with a good understanding of the
suitability of the safety and quality of the material, and the ability to supply this quality on a
consistent basis.
2.2.1 Determination of the Intended Target Market and Route of Administration

The intended end use of the excipient should be identified and considered in determining
the appropriate regulatory and GMP requirements for the excipient and its manufacturing
facility <1.2>. Of particular importance is whether the excipient will be a component of a
finished drug product. The route of administration is critical to defining the requirements
for the excipient because the key principle throughout pharmaceutical supply is that of
protecting the patient. The risks to the patient are proportional to the route of
administration, approximately increasing in the following sequence:
• Topical
• Oral, vaginal, and rectal
• Pulmonary/Inhalation
• Parenteral, ophthalmic, and preparations intended for use in open wounds
Parenteral dosage forms normally require an excipient to have a low bioburden or be

produced as pyrogen-free. An excipient to be used in a sterile drug product may be
required either to be sterile or capable of remaining unaffected by the drug manufacturer’s
sterilization process. The excipient supplier is responsible for ensuring that excipients meet
bacterial endotoxins specifications or are pyrogen-free, only if the excipient manufacturer
makes such a representation in specifications, labeling, contractual agreement, a Drug
4
ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use: http://www.ich.org

Master File (DMF), or a Certificate of Suitability to the European Pharmacopeia
(CEP).
2.3 Regulatory Assessment
2.3.1 Safety, Toxicological, and Precedence of Use Issues

There are several safety related issues that should be assessed by the potential excipient
manufacturer as part of their decision to introduce an excipient to the pharmaceutical
market <1.3>.
First an assessment should be made as to whether there is a precedence of use for the
material in a drug product or a similar application such as a food additive, food contact
packaging component. If a precedence of use can be shown in applications where there is
human exposure, the safety of the material might already be appropriate for potential
application as an excipient in the pharmaceutical industry.
In the U.S., the Food and Drug Administration (FDA) maintains a database of excipients
that is posted on their website as the Inactive Ingredient Database (IID) 5. The IID should
be used to establish precedence of use since it lists each excipient which has been allowed
as a consequence of its presence in an approved innovator drug product. Each excipient is
listed by name, dosage form, and the maximum amount of excipient contained in an
approved drug of that listed dosage form. Care must be exercised in searching the database
because an excipient can be listed by various names, including trade name, compendia
name, chemical name, or generic description (for dyes and flavors).
In Japan, an assessment for precedence of use can be made by referring to the Japanese
Pharmaceutical Excipients Dictionary (JPED) which is edited by the Japan Pharmaceutical
Excipients Council in conjunction with the Ministry of Health, Labor, and Welfare. The
JPED is a compilation of all excipients for which there is a precedence of use in drug
products in Japan. It includes monographs from the JP or Japanese Pharmaceutical
Excipients (JPE) as well as all non-monograph excipients that have been previously used.
Each monograph lists the nonproprietary name and synonyms along with the application
and maximum dosages for the various routes of administration in approved drugs6.
In Europe, there is no comprehensive European Union list of excipients that have been
approved in drug products. Therefore, in order to establish precedence of use, it is
necessary to review the drug catalogues such as the “Dictionnaire Vidal” (France),“Die
Rote Liste” (Germany), or “The Electronic Medicines Compendium” (UK)7.
At the time this Guide was prepared, the European Union had mandated the application of
GMP principles to “certain excipients”8. Materials in this category are those that could pose
a higher safety risk to the patient including excipients:
• prepared from materials derived from a TSE-relevant animal species (excluding
lactose)
• derived from human/animal material with potential viral contamination risk
5
Instructions: http://www.fda.gov/cder/iig/iigfaqWEB.htm,
Database: http:www.accessdata.fda.gov/scripts/cder/iig/index.cgm
6
Maximum dosage information is only contained in the Japanese language version of the JPED.
7
Electronic Medicines Compendium; http://www.medicines.org.uk/emc.aspx
8
Draft: Specific Conditions of the Application of the Principles and Guidelines of Good Manufacturing Practice
for Certain Excipients EC-Directive 2001/83/EC, as amended by EC-Directive 2004/27/EC

• claimed to be sterile (or sold as sterile) and used without further sterilization
• with the specification or claim that they are endotoxin/pyrogen controlled, or
• the following specific materials:
o propylene glycol
o glycerol
Following a public and industry consultation in the summer of 2007, an economic impact
assessment suggested that it was not in the public benefit to mandate the application of GMP
for certain excipients. However, a final decision has not been taken; nevertheless IPEC
recommends the application of the GMP principles described in the IPEC-PQG Excipient
GMP Guide to all excipients.
If there is no precedence of use in a drug product, then the material is to be considered a new
excipient (see Sections 2.3.2 and 2.3.5).
2.3.2 New (Novel) Excipients

An excipient used for the first time in a drug product or by a new route of administration is
classified as new according to the ICH Guideline M49, Organisation of the Common
Technical Document for the Registration of Pharmaceuticals for Human Use. Conversely,
this guideline defines known excipients as “excipients that are well-established and
commonly used in registered drug products and are usually included in pharmacopoeias”.
When an excipient has not previously been used in a pharmaceutical dosage form then
there are a number of conditions set out by the US and European regulatory authorities to
allow for its use.
The U.S. FDA has issued a Guidance concerning the safety testing required for novel
excipients10 as has IPEC in their IPEC New Excipient Evaluation Guidelines dated October
199611 which were the basis for the USP-NF 26 General Chapter Excipient Biological
Safety Evaluation Guidelines <1074>12 on this topic. The information contained in these
documents is useful for assessing the safety of a chemical for use as an excipient. The IPEC
Europe Safety Committee has published a similar guideline13. The manufacturer of a new
or novel excipient should develop the safety information recommended in these guidelines
appropriate to their intended use. This information provides the basis for establishing the
suitability of the material for use as an excipient in a particular type of dosage form.
The terms “new” and “novel” as related to excipients are difficult to define precisely.
Clearly an excipient is new if it is not listed in:
• the FDA Inactive Ingredient database,
• any of the 3 major compendia, U.S. Pharmacopeia (USP-NF), European
Pharmacopoeia (Ph. Eur.), or Japanese Pharmacopoeia (JP), or
• other widely known compendia such as the “Handbook of Pharmaceutical
Excipients” or “Fiedler: Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und
angrenzende Gebiete” (Encyclopedia of excipients for pharmaceutical, cosmetic
9
ICH M4, Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human
Use, Step 4, 2004.
10
U.S. FDA, Nonclinical Studies for Development of Pharmaceutical Excipients (final version May 2005)
11
Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshita, F.K., Loper, A., Mitchell, D.B., Tamulinas, C.B., and
Weiner, M.L., A New Approach to the Safety Assessment of Pharmaceutical Excipients, Regulatory Toxicology
and Pharmacology, 24, 2, 1996.
12
USP-NF General Chapter <1074> Excipient Biological Safety Evaluation Guidelines
13
The Proposed Guidelines for the Safety Evaluation of New Excipients (European Pharmaceutical Review,
November 1997)

and related use).
The industry recognizes that any change in the chemical composition of an excipient
produces a new excipient, no matter how minor the modification to the chemical
composition. Mixtures of excipient ingredients can result in a novel excipient when the
subject mixture is to be used in a dosage form for which its constituent excipients have not
already independently been used in that intended route of administration. Physical
modification of an excipient, such as micronizing or compaction does not generally
produce a new or novel excipient.
However, co-processing can produce a synergistic physical interaction between two or

more excipients that is patentable and create unique properties that cannot be achieved
through simple blending3. The safety assessment for these co-processed excipients made
with commonly used pharmaceutical excipients will generally be less stringent than for a
new chemical entity.
If the excipient is already described in a pharmacopoeia or used as such in other

pharmaceutical dosage forms, the excipient is neither new nor novel and the detailed safety
review recommended in the above guidelines will not be necessary.
2.3.3 Compendial Requirements

General Comments
There are three major compendia that are routinely referenced globally; the United States
Pharmacopeia – National Formulary (USP-NF), the European Pharmacopoeia (Ph.Eur.),
and the Japanese Pharmacopoeia (JP). These compendia describe the quality of substances
to be regularly used in pharmaceutical products, how to test them and the other general
conditions required to assure the quality of pharmaceutical substances so that they are not
harmful to the patient. The descriptions of substances for pharmaceutical use are called
monographs and these list the analytical specification and other quality attributes required
to assure the safety and quality of the excipient.
In order to market an excipient, there is no regulatory requirement that there must be a

compendial monograph for the material. However, if a compendial monograph exists for an
excipient in a particular region’s pharmacopoeia, then the excipient should comply with
that monograph because the regulatory authorities require conformance. However, other
regulations may define a suitable quality which could be used (e.g. Food Chemical Codex).
In all cases, the use of a specification that at least meets a compendial monograph or a
similar standard is preferable to the supplier’s own internal document. In particular
conformance to a pharmacopoeial monograph and other relevant general notices and
chapters of the compendia means that the excipient already has a suitably defined quality
for pharmaceutical use.
In some instances, other specific regulations apply for a specific use such as for parenteral
applications as discussed above (see Section 2.2.1).
In the United States, certain food additive materials are produced in conformance with the
Food Chemical Codex (FCC) while in Japan, there is the Japanese Pharmaceutical Codex
and also a series of supplementary books called the Japanese Pharmaceutical Excipients
(JPE). Many other national pharmacopoeias delineate the quality requirements of
pharmaceutical ingredients and these will take precedence over the three major
pharmacopoeias.

Where an excipient is described in a pharmacopoeia, the quality of material for
pharmaceutical use must comply with this monograph (regulatory requirement).
The compendia are concerned with the presence of additives and processing aids in
excipients. While the issue is still under active consideration by the pharmacopoeias, it is
suggested that excipient manufacturers compile information on the identity and quantity of
additives and processing aids that are or may be present in excipient products.
For an excipient listed in multiple compendia that may be marketed for global use, the
manufacturer is advised to ascertain the conformance of the excipient to the monograph
requirements found in all those compendia. While considerable efforts are underway to
harmonize the requirements for excipients with monographs in the three major compendia,
currently there are often different monograph requirements found in one or more of these
compendia. Even for excipients whose monographs have completed the harmonization
process, they may still contain non-harmonized attributes. As a consequence, it is advisable
to tabulate all monograph testing requirements from all compendia having an appropriate
monograph. Such a table should contain not only the test name and specification range but
a brief description of the test method since often the method of analysis differs between
compendia. Once the tabulation is complete, the excipient supplier can develop a testing
plan to ensure conformance to all monograph requirements in the various compendia.
Where multiple test methods are referenced for the same property (attribute), it would be
satisfactory to validate the manufacturer’s method to demonstrate it provides assurance that
the excipient, when tested to each monograph method, will conform to each monograph
requirements.
The commercial relevance of an excipient and therefore the use of the excipient in at least
one approved drug product is a prerequisite for inclusion of a monograph in the Ph.Eur.,
USP-NF, or JP/JPE. Both users and suppliers of excipients may request their local
pharmacopeia to develop a new monograph once a material’s use in a commercial
pharmaceutical product has occurred. When there is no pharmacopoeia or other compendia
monograph, the manufacturer can establish its own specification, based on an existing
similar pharmacopoeia monograph. If not available, the specification can be based on its
own experience and the excipient’s chemical and physical properties and intended use.
United States Pharmacopeia– National Formulary

The USP and NF are legally separate compendia officially mandated in the U.S. Federal
Food, Drug and Cosmetics Act. However, they are published together in a single book.
To be considered for inclusion in the USP-NF, a new excipient should have been used in an
approved drug product or be listed in another pharmacopoeia. A monograph is prepared for
the new excipient with input from both the excipient manufacturers and pharmaceutical
users. The draft monograph is then published for comment in the Pharmacopeial Forum and
then submitted to the USP for approval.
The USP-NF General Notices require the use of appropriate GMPs in the manufacture of
compendial materials14. The USP-NF includes a General Information Chapter which
elaborates on the GMP requirements for producing an excipient.15 The USP-NF also
specifies the requirements for properly testing an excipient both in terms of the
14
USP-NF General Notices subsection Ingredients and Processes, second paragraph.
15
USP-NF <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients

requirements for validated test methods as well as by detailing specific test methodology.
Generally, excipient monographs (specifications) are contained in that portion of the USP-
NF called the National Formulary (NF) unless they also have been used in a dosage form
where they function as the Active Pharmaceutical Ingredient (API), in which case they
are contained in the United States Pharmacopoeia (USP). The monographs detail the test
methods and specification limits which must be achieved in order to market an excipient as
compendial grade. Certain monographs also contain additional information such as labeling
and storage requirements.
In order to label an excipient as compendial grade, regardless of the pharmacopoeia, all

monograph and appropriate General Chapter or Notices requirements ordinarily must be
met. There is an exception to this for USP and NF grade excipients, under certain
circumstances, as noted in the USP-NF General Notices16. Nevertheless, alternative test
methods used must be validated17 and shown to produce results comparable to those
obtained using the compendial method. Non-compendial test methods used must be
validated.
European Pharmacopoeia
For a new excipient to be added to Ph.Eur. it must have been a component of a previously
approved drug product and no longer protected by patent. The drug product formulated
with the new excipient ingredient is reviewed and approved by the member state or states to
which the application has been submitted. Once used in an approved drug product, to be
added to the Ph.Eur. the new excipient; must be included in the work program of the
European Pharmacopoeia Commission. To be added to the work program typically requires
the support of several member states at the biannual meeting of the Commission. The
excipient is usually assigned to an expert group and the secretariat will identify the
excipient manufacturers. The excipient suppliers are then asked to provide specifications,
test methods, and samples from which the expert group will develop a draft monograph for
public review by publication in PharmEuropa and subsequent approval by the European
Pharmacopoeia Commission. Upon approval by the Commission, the excipient is added to
Ph.Eur.
Japanese Pharmacopoeia
In Japan, new excipients are also approved as a consequence of the approval of a drug
product application containing the excipient. The pharmaceutical manufacturer makes an
application through a prefectural office to the Pharmaceuticals and Medical Devices
Agency (PMDA). If the drug formulation contains an excipient with no precedence of use
in Japan, the application goes to the Subcommittee on Pharmaceutical Excipients of the
Central Pharmaceutical Affairs Council (CPAC). Their review of the quality attributes and
safety of the excipient is done concurrently with the drug product approval conducted by
the Subcommittee on New Drugs of CPAC. The Subcommittee reports are used by the
Evaluation and Licensing Division to approve the drug product. Once the drug product has
been approved, the Japanese Pharmacopoeia can consider the addition of a monograph.
New and Novel Excipients not listed in a Pharmacopoeia

An ingredient can be used in a pharmaceutical product as an excipient even when there is
no monograph for the material in a compendium. Regulatory authorities require a full
safety and toxicological evaluation10, 11,12,13. Once a regulatory authority has approved a
drug application containing such an excipient, that excipient is generally considered
16
USP-NF General Notices subsection Official and Official Articles, fourth paragraph.
17
USP-NF <1225> Validation of Compendial Methods

acceptable for the same route of administration up to the same level of use providing the
same specifications are met as those used in the previously approved drug.
For new excipients a toxicological assessment should be made to demonstrate the safety of
the material in the intended pharmaceutical application at the specified use level. The USP-
NF Excipient Biological Safety Evaluation Guidelines <1074>12 provides guidance on
conducting a safety assessment for a novel excipient. In the U.S., the FDA has also issued
guidance on non-clinical studies for new excipients10.
When new excipients are developed and being used in an approved drug, the manufacturer
may request that a monograph for the excipient is added to the compendia. “The purpose of
a pharmacopoeial excipient monograph is to provide standards to assure the excipient’s
quality in pharmaceutical use.” “The tests, procedures, and acceptance criteria for an
excipient specification should address: appearance, identity, chemical purity,
microbiological purity, physical characteristics (e.g., optical rotation), packaging, labeling,
and storage.”18
Generally an excipient monograph contains the following information19:

• Monograph Name: The name by which the excipient will be primarily found in
the compendia,
• Official Title: The name by which the excipient is generally known in industry,
• Definition: The acceptance criteria for the assay often expressed as a percentage
range,
• Packaging and Storage: Special packaging or storage conditions necessary to
protect the excipient,
• Labeling: Special requirements for labeling to differentiate various grades of the
excipient such as by molecular weight or listing of additives present,
• Description: The excipient is characterized as to chemical structure, molecular
weight, physical form, and solubility,
• Identification: There should be a test or tests that confirm the identity of the
excipient,
• Composition: There should be specific tests, where possible, for concomitant and
other components especially for those above 0.1%. There should be tests, where
appropriate, for organic, inorganic and heavy metal components as well as
residual solvent(s),
• Assay: There should be a test to quantify the excipient content, where possible,
and
• Other tests: Where further characterization is needed, other tests such as pH,
preservative content, or bacterial endotoxin should be recommended.
The European Medicines Agency (EMEA) also requires for excipients not in the Ph.Eur.20:
• Physical Characteristics
• Tests for parameters that may influence the performance in the dosage form
called functionality-related characteristics.
18
Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, page 67 October 8,
2003
19
Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, pp 57-64 October 8,
2003
20
The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use, Note
for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for
Marketing Authorisation of a Medicinal Product, (DRAFT) CPMP/QWP/419/03, February 2003

This list is not exhaustive but is intended to provide preliminary guidance on the content of
a proposed monograph.
In addition, the manufacturer will have to submit information about the appearance and
solubility characteristics of the new excipient. This information appears in a separate
section of the USP-NF. In Europe, the user will also have to justify the specifications for
the excipient. For new or novel excipients, there should be documentation in accordance
with their “Guideline on The Chemistry of New Active Substances”21.
Other regulatory requirements

Although the monographs specify the characteristics an excipient must meet in order to be
used in pharmaceutical applications, there are other requirements which can be found in the
General Notices and/or General Chapters and which can apply if the criteria are met. Some
of these are described in Section 2.3.6.
2.3.4 Desired Properties for Intended Use

The initial step in bringing a new excipient to market is to determine its functionality as
required in the manufacture, administration, identification, or stability of the intended drug
product.
Suppliers may have a range of data available describing the functionality of their materials
if they have been used in other applications, e.g., food, cosmetics. This information can be
valuable to pharmaceutical users as it will help define the functionality and to some degree
the safety profile of the excipient. Some of this data and knowledge can be considered
proprietary. If it is to be shared with excipient users, suitable confidentiality agreements
may need to be drawn up.
For genuinely new materials that are to be used as excipients, the corresponding data would
need to be generated to show the utility of the material in the intended applications.
2.3.5 Excipient Master Files and Other Filings

A Drug Master File (DMF) is a compilation of technical details related to the manufacture
of the excipient and is formatted so that it is aligned with the ICH Common Technical
Document (CTD) format for easy future application. The DMF typically includes
specifications and test methods for raw materials, in-process testing, and the finished
excipient product, a complete description of the manufacturing process, safety data,
packaging details, and label content.
In the U.S., an excipient supplier will often submit a DMF to the Food and Drug
Administration to provide confidential information relative to the excipient, its safety, and
conformance with appropriate GMP requirements. A similar system of DMF exists in both
Canada and Japan. In Europe, for materials where a Certificate of Suitability is not
available, such confidential information needed to support the drug product filing by a
pharmaceutical manufacturer must be supplied directly to the user for inclusion in their
marketing authorization, using confidentiality agreements where necessary.
United States Drug Master Files

Submission of an excipient Drug Master File (DMF) to the FDA is not required by law or
FDA regulations22. A Type IV DMF for Chemistry, Manufacturing and Controls (CMC)
21
The European Agency for the Evaluation of Medicinal Products, Guideline on The Chemistry of New Active
Substances, CPMP/QWP/130/96/Rev 1, February 2004
22
FDA Guideline for Drug Master Files, September 1989.

information, or a Type V DMF for excipient safety information can be used to submit this
type of data. The DMF may be used to support an Investigational New Drug Application
(IND), New Drug Application (NDA), Abbreviated New Drug Application (ANDA),
Biological License Application (BLA), Veterinary Drug Application, another DMF, or an
Export Application. The FDA assigns a unique number to the DMF but does not approve or
disapprove them. The FDA maintains the DMF as a confidential document that cannot be
referenced by third parties without the written agreement of the excipient DMF holder.
The FDA references the DMF only in conjunction with their review of a submission or
application to the FDA in the form of a drug application (IND, NDA, ANDA etc.). The
review occurs when the excipient DMF holder has given the drug formulator permission to
reference the DMF in their drug filing to the FDA. In the FDA review of the drug filing,
when the agency requires details concerning the manufacture of the excipient, the FDA will
review the information in the DMF. The excipient DMF holder has the obligation to assure
the content of their DMF remains current and should update the DMF on an annual basis or
indicate to the FDA that no changes are required.
IPEC has issued a guideline that describes the organization and composition of an excipient
DMF23.
These types of systems are also being considered in other regions at this time and could be
implemented elsewhere in the future.
European Certificates of Suitability (CEP)

The system in the European Union (EU) is somewhat different from other areas. There are
three types of marketing authorization procedures for drug products which use DMFs or
CEPs as applicable:
1. Centralized (submission to the European Medicines Agency EMEA, London, UK
obligatory for biological and biotech products, certain therapeutic indications and
open to innovations), two countries identified as rapporteur and co-rapporteur each
evaluating the dossier.
2. Mutual Recognition Procedure (MRP - submission to and approval by one EU
member state which then becomes the reference country for extension within the
EU).
3. Decentralized procedure (submission to all EU countries desired, one of them
identified as the reference country. The procedure is similar to, but quicker than,
the MRP).
No matter which procedure applies, pertinent excipient data must be provided directly to
the pharmaceutical company for inclusion in their drug product dossier. It is recommended
that it be provided under a suitable confidentiality agreement.
Although a DMF system exists for drug substances (APIs) at this time this system is not
available for excipients.
There are two types of CEP; the “ordinary” one can be obtained by excipient manufacturers
for an excipient described in a Ph.Eur. monograph by submitting a file using the Common
Technical Document (CTD) format to the European Directorate for the Quality of
Medicines (EDQM) in Strasbourg, France. The CEP acts in much the same way as a U.S.
Type IV Drug Master file and allows the excipient supplier to retain confidential
23
IPEC-Americas, Excipient Master File Guide, 2004.

information which is not shared with the excipient user. These Certificates of Suitability are
not available for excipients for which there is no monograph in the Ph.Eur.
A second type of CEP exists to document that there is no potential concern about
Transmissible Spongiform Encephalopathies (TSE; including Bovine Spongiform
Encephalopathy - BSE) which is open to APIs and excipients (even those without a
pharmacopoeia monograph). Granting the CEP indicates that the excipient is of low or no
risk of transmission of TSE to humans through the drug product.
Japanese Drug Master Files

In Japan the drug product application is submitted to the regulatory authorities by the
pharmaceutical company typically containing all relevant details concerning the excipient.
The new excipient Drug Master File system in Japan can be used in certain circumstances;
however this system is still undergoing some changes to allow it to be used for all types of
excipients and applications. Currently, this system can be used fairly easily for individual
excipients. However, it is not designed to easily handle multiple excipient grades or
combinations of excipients which are part of a range of products that comprise an excipient
family. Since a unique file would be needed for each formulation or grade, this makes the
system somewhat burdensome.
2.3.6 International Conference on Harmonisation (ICH)

The International Conference on Harmonisation (ICH) was organized to develop uniform
global requirements for various technical aspects of pharmaceutical product registration.
ICH has approved guidance documents on the technical requirements for drug products
containing new ingredients. While the focus is primarily on the dosage form and active
ingredients, several of the guidelines have an impact on excipients and can affect the
marketing of an excipient. Excipient suppliers should familiarize themselves with the
following two documents as pharmaceutical customers will expect to see compliance to
these guidelines.
2.3.6.1 Q3A, Impurities in New Drug Substances

ICH has issued the Q3A guideline24 for drug substances which recommends steps
for qualifying impurities in the active pharmaceutical ingredient. Since such
materials when found in excipients are often beneficial to excipient performance,
they are referred to as other components. While ICH Q3A guideline is not
specifically intended for excipients, it is suggested that other components which are
potentially harmful or do not contribute to the performance of the excipient are
identified and reported using the provisions of the guideline. Where appropriate,
consideration should be given to establishing specification limits for certain other
components. It is suggested that a composition profile3 is developed so that:
• The potential for drug interactions with other components can be
determined by the user.
• The impact on the composition can be assessed following changes to:
o The Manufacturing Process
o Raw materials
o Packaging
The composition profile defines all components that comprise the excipient.
2.3.6.2 Q3C, Impurities: Guideline for Residual Solvents
24
ICH Q3A, Impurities in New Drug Substances, http://www.ich.org/LOB/media/MEDIA422.pdf

ICH has also issued the Q3C guideline25 on residual solvents which lists various
organic solvents in one of four classifications. They include solvents to be avoided,
solvents to be limited, solvents with low toxic potential, and solvents for which no
adequate toxicological data was found. The presence in the excipient of any solvent
listed in the ICH guideline should be within the limits specified in the guideline for
the intended application. However, it is important to note that these levels are for
the presence of the stated solvent in the finished dosage form and not in the
individual excipient ingredients. Therefore, in calculating the maximum allowable
residual solvent level in the excipient, the intended use concentration of the
excipient in the finished dosage form along with other sources of the listed solvent
must be taken into account. Residual solvents should be limited as much as
possible in the excipients so that they are below those listed in Q3C or are present
only very low levels in the drug product. This will then reduce or limit the need for
routine testing of residual solvents in the drug product, except for those used in its
manufacture. If the level of residual solvent exceeds those in the Q3C guideline,
the manufacturer should measure and report the quantity of the residual solvent in
each lot of excipient and report on the COA. In the absence of information
concerning the usage level of the excipient in the drug product, the levels in Q3C
should be adopted.
This ICH guideline for Residual Solvents has been adopted by the Ph.Eur. as
Chapter 5.4, and the USP has replaced the General Chapter Organic Volatile
Impurities <467> with the Q3C text which is now General Chapter Residual
Solvents <467>.
2.3.7 Specific Safety Issues

Depending on applicability, excipient suppliers should have knowledge of and control over
the following aspects of excipient quality since they may also have implications for end
user safety:
• Origin of raw materials
o Animal derived materials lead to concern for issues related to BSE or other
TSE which can restrict acceptance. Issues may also arise if raw materials are
derived from certain other natural substances (e.g. peanuts) since some of these
materials can lead to allergic reactions in the patient. Finally, concerns may
arise about excipients produced from genetically modified organisms (GMOs)
such as corn (maize) or soy products. These issues may restrict the acceptance
and use of excipients. It is therefore critical that the excipient supplier
determines and controls the origin of their raw materials.
o Viral safety information may be needed in case of excipient raw materials of
human or animal origin. For such materials, viral safety evaluation study
results may be required. They should demonstrate that materials used in
production of the excipient are considered safe and that the approaches
(methods) used to test, evaluate, and eliminate potential risks during the
manufacturing are suitable.
• Degradation products of the excipient
o For a well established excipient, the excipient supplier will often know how it
changes as a result of atypical processing conditions or due to thermal and
related stresses to which it may be exposed in the supply chain. Such
25
ICH Q3C, Impurities, Guideline for Residual Solvents, http://www.ich.org/LOB/media/MEDIA423.pdf

knowledge should be made available to the user. Where formal stability studies
on the excipient are conducted, such studies can provide similar information
(see Section 2.5.1).
• Presence of catalyst residue, decomposition or degradation products, and process
related components. This is particularly relevant where the catalyst residues are
heavy metals26.
• Inclusion of additives and processing aids
o The presence of additives and process aids in the excipient such as biocides,
anti-oxidants, or stabilizers can lead to safety concerns for the user, and their
selection should be carefully reviewed and assessed for acceptability in the
intended market application. A composition profile should be developed for the
purpose of establishing the presence of process- related components and the
quantity present. The excipient supplier should endeavor to provide a
consistent quantity of these components in the excipient.
While safety issues such as these may be evident in the excipient, it is not suggested that
this precludes their acceptance in all instances. It is important that the original manufacturer
evaluates their effect as part of the regulatory assessment.
2.3.8 Concluding Comments on the Regulatory Assessment

Upon the completion of regulatory assessment, the market minimum requirements should
have been established along with any “regulatory” constraints <1.4>. To proceed with the
introduction of the excipient, the conclusion of the evaluation should be that the material
can be suitably produced for the intended use. If not, the project should be discontinued
<1.5>.
2.4 Manufacturing and Packaging

From the point where GMP starts27, all operations including packaging and distribution should be
conducted in conformance with appropriate excipient GMP or GDP requirements <1.6>.
It is important that the excipient is produced using a manufacturing process that is in a state of
control, often referred to as a capable process. Whether the process is by batch or continuous,
there should be a written set of manufacturing instructions listing the raw materials, operating
equipment, operating conditions, in-process controls, sampling plan, packaging operations,
packaging components, and labeling materials with their content. While dedicated manufacturing
equipment is preferred, multi-use equipment is acceptable provided there is no incidental
carryover of contaminants from the manufacture of another chemical <1.6>.
Packaging operations include steps in the manufacturing process where the excipient may be
exposed to potential environmental contamination, which raises another potential GMP
compliance issue. Suitable controls need to be put in place in this area to ensure excipient quality.
It is recommended that a quality risk assessment is conducted to ascertain the optimum controls in
question <1.7>.
Packaging and labeling materials should also be considered. Packaging materials should be
shown to suitably protect the excipient from potential environmental contamination and
degradation while minimizing potential excipient contamination due to packaging components.
26
See EMEA Note for Guidance Guideline on the Specifications Limits for Residues of Metal Catalysts or Metal
Reagents, EMEA/CHMP/SWP/4446/2000
27
The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006, p 3

The container label should list the following as a minimum:
• The manufacturer’s trade name
• The grade, if applicable
• The manufacturer’s and/or distributor’s name
• The batch number
• Special storage conditions required to assure excipient quality
As required, excipient labeling, which is inclusive of the container label, Certificate of Analysis
(COA)28, and Bill of Lading (BOL)29, should also contain the following:
• The identification of all added substances such as preservatives or antimicrobials,
• Suggested storage conditions other than typical warehousing (ambient conditions),
• Special customer-requested information such as the customer raw material code,
Kosher or Halal compliance, and
• Clear identification of the manufacturing plant site.
This information can be applied either at the site of manufacture or prior to final shipment to the
pharmaceutical customer. For bulk shipments, the label content can appear on a combination of
the Bill of Lading and the vehicle placard (where regulations on showing safety information
permit such additions).
The manufacturing process, including packaging and labeling operations should be evaluated for
their conformance to appropriate GMP requirements <1.8>. The excipient container should be
sealed with a tamper-evident device. Such devices include security tape, embossed metal seals
(for bulk shipments), and embossed bung seals.
2.4.1 Process Capability and Validation

The process for manufacturing the excipient should be capable of producing an excipient
that consistently meets the established specifications. In the chemical processing industry,
this is often referred to as having a capable process <1.9>. Demonstration that a process is
capable is called a validation study in the pharmaceutical industry and often referred to as a
process capability study in the chemical/excipient industry.
Capability is often determined by producing several batches using the manufacturing

instructions. A Process Validation study, a requirement in the pharmaceutical industry,
begins with the preparation and approval of a Process Validation protocol. The protocol
delineates the details of the process validation study including a description of the
equipment, process, sampling plan, and the validation approval criteria. The protocol is
reviewed and approved and then the study is executed. A final report is prepared to
document the study and its conclusions. The report is reviewed and approved by
appropriate quality personnel.
As an alternative to a process validation study, statistical techniques can be used to

demonstrate that the process capability is sufficient so that lot selection of excipient grade
material is unnecessary. A useful and effective means of performing this is to determine the
Process Capability Index (Cp and Cpk). Cp is a statistical measure of the ability of the
process to generate batches near the midpoint of the specification, with numbers greater
than 1.3 being typically deemed “capable”, i.e. a process whose output meets specification
with a likelihood of 99.7%. Cpk is a measure of how far the average value of the process is
from the center of the specification. If it is identical to Cp, then the process is perfectly
centered. Lower values indicate a process that is skewed to one side or the other of the
28
IPEC-Americas Certificate of Analysis Guide for Bulk Pharmaceutical Excipients, 2000.
29
A document used when shipping goods that describes the content of the shipment and accompanies it.

specification midpoint. These studies rely upon the process to be performing with only
random variation. The process capability study should be documented and should satisfy
the requirements to demonstrate that the manufacturing process is in control. This provides
assurance to users that the quality of each batch of excipient will be consistent (see also
Section 5.4).
If the process fails to reliably produce acceptable excipient, i.e. the process capability is too
low, or the process validation failed, the manufacturer should consider modifications to
process parameters and assess controls <1.10>. Since a lower process capability can result
from problems with the test method, an assessment of the analytical methods may also be
needed <1.11>. It is undesirable to select individual lots of material meeting excipient
requirements (see Section 5.4.1). Therefore if the methods are satisfactory and the process
cannot be adjusted to achieve the required process capability <1.12>, the manufacturer
should reevaluate the suitability of using the chemical as an excipient for the target market,
including the route of administration of the dosage form<1.2>. It is not normally acceptable
to increase the specification limits in order to obtain a capable process.
2.4.2 Test Methods and Validation

In conjunction with the development of a suitable manufacturing process, the excipient
producer should develop appropriate Quality Control test methods. Where the excipient is
labeled as conforming to a compendial monograph, these test methods must either utilize
the method described in the monograph or be demonstrated to provide comparable results.
Test methods that do not follow all of the details described in the monograph should be
validated. This requires documented scientific evidence showing the manufacturer’s
method adequately assures the excipient meets the designated monograph specification
parameter.
For excipients listed in a regional compendium, the material is expected to conform to that
monograph when used in that region. If other methods are developed and deemed more
satisfactory, they must be validated against the compendia method and found to be
equivalent to or better than the compendia method. Their use should be justified. It is
important to note that where there is a discrepancy between the results obtained using the
compendia method and the manufacturer’s method, the compendia method is considered
the official result.
Often an excipient manufacturer will develop its own test method for various reasons such
as to provide assurance the excipient meets the intended performance requirements or to
monitor or control the presence of other components. These non-compendial methods
should meet the requirements for an appropriate test method as detailed in the compendia.
Test methods fall into two categories; those which can and those which cannot be validated.
Examples of methods which cannot be validated include measurements, usually involving
physical methods, such as bulk density, viscosity, and refractive index which rely on direct
measurement using calibrated devices. Such methods cannot be validated in the classical
sense.
The other category is for methods which can be validated. There should be a validation
protocol and report for all methods that are non-compendial. The validation protocol should
describe the study in order to show the method is appropriate including such details as a
description of the test method, the equipment, reagents, standards etc. The protocol should
also delineate the test results that must be achieved in order to consider the method
validated. Once the validation has been conducted, there should be a report documenting
the test results and conclusion. Test method validation may include evaluation of items

such as accuracy, precision, specificity, method linearity, ruggedness, limit of detection and
limit of quantitation. ICH Q2 validation guidance30 provides additional details on
validation.
2.5 Excipient Specifications

A specification is a list of tests to be carried out and criteria to be met, in line with the established
substance (or product) monograph (see also subsection 2.3.2 “New (Novel) Excipients”).
Draft or tentative specifications should be developed that are in accordance with accepted
standards and are consistent with the manufacturing process and its process capability <1.13>.
The excipients’ end use should also be considered, e.g., oral, sterile, dermal, in establishing these
specifications. The specifications should include control of the composition (e.g. organic
components, inorganic components, and residual solvents) related to both the raw materials and
the manufacturing process. As necessary, appropriate limits for total microbial counts and
compendial indicator organisms should be established based on the likelihood for microbial
contamination and the ability of the excipient to support microbial growth. If the excipient is
intended for use in parenteral drug products, appropriate limits should also be established for
endotoxins.
Where the excipient is to be a compendial grade, the specification test methods should either
follow the compendial methods as written, or be validated (if appropriate as noted in Section
2.4.2) to demonstrate scientifically that they produce comparable results. If the excipient is not
compendial, then the test method should conform to the general requirements described in
compendia or ICH guidelines on validation of analytical methods. The suitability of all test
methods should nonetheless be verified under actual conditions of use and documented. The
detection limit for each method should be sufficiently sensitive to discriminate between
acceptable and unacceptable material, if appropriate.
The draft specification for compendial excipients should contain specified ranges for all
parameters that assure the excipient meets the compendial requirements. If the excipient is not
compendial, then the specified ranges should assure the excipient meets the technical and
regulatory requirements appropriate to the use and route of administration.
Consideration should be given to the development of specifications that reflect customer

requirements and those needed to assure adequate control of the excipient for its intended use.
The specification should include those properties and specified ranges, within the process
capability, necessary for the excipient to meet the customer’s use requirements.
2.5.1 Excipient Stability

It is important to demonstrate that the excipient remains in conformance with the sales
specification until the end of the re-evaluation interval, retest interval or expiration
period. The excipient supplier should provide data to show stability in the commercial
packaging and defined storage conditions that are intended to protect the excipient from
degradation throughout the supply chain31. If stability data is not available, the excipient
user may have to generate it themselves <1.14>.
Preliminary information can be developed using accelerated stability protocols and

conditions described in the ICH guideline Q1A Stability Testing of New Drug Substances
30
ICH Q2, Validation of Analytical Procedures: Text and Methodology,
http://www.ich.org/LOB/media/MEDIA417.pdf
31
IPEC Stability Guide (in development)

and Products32. Although this guideline was developed for drug substances (APIs) and
drug products it is suggested that the stability of new excipients be evaluated according to
the concepts of the guideline. It is important to determine the length of time the excipient
will continue to meet the established specification in the unopened market package,
referred to as the re-evaluation interval, retest interval or expiration period.
Ideally, the excipient re-evaluation interval or expiration period should be sufficiently long
to allow the excipient user to receive and use the excipient prior to expiry <1.15>. Many
pharmaceutical manufacturers desire excipients with a minimum re-evaluation interval
exceeding one year. However, excipients may be considered suitable with shorter intervals
provided appropriate controls are in place to ensure the excipient is used while in
conformance with the specification. If this is not the case, then special arrangements may
have to be made, for example temperature controlled storage and transportation,
manufacture to order. Alternatively, it may be necessary, where appropriate (and if not a
compendia, safety, or regulatory requirement), to adjust or broaden the specification
range(s) so as to extend the re-evaluation interval or expiration period if possible <1.16>.
If the excipient is not sufficiently stable for the intended application, a study should be
conducted to assess the possibility of improving the excipient stability <1.17> through
process adjustment <1.12>. However, it is necessary to ensure the excipient continues to
meet the expected technical and regulatory requirements. If the excipient stability cannot be
sufficiently improved, it is unlikely the excipients would be accepted in the market place,
and the manufacturer would be advised to re-consider their strategy <1.2>.
Ideally, samples of three commercial lots of the excipient should be used to establish the
stability of the excipient in the commercial package. Samples of the excipient from these
lots should be stored in commercial or worst case packaging material under the
recommended storage conditions31 (see the Stability Guide for more details). Periodically,
excipient should be sampled from the three lots and tested for conformance to the sales
specification and/or stability indicating tests to demonstrate continued conformance
through the stated expiration period.
As an alternative to conducting a stability study under recommended storage conditions,

which will take the full stated expiration period to complete, an accelerated stability study
can be conducted. ICH has issued a guideline Q1A32, which, while focusing on the API and
dosage forms, provides guidance on test conditions also useful for excipients.
In either approach, stability indicating test(s) are desirable to monitor the impact of storage
conditions on the excipient. A stability indicating test method is one where the
measurement is capable of quantifying the degradation of the excipient. In the absence of a
stability indicating method, testing to those parameters that are indicative of excipient
stability and expected degradation (e.g. color) can be used.
3. EXCIPIENT DEVELOPMENT AND SPECIFICATION PROCESS
3.1 Excipient Consistency and Control

Each step of the excipient manufacturing process should be controlled, to the extent necessary, to
ensure that the excipient consistently meets required specifications <1.18>. Various experimental
strategies are available for identification of these operating parameters. One technique to identify
32
ICH Q1A, Stability Testing of New Drug Substances and Products

these parameters is use of a Design of Experiments (DoE) protocol33. Such experimentation can
provide the basis for performing a process capability study to support process validation.
Excipients are normally subject to various in-process tests <1.24> (See Flow Diagram, Phase
One, Page 2) to show that a manufacturing process is in a state of control. Based upon the
operating parameters, a plan for process control should be developed. In-process inspection and
testing should be performed based upon monitoring the process or actual sample analysis at
defined controlled points and times. The plan should identify what in-process measurements
should be made to monitor the process, what measurement techniques will be utilized, where and
how any necessary process samples will be taken, and who will perform the testing (see also
sections 2.4.1 and 5.4).
It is important to identify and set appropriate limits for excipient components. Such components
arise from their presence in raw materials or their development during the manufacturing process
either as by-products or residues from a catalyst, solvent, polymer initiator etc. These limits
should be based upon appropriate toxicological data, or limits described in compendia, as well as
considering the manufacturing processes and reaction chemistries.
The excipient supplier should have sufficient information at this point to evaluate the target
market and use, and confirm that the business potential is sufficient to proceed with excipient
development <1.19>. In addition, the manufacturer should confirm that the process is suitable to
consistently produce a material that meets the market needs. If the information fails to confirm
the market potential, the supplier may decide to discontinue the project <1.20>.
3.2 Performance Indicators

An excipient is included in a drug product because it performs a role in the formulation.
Conformance to monograph requirements or product specifications is sufficient to establish
consistency in the quality of the excipient <1.21>. However such testing may not establish that a
change in the manufacturing process has altered its performance in the dosage form. Therefore for
the purpose of evaluating process changes, appropriate performance indicators should be
established, for the intended target use.
As an example, if the intended target use is solid dosage forms, several tests have been developed
for use in establishing the performance characteristics of the dosage form, such as dissolution
testing and tablet hardness. In this example, the excipient manufacturer might determine a
baseline of these performance characteristics for the excipient in the target dosage form, e.g.
using a model formulation. The excipients’ performance characteristics might then be correlated
with its physical properties such as particle size, particle shape, particle size distribution, specific
gravity, viscosity, the hygroscopic nature of the excipient, etc. It is also possible that these
characteristics might be correlated with the chemical composition such as the level of
concomitant and other components. The excipient manufacturer would be able to evaluate the
impact of a process change by comparing these excipient properties before and after the change to
ensure consistent excipient performance.
Assessing excipient performance is an inexact science. Therefore, for most critical end-use
applications, a strong collaboration with the excipient user is recommended so that this issue can
be addressed.
3.3 Production Specification and Master Batch Record

Specifications for the manufacture and for the sale of the excipient should be developed. As noted
earlier, the sales specification should meet the regulatory and market requirements for the
33
IPEC QbD Guide (in development)

excipient <1.22>. The production specification delineates the requirements that the excipient
must meet to assure not only conformance with the sales specification developed in Section 2.5
but also to assure conformance to regulatory requirements <1.23>. For example, a production
specification may require demonstration that certain other components fall below established
limits which the manufacturer may not wish to disclose to the customer in the sales specification.
Specification limits for certain parameters appearing on both sets of specifications may be tighter
on the production specification to ensure that the excipient continues to meet the sales
specification limit throughout the re-evaluation interval.
For materials manufactured using batch processing, the Master Batch Record should be
developed at this stage. Clear and complete manufacturing instructions help ensure uniform
product quality. It should identify the raw materials, describe the process for manufacturing the
excipient, identify GMP instruments and manufacturing equipment and their operating
parameters, the in-process sampling and test requirements <1.24>, and describe the packaging
and labeling of the excipient.
The Master Production Record documents all of the information needed to produce an
excipient lot/batch. The record confirms the step-by-step progress in manufacturing the lot of
excipient to the Master Batch Record. It should contain records of such items as the lot number
and quantity of all raw materials used, the start and stop time for process steps requiring a
specified duration, measurements made during the process, sampling intervals and test results
where indicated (in-process controls), and the quantity of the excipient produced. For each entry
on the production record there should be an indication of the person recording the information.
Where the excipient is produced using continuous processing, the Master Production Record
should contain appropriate relevant information. The aim is to ensure that the critical processing
aspects are recorded to demonstrate that the batch/lot has been manufactured according to the
planned arrangements. Often this information is contained in log sheets or electronic files which
record the process parameters and measurements on a periodic basis. Such information may be
presented in a Master Process Flow, or a Master Process Log.
3.4 Marketing Materials

A literature package should be prepared for distribution to potential customers. The package
should contain the sales specification (or draft as appropriate), Material Safety Data Sheet
(MSDS), an Excipient Information Package (EIP)34 <1.25>, and technical (promotional) literature
including storage and stability information (as available) <1.26>.
Technical literature should be prepared describing the performance of the excipient for the target
market, intended use, and the intended route of administration. The literature should clearly
identify the material as an excipient and demonstrate the advantage(s) in using the excipient or
the benefit derived from developing a drug formulation using the excipient. All labeling,
technical, and promotional literature should be periodically reviewed to ensure that they are
aligned with the excipient manufacturer’s intended use of the excipient.
Certain excipients may also have been used by drug manufacturers as an API. Such applications
tend to be historic and in some cases the excipient supplier is either unaware of the dual
classification of their product or does not support the materials use as an API. At this time the
legal position is clear, an API should be manufactured according to the GMP defined in ICH
Q735. In the U.S., the manufacturing site is required to be registered with the FDA as a ‘drug
34
IPEC-Americas Standardized Excipient Information Protocol User Guide, 2005
35
ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

manufacturing establishment’ as stated in Section 201 of the Federal Food, Drug and Cosmetic
Act (FD&C Act). In Europe likewise, API manufacturers have to work according to ICH Q7
(elaborated as Part II in European GMPs), and for APIs imported from non-EU countries, GMP
manufacturing must be audited and confirmed. Clearly, this meets or exceeds all requirements for
an excipient. Where it is known that a material has the dual application, the excipient supplier
should clearly indicate the intended application in marketing materials and on labeling.
The excipient supplier should begin to establish a formal system to answer customer inquiries
concerning the excipient. In addition to the information contained in the EIP, the customer may
require additional information on the excipient such as:
• Safety
o Toxicology studies
o Precedence of use
o Human exposure data
o Literature reviews, etc.
o Animal testing
• Regulatory Status
o Details of the regulatory status in specific target countries.
¾ Note: It is the pharmaceutical formulator’s or the pharmaceutical user
company’s responsibility to ensure the excipient meets regulatory
requirements.
3.4.1 Sampling Guidelines

Sampling of excipient ingredients by the user is often critical to their obtaining proper
Quality Control test results. Therefore, the excipient supplier may prepare sampling
guidelines. Such guidelines should begin with an indication as to the homogeneity of the
excipient in the package, as received by the customer. A sampling technique could be
developed based on the homogeneity characteristics of the excipient, so as to assure a
representative sample from the packaged excipient is taken. Where the quality of the
excipient is affected by the sampling technique, such as moisture absorption for a
hygroscopic excipient, additional guidance should be provided.
Traditionally, users have required samples of excipient from at least three discreet
production lots for their evaluation <1.27>. While a customer may evaluate the
performance characteristics of the excipient produced in the lab or a pilot plant, full
evaluation by the pharmaceutical formulator will generally require excipient produced
under appropriate GMP requirements in a commercial scale facility. For excipients
produced in batch processes, it has been common to have these three commercial lots
representing the extremes of the process, so as to demonstrate to the customer satisfactory
performance within the range represented by the excipient sales specification (e.g. at the
limits of one or more critical parameters that define excipient quality). Where such samples
are unavailable, other techniques for assessing the excipient should be used (see Section 4).
The reliance on three lots of a new excipient for validation purposes is now changing. The
Regulatory Agencies, particularly in the US with the introduction of Quality by Design36
(QbD) and the Design Space concept, recognize that three lots may not be the appropriate
number. In this new paradigm, the number of lots and the scale of manufacture required to
allow the evaluation of a new excipient should be scientifically justified. It may be that
three lots are adequate under certain circumstances. However, it should be anticipated that
more than three lots may be required for some projects. In any case, the excipient
36
See ICH Q8, Pharmaceutical Development. http://www.ich.org/LOB/media/MEDIA1707.pdf

manufacturer should plan to have available at least three lots manufactured at a scale that
adequately represents the final manufacturing scale for initial customer trials.
Preparation of distinct lots of excipient should be part of the marketing plan for the
introduction of the excipient to the pharmaceutical market. For batch processes, there is not
usually an issue with defining what constitutes a discrete batch. However, where
continuous processing is used, what constitutes distinct lots can be open to interpretation.
Careful consideration should be given to the manufacture of the representative lots that
should wherever possible, encompass the full range of acceptable material within the
process capability.
3.5 Customer Feedback

Often the customer will commence trials upon the satisfactory completion of the technical inquiry
and evaluation by their pharmaceutical development personnel. Feedback from these trials
<1.28> may identify the need to change the manufacturing process and/or the production or sales
specification for the excipient. This may lead to an iterative process of additional customer trials
followed by process modifications. Customer feedback can also identify the need for changes in
the packaging and or labeling of the excipient <1.29>.
If the customer trials are satisfactory, the specifications should be finalized. If the trials are
unsatisfactory and specifications need to be revised, then additional samples should be provided
to the customer <1.27>, along with the revised sales specification, <1.23> and with a request for
their feedback <1.28>.
Once the customer feedback is satisfactory and no further changes in the specifications are
indicated, a Quality Agreement Documentation Package should be developed <1.30>. The
Quality Agreement Documentation Package should contain the Sales Specification, Certificate of
Analysis (COA), technical literature (3.4), sampling guidelines (3.4.1), and Excipient Information
Package (3.4) which includes stability/retest and expiry information (2.5.1). The COA format and
content should be established as described in the IPEC-Americas Certificate of Analysis Guide
for Bulk Pharmaceutical Excipients28.
3.6 Post Product Launch

Often an excipient product is launched with only a small number of lots produced <1.31>. As the
manufacturer gains production experience, their ability to produce conforming material increases.
Thus, the manufacturer should reevaluate the process capability after approximately 10 lots and
again after about 30 lots <1.32>, using this information to adjust the Quality Agreement
Documentation Package, specification etc. accordingly <1.33>. It is desirable for there to be an
ongoing assessment of process capability.
3.7 Confidential Information

As noted in 2.3.5 (Drug Master Files), formulators require detailed manufacturing and quality
information from the excipient manufacturer for inclusion in their drug registration
documentation. Excipient manufacturers often consider some of this information to be
confidential. Therefore the excipient manufacturer should consider how this confidential
information will be made available for regulatory review<1.34>. There are essentially two
possible ways to provide this data to the regulatory agencies:
• the first is to provide the detailed data to the dosage form manufacturer directly
after they have agreed to keep the subject information confidential <1.35>, and
• the other is to make a regulatory submission where a suitable system exists (see
2.3.5 e.g., Drug Master Files in the U.S., Japan and Canada and CEP in Europe)
<1.36>

It should be noted that for countries that have a Mutual Recognition Agreement with the
European Union, reference to the CEP may be made in regulatory filings.
The subject of confidentiality agreements is normally addressed by the legal department of both
parties and will not be further addressed in this guide.

PHASE TWO: THE USER’S PROCESS
4. ASSESSMENT, SELECTION AND SPECIFICATION PROCESS
4.1 Project Initiation

The excipient user will typically initiate a formulation project when they have identified a
business opportunity that requires formulation design and development. Such needs could include
a new active pharmaceutical ingredient (API), reformulation of an existing product, a formulation
for a product line extension, development of a generic equivalent, or identification of an
alternative supplier for an existing grade of a pharmaceutical excipient <4.1>. The type of project
will determine the composition of the project team with the objective of developing the new drug
or approving a new supplier.
4.2 New Formulation Development Projects

For new formulation development projects, the project is often initiated by forming a project team
with the objective of developing the new drug product. The project team will have responsibility
for defining the business opportunity for a marketing application for the intended therapeutic use
<4.2>. The first decision prior to finalizing the team is whether the project is a drug or
formulation development project <4.3>. If it is not either of these, then the project involves the
selection of an alternative supplier (see Section 4.3)
With the business opportunity identified, the project team is formed and identifies route of
administration, dosage form, and target market taking into account the difference in the various
geographical regions <4.4>. Once the route of administration is decided, the team can then
determine the various strengths for formulation. At this stage the project team should carefully
assess formulation constraints and opportunities that could impact the quality and performance of
the product at later stages. Quality by Design principles should be applied as early in the process
as possible.36
The project is assigned to a formulation scientist (or team) who is tasked to identify the functional
requirements necessary to incorporate the API in the dosage form so as to deliver the API to the
patient with the desired therapeutic effect <4.5>. Excipients will be expected to provide various
functions in the dosage form or it’s processing, including, but not limited to:
• Binder
• Compression Aid
• Disintegrant
• Color/Flavor
• Filler
• Sweetener
• Lubricant
• Preservative
• Glidant
• Suspending/Dispersing Agent
• Humectant
• Buffer
• Coating/Film Former
• Identity through printing with ink
• Release Modifier
• Adhesive
• Penetrant
• Vehicle
• Thickener

• Solvation
The use of combinations of excipients in formulations is common since typically no one excipient
can provide the complete range of functions necessary to produce the desired dosage form.
Excipients:
• “aid in the processing of the drug delivery system during its manufacture,
• protect, support or enhance stability, bioavailability or patient acceptability,
• assist in product identification,
• enhance any other attribute of the overall safety, effectiveness or delivery of the
drug during storage or use.”38
The use of excipients of multiple functionality in the formulation may result in simplification of
the drug formulation design stage since there are fewer excipient suppliers to assess and monitor.
The use of fewer excipients may simplify the manufacturing process at the small scale. However,
scale up to commercial manufacture may require additional excipients not required in the initial
formulation design studies.
4.2.1 Selecting the Excipient

Once the formulation team has identified the excipient functionalities that are needed for
the dosage form, they will then develop a list of candidate excipients that meet the project
requirements (functionality, etc.) <4.6>. The list will be developed from various sources
such as the company formulary of excipient ingredients, excipient manufacturers’ literature,
and technical articles. At this stage, it would be expected that for each desired function, the
list contains multiple excipients.
There are several benefits in working with an excipient that has been used by the company
in other products. Knowledge will have been gained about the sampling and testing of the
excipient for incoming Quality Control approval. The company will have experience with
handling the excipient in a safe manner and minimizing the risk of cross contamination.
The proper storage conditions for the excipient will also have been established, as well as
the retest interval for the excipient. Finally there will often be information related to the
cleaning of utensils and equipment after their use with the excipient.
Once the list of excipients has been assembled, the formulator will determine those most
appropriate for use with the particular API. Final excipient selection will include an
assessment of their prior use within the company <4.7>, and could include:
• Name of approved suppliers,
• Identity of the dosage forms where the excipient has been used,
• Functionality the excipient provides to the dosage form,
• Excipient use level in the dosage form,
• Number of years the supplier has been providing the excipient, and
• Performance history of the excipient supplier.
Other factors to consider include:

• Confidential Disclosure Agreement (CDA),
• Price,
• Manufacturing capacity,
• Supply chain,
• Special requirements, such as minimum order quantity or lead time,
• Packaging available,
38
The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006, p. 3

• Technical competence,
• Quality Assurance systems,
• GMP conformance,
• Audit findings, and
• Source (site of manufacture)
The information gathered for each candidate excipient is used as a preliminary screen to
rank the excipients in order of desirability for use in the formulation. The preferred
candidate excipients should be compatible with the API39, and be considered capable of
providing the desired functionality at an acceptable use level.
Excipient compatibility studies are conducted at elevated temperatures so as to get quicker

indications of physical and chemical interactions with the API. Such interactions may
adversely affect the stability or manufacturability of the drug product. Examples of such
incompatibilities are:
• Detrimental physical interactions exemplified by binding of the API to the
excipient so as to make it unavailable to the patient;
• Interaction between the API and excipient such that the integrity of the API cannot
be maintained and an adequate product shelf-life cannot be achieved,
• Detrimental physical interactions that may result in inadequate ability to
manufacture the dosage form,
• Compromised performance of the finished product, and
• Interference with the ability to measure the presence of the API in the dosage form.
Chemical interactions generally result in new chemical entities that are usually classified as
degradants. If there is no alternative excipient, these degradants must be characterized and
evaluated for safety. Where appropriate, limits are assigned to the degradant.
4.2.2 Selecting the Supplier

If it is determined that there are no candidate excipients to provide the desired functionality
that have a prior use within the company, then other candidate excipients will be considered
<4.8>.
Where the candidate excipient has no history of use at the drug manufacturer, the
purchasing department will usually be asked to obtain certain information from each
supplier of the excipient <4.9>. This information may include, but is not limited to the
following:
• Excipient Information Package (EIP)34 from the manufacturer and where
appropriate, the distributor. This document would include:
o The supplier’s commitment to conforming to appropriate excipient GMP
requirements,
o Characterization of the composition of the excipient,
o Regulatory information,
o Description of the excipient manufacturing process and facility,
o Site and supply chain security measures, and
o BSE/ TSE and allergen information/certifications.
• Technical information supporting the functional performance of the excipient. Such
information may include:
39
Moreton, RC, Excipient Interactions, in Excipient Development for Pharmaceutical, Biotechnology, and Drug
Delivery Systems, edited by Katdare, A and Chaubal, MV, (EDs), Informa Healthcare, New York, 2006, 93-108

o Data showing the performance of the excipient in achieving the desired
functionality in model formulations and
o Studies showing the stability of the excipient under model drug product
processing conditions.
• Understanding the origin and handling of excipient samples
• Understanding the full supply and distribution chain2, and
• Pricing and availability at the intended manufacturing site
Experience from working with previously known excipient suppliers is a benefit since the
company will have had experience with:
• Supplier’s order entry process,
• Delivery performance,
• Certificate of Analysis (COA),
• Suitability of information (e.g. conformance to IPEC guidelines28, 40),
• Reliability of the supplier’s measurements,
• Packaging,
• Labeling,
• Tamper evident seals,
• Supply chain security measures,
• Conformance to appropriate GMPs, including prior audit history,
• Established supplier profile in the organization, e.g.
o minimum order quantity,
o order lead time, payment terms, etc,
o delivery performance, ability to meet delivery requirements, and
• Reliability of the supplier’s measurements reported on the COA.
Such factors may allow the excipient user to go to reduced testing of the incoming
excipient more quickly, where justifiable.
Previously qualified suppliers should have been audited by either the user or a suitable third
party and should be on a re-audit schedule. IPEC has issued a guideline suitable for
conducting audits for conformance to IPEC-PQG excipient GMP requirements41.
For new suppliers all these issues would need to be addressed as part of supplier
qualification, a process that is likely to be undertaken in parallel with the evaluation of the
excipient in the intended formulation.
Users should generate audit information through site visits, either using their own audit
resources or qualified third party audit providers, for all excipients and their supply chain.
Questionnaires should not be used as a substitute for on-site assessment. The user should
evaluate this audit information (audit report and site response) to confirm the suitability of
the site Quality System and excipient quality for the intended purpose.
The project is now ready to proceed to the suitability assessment step. The candidate
excipients are evaluated for their compatibility with the API and therefore samples of the
candidate excipient are needed. If the excipient has a history of prior use within the
company, samples are usually available or will be requested <4.10>. For those excipients
not in the company formulary, once the information from the supplier has been reviewed
and the supplier has been found to be conditionally acceptable, the formulator requests
40
IPEC-Americas Significant Change Guide, 2005
41
The Joint IPEC-PQG Good Manufacturing Practices Audit Guide for Pharmaceutical Excipients 2007

samples of the candidate excipient. As noted in the Phase 1 portion of this guide, the
formulator will need samples representative of the typical commercial excipient.
With samples of the excipient on-hand, assessment of the compatibility of the excipient
with the Active Pharmaceutical Ingredient can proceed <4.11>.
At this stage of the drug development process, it is critical to inform the excipient supplier,
who should then inform the manufacturer as appropriate, that their excipient is being
considered for use in a new drug application <4.12>. There is considerable benefit to the
excipient user in providing as much information as possible about the new drug application.
The excipient supplier may have the expertise to:
• Acknowledge the excipient is suitable for the intended route of administration and
geographical region,
• Assure the excipient is available in the quantities anticipated,
• Confirm the excipient is stable under the expected processing conditions,
42
• Provide information on the excipient composition profile to the user, where
appropriate, and
• If possible, discuss the reactivity of the excipient to provide information useful to
assessing excipient compatibility with the API and other ingredients, etc.
The technical information assembled is used to assess the appropriateness of the excipient
for the intended use <4.13>. The formulation team would consider all the information
available from the pre-formulation assessment to confirm that the excipient remains a
viable candidate for inclusion in the drug product.
4.2.3 Regulatory Assessment

While the formulator evaluates the sample of the excipient, personnel with appropriate
excipient regulatory expertise confirm that the excipient is acceptable for use in the
formulation<4.14>. This will involve an assessment of the excipient regulatory status in the
intended markets. This assessment should confirm the excipient is permitted in the target
dosage form or route of administration, and that the expected quantity of excipient to be
used in the new drug product is within the maximum quantity previously approved in such
applications <4.15>. Otherwise the formulator can expect the Regulatory Authorities to
request additional safety data.
In conjunction with the excipient supplier communication <4.12>, the regulatory

department would want to know how the excipient manufacturer would convey pertinent
information regarding Chemistry, Manufacturing, and Controls to the regulatory agencies.
In countries where an excipient Drug Master File (DMF) system is available and the
excipient manufacturer has filed a DMF, the excipient manufacturer can then inform the
regulatory agency via an appropriate DMF reference letter that allows the agency access to
view the DMF in response to a specified drug filing by the pharmaceutical manufacturer.
Where the excipient manufacturer has not filed a DMF with the regulatory authority or in
markets where an excipient DMF system is not available, the user can require a
commitment from the excipient manufacturer to supply appropriate information under a
confidentiality agreement. Whether a DMF has been filed or not, the excipient
manufacturer should be prepared to address requests from the drug manufacturer for
additional information. In the United States, a DMF is not necessary for excipients
complying with a monograph in the USP-NF; however, many excipient manufacturers do
maintain DMFs for their compendial excipients for other reasons.
42
IPEC Excipient Composition Guide (in development)

In Europe a supplier can apply for a European Certificate of Suitability (CEP) from the
European Directorate for the Quality of Medicines (EDQM) where there is a monograph in
the European Pharmacopoeia. The CEP confirms that the European Pharmacopoeia
monograph is adequate to control the excipient. Where a CEP has been issued, this helps to
confirm that the excipient is suitable for use in the European region and serves the same
purpose to suppliers and users as an U.S. DMF. For those materials for which BSE/TSE
precautions are required, a special CEP is available and this is applicable to any excipient,
regardless of whether or not it has a monograph in the European Pharmacopoeia.
At this stage of the drug development process, the formulation team would assemble all of
the information for review <4.13> to confirm that it is appropriate to proceed with
formulation development using the candidate excipient <4.16>. This review would be both
a technical (including pre-formulation <4.17>) and regulatory assessment to show that the
formulation would provide the intended therapeutic effect and would be likely to receive
regulatory approval. With positive indications for both aspects of the assessment, the drug
manufacturer would develop a list of preferred excipients for use in the desired formulation
<4.18>. Where the assessment indicates an excipient in the formulation may not provide
the desired performance or may prove to be incompatible, the formulation work would
revert to a review of other excipients available <4.7>. If no other excipients are suitable,
then the formulator proceeds to identify potential excipients not already in the formulary
<4.8>.
4.2.4 Refining the Excipient List

At this stage in the formulation development process, if no excipients have been identified
that provide the desired functionality in the formulation, or if technical and regulatory
problems are identified; the formulation team should re-evaluate the feasibility of the
project scope by referring back to <4.2> or <4.16> as appropriate. Where the list contains
several excipients that can provide the desired functionality, the list of excipients should be
refined to develop a short list of excipients <4.19>.
Where the excipient list contains multiple items, the formulator or team would prioritize
and screen the excipients using the information available. The evaluation criteria may
include at this stage <4.20>, excipient:
• Stability,
• Storage conditions,
• Supplier testing to user specifications,
• User confirmation of supplier COA,
• Global regulatory acceptability,
• Availability of supply local to the proposed drug manufacturing facilities (e.g.
import restrictions),
• Supplier Quality Assessment information,
• Supplier GMP conformance (based upon qualified audit information),
• Labeling issues,
• Issues involving tamper-evident seals,
• Supplier agreement to notify in the event of significant change,
• Regulatory constraints, and
• Cost considerations.
A comparison of the listed excipients using the above criteria would be expected to identify
the preferred excipient(s).
A business decision is often made concerning the need for multiple suppliers of the
excipient <4.21>. Where more than one supplier is desired, the formulator would determine

if samples from alternative suppliers are available for evaluation. If suitable samples are
unavailable, the formulator would request samples.
The final step at this stage of the dosage development project is to perform a risk
assessment to select the excipients and processing method with the best likelihood of
success for the project <4.22>. This assessment should include a review of the results from
either an on-site or qualified third-party audit, including distributors. If other assessment
techniques are used, they should be justified43. If the likelihood of success is unacceptably
low, the project would ordinarily either be cancelled, or the project’s scope would be
changed <4.23>.
4.2.5 Formulation Design, Development, and Optimization

Initial formulation and process design studies may cover a broad range of excipients used
in a number of trial formulations <4.24>. At this stage the emphasis is to find at least one
formulation that meets the target profile. Once suitable formulations have been identified
and assessed for potential use, the project can progress to formulation and process
optimization.
QbD is an approach to designing and developing formulations and manufacturing processes

to provide optimum product quality. QbD facilitates the understanding and control of the
formulation and manufacturing process variables that affect the quality of the drug product.
QbD begins with the pre-formulation assessment (e.g., excipient compatibility), and
continues with the development of a drug formulation having the required performance
characteristics to meet the expectations of the regulatory agency, patient or caregiver. QbD
typically leads to the following stages of the development process:
1. Definition of the target product quality profile to meet expectations
2. Design and development of product and manufacturing process to meet the target
product quality profile
3. Identification and understanding of:
a. critical raw material attributes,
b. critical process parameters, and
c. sources of variability.
4. Monitoring of the process and adjustment within normal variation of process
variables (as identified in 3 above) to produce consistent product quality, leading to
appropriate in-process controls.
QbD properly executed leads to an understanding of the Design Space, which is the range
of input variables within which the process can operate and still produce conforming drug
product. These input variables include raw materials as well as equipment operating
parameters. The Design Space may be determined through such techniques as Design of
Experiments (DoE)33.
The process for finalizing the drug formulation begins with a review of the decision
whether alternative suppliers are required or that single sourcing is acceptable <4.25>. If
the decision is made to seek alternative suppliers, then the process returns to identifying
suppliers and requesting samples <4.34> (see Section 4.3).
In either event, samples are obtained from multiple lots of the excipient from the candidate
suppliers <4.26>. The pharmaceutical manufacturer prefers samples that represent the range
of specification properties and performance expectations that result from the excipient
manufacturing process capability. While desirable, it may not be possible for the excipient
43
GMP paper audits or EIP Site Quality Overviews alone are insufficient for this purpose.

manufacturer to provide such samples, particularly with excipients manufactured by
continuous processing, but also sometimes with excipients produced using batch
processing. Other options for such investigations can be considered; for example the use of
samples from other appropriate pharmaceutical grades, or even non-pharmaceutical grade
samples at the user’s discretion. Nevertheless, multiple lot samples should represent current
excipient manufacturing process variability to the extent possible. To facilitate provision of
proper samples that demonstrate excipient functionality and variability, intercompany
technical discussions should be held.
With proper samples and a well designed DoE approach, a robust formulation can be
developed that will provide an acceptable drug product as long as the excipients used
conform to their sales specification. Representative samples from the excipient lots are
taken and tested for conformance to the excipient sales specification and where applicable,
the excipient compendial monograph. The multiple excipient lots will be tested using
methods intended to confirm that the excipient will provide the desired performance in the
formulation.
When the testing of the multiple lots of excipient meets requirements, the excipient will be
available for formulation work. Once all excipients and the API have been identified, and
feasibility of the formulation confirmed, formulation development and process optimization
will be initiated <4.27>. In addition, two further simultaneous activities will be undertaken:
the evaluation of excipient test methods, the frequency of testing, and specifications
<4.28>; and the identification of performance indicating requirements and related test
limits <4.29>. As performance indicating requirements and related test methods are
identified, if these are different from those already supplied by the excipient manufacturer,
they should be communicated to the supplier. Evaluation of the excipient manufacturer’s
ability to test against these requirements, and the frequency with which they can do so,
should be understood <4.28>.
Information should flow between technical personnel at the supplier and the user. The
evaluation of supplier test methodology can include discussions with the supplier to gain an
understanding of their release testing and validation activities The supplier should disclose
sufficient details concerning the Chemistry, Manufacturing, and Controls (CMC) relating to
the excipient so that the drug manufacturer can assess the quality and consistency of the
excipient, and to enable development of a pharmaceutical product using QbD concepts. The
dosage form manufacturer should disclose sufficient details of the dosage form so that the
excipient supplier can confirm the selected grade is appropriate for the intended route of
administration and geographical region. The outcome of the discussion between supplier
and user should allow the updating of the specification for the excipient including any
additional requirements <4.30>. Confirmatory testing is performed on multiple lots to
assure that the proposed tests can be performed and the limits can be met <4.31>. This
information is used to develop the draft excipient specification for the intended application
<4.32>. The draft specification is then communicated to the excipient supplier for review
(see Phase 3). Any refinement of performance requirements or specifications <4.33> should
result in modification to test limits <4.29>.
4.3 Alternative Excipient Source Projects

The specification and performance of the excipient will already have been defined in this case
and so the requirement is simply to find an alternative that provides the same functionality.
Having defined the project as not being a ‘new formulation development’ project <4.3>, the
project should be confirmed as an ‘alternate source’ project.

‘Alternative source’ projects may be motivated by a number of reasons:
• Cost savings,
• Addition of further suppliers,
• The existing supplier may no longer be able to supply the material, or
• Business continuity planning:
o contingency plan,
o reduce reliance on a single source for capacity purposes.
Typically, such projects will be undertaken in a commercial manufacturing setting, rather than
R&D. A project team would be organized, and the project goals defined. The team would be
comprised of representatives from several functions, but as a minimum should include
representatives from: Manufacturing, Production Planning, Quality Assurance, Purchasing, and
Technical Services, or Production Support. Representatives from other disciplines may also be
included such as Regulatory Affairs, R&D, and Finance.
An evaluation should be performed to determine the potential interchangeability for the existing
excipient. Based on the results of the evaluation, a decision on the suitability of the supplier(s)
would be made <4.34>. Where there are suitable alternatives, those suppliers would be contacted
<4.35>.
An evaluation of potential alternative suppliers is performed using criteria <4.36> including:

• Competitive pricing,
• Production capacity,
• Suitability of their supply chain,
• User specified requirements,
• Performance history as a supplier to the company and the pharmaceutical industry,
• Suitability of excipient packaging,
• Potential for cost saving,
• Technical competence and support available,
• Appropriateness of the quality system, and
• Conformance of the site to GMP requirements.
If there are discrepancies, or an ideal supplier cannot be found (i.e. meeting all the preferred
criteria for interchangeability, as defined by the Project Team), an assessment of the likelihood of
satisfactorily resolving the issues would be made <4.37>. This assessment would necessarily
include discussions and negotiations with the potential supplier(s) <4.38>. If the discrepancies
can be resolved, the progression of the project will depend on the willingness of the excipient
manufacturer to implement the necessary changes <4.39>. If the supplier is unwilling or unable to
implement the changes, the user company has the option to either seek another supplier <4.40>,
to terminate the alternative supplier project, or explore other options <4.41> (as discussed in
Phase 3). If the supplier will implement the proposed changes, the project progression
could/would be dependent on the final implementation of the changes <4.42> followed by
another evaluation of the supplier <4.36>.
Assuming the evaluation ultimately identifies an acceptable alternative supplier, the next stage
would be to obtain appropriate samples of the excipient from that supplier <4.43>, as necessary.
This may require sample from several lots of the excipient covering the range of material
characteristics seen with the particular grade (see Phase 1, Section 3.4.1).
Once the appropriate samples are available, the project would progress through:
• Laboratory/small scale evaluations (including excipient characterization) <4.44>
• Pilot scale investigations (studies) <4.46>

• Pivotal scale investigations (studies) <4.49>
• Commercial scale investigations (studies) <4.51>, and
• Validation and commercial production (studies) <4.53>.
This list of activities at the different scales of manufacture listed above is not intended to be
followed rigorously. Depending on the nature of the excipient and the type of product being
considered, it may be possible to skip e.g., the pilot scale investigations and/or the pivotal scale
investigations.
Before transitioning from one stage to the next, the results from the current stage would be
assessed <4.45>, <4.48>, <4.50> and <4.52>. If the assessment is satisfactory, the project would
move to the next stage as designated by the Project Team. If there are any issues, the progress and
the project would need to be reassessed <4.47>.
In ‘alternative source’ projects, the ideal is to identify the source of an excipient grade that is
functionally equivalent in all respects to the original source material (interchangeable). However,
this may not be entirely possible, and ‘functional equivalence’ may mean addressing the question,
“What changes in the unit processes are required to produce an equivalent drug product using this
source of the new excipient?”
Since these projects typically concern commercial products, the U.S. FDA’s SUPAC Guidance
(Scale-up and Post Approval Change) will apply to any products manufactured for the U.S.
market. In Europe, the Variations Regulation will apply. There may be equivalent rules in other
regions. The type of product (immediate release vs. modified release), the biopharmaceutical
classification of the API (Biopharmaceutical Classification System Class 1 vs. Classes 2, 3, and
4), and the criticality of the excipient (particularly for modified release products) will all
influence the sophistication of the data required to support the regulatory filing of the change.
Such data may include, but is not limited to:
• Stability,
• Dissolution,
• Bioequivalence requirements, and
• Revalidation of
o Manufacturing and
o Analytical methods.
For modified release products, particularly with a release controlling excipient, it is likely that the
pharmaceutical manufacturer would consider a bioequivalence study at least at the pivotal scale,
even if they have a good in-vitro-in-vivo correlation.
Assuming the project is successful, there will be a need to formally negotiate a Supply Agreement
(see 4.4 below). The precise timing will depend on the organizations involved. However, it is
likely to be before the commercial scale investigations <4.51>. The negotiation process is
covered in Section 5 (Phase 3) of this Guideline.
4.4 Negotiation Process Impact

It is recognized that the negotiation process discussed in Phase 3 may require the re-assessment of
performance requirements and specifications <4.32> or <4.33>. When the need for additional
refinement of performance requirements and specifications is indicated, the process will revert
back to <4.29> for the further identification of performance indicating requirements and test
limits.

PHASE THREE: THE NEGOTIATION PROCESS
5. NEGOTIATION PROCESS
The negotiation process may be invoked for a variety of reasons including:
• New material,
• New grade,
• Updated specification,
• Revision or renewal of an existing Quality Agreement,
• Move to an alternative supplier, and
• Disagreement related to issues discussed in Phases 1 or 2.
Apart from quality of material matters which have been extensively covered in Phase 1 and Phase
2 of this document, the following quality of service issues should also be communicated by the
excipient user and evaluated by the excipient supplier before entering into a supply agreement.
Typically, negotiations will be formally initiated when the excipient user issues a Request for
Pricing (RfP) or solicits a ‘bid’ or ‘quote’.
5.1 Review of Excipient User Requirements

The excipient user initiates the negotiation process by providing written copies of their excipient
specification and any other requirements to the manufacturer or distributor (supplier) <5.1>. The
specifications for the excipient may stipulate either compendial grade, where available and
suitable, or provide specification parameters, test methods, and acceptance criteria for the
specified properties. It is also appropriate to provide the supplier with any other atypical or
important requirements including:
• Minimum order size and number of lots per receipt,
• Remaining shelf life or reevaluation interval upon receipt,
• Special packaging,
• Special labeling,
• Special shipping, or
• Specified manufacturing facility.
The supplier reviews the proposed specifications and other requirements to ascertain their ability
to meet customer expectations using their standard excipient grade <5.2>. An objective technical
review should be conducted by such groups as the Quality Unit, Regulatory, Manufacturing,
Technical Services, etc. Sales or Marketing should not perform this review without subsequent
review by a technical department, since the former have a vested interest in making the sale.
The evaluation of the excipient specifications by the supplier should include review of:
• Specified parameters: to confirm that test data are available,
• Test methods for those parameters: to confirm that those tests can be performed or that
suitable alternatives are available,
• Test results: for the specified parameters,
• Frequency of testing, and
• Conformance statements: usually relating to supply of compendial excipient.
The reviewer can then determine the manufacturer’s ability to reliably supply excipient to the
customer’s specification.
There is agreement on the specifications when the specification proposed by the customer is
congruent with the excipient manufacturer’s specification. Where there are differences in the
customer requirements and the supplier’s standard product, the manufacturer should review their
process capabilities to determine the feasibility of meeting the unresolved customer requirement.

Caution should be exercised in agreeing to meet a customer specification where the known
process capability studies indicate there is a low likelihood of meeting the specification.
A similar review of other customer requirements should be conducted <5.3>. It is important for
the supplier to involve parties with direct knowledge of the ability to meet specified requirements.
By involving such knowledgeable personnel there is increased assurance the supplier will be able
to routinely meet customer requirements. Examples of such requirements are requests for special
packaging, label content, palletizing, floor versus pallet loading, and pallet construction.
Agreement on specifications should be formally documented <5.4>. A written agreement should

be established between the customer and supplier. Where a distributor is used, there must be a
process between the distributor and excipient manufacturer to assure the specifications are
reviewed and accepted by the manufacturer2. It is critical that the specifications are reviewed and
approved by the appropriate technical personnel at the excipient manufacturer to acknowledge
agreement.
If the excipient manufacturer agrees to meet the customer specification and specified
requirements, the supplier would provide pricing to the customer <5.5>. The pricing should
include the cost of supply chain issues such as <5.6>:
1. Product ownership: where the supplier is expected to retain ownership of the excipient
even after the excipient has left the manufacturing site (e.g., consignment stock).
2. Packaging and Labeling:
a. Additional label content such as customer specified product coding and barcodes,
b. Use of unique packaging components such as specified plastic bags and
container/closure materials, and
c. Special size packages or net weight such as bulk containers.
3. Shipping:
a. Special configurations:
• palletizing and shrink-wrap,
• container floor loading, or
• pallet configurations and materials of construction.
b. Minimum order quantity,
c. Lead time: to assure conforming excipient is available to ship,
d. General carriers, specified carriers, or customer pickup,
e. Multiple lot versus single lot shipments,
f. Pre- and Co-shipment samples (if mutually agreed) including:
• how and from where the samples are to be collected (including the sampling
plan),
• the quantity of sample,
• how the sample is to be packaged,
• how they are to be shipped,
• the recipient address, and
• for pre-shipment samples.
o when in the order cycle samples should be provided, and
o whom at the supplier should receive the users approval to ship.
Note: Where the parties agree to such sampling, caution should be exercised to assure
that appropriate GMP requirements are met.

5.2 Quality Agreement
It is good practice for the excipient supplier and user to define and enter into a Quality Agreement
<5.7>44.
The Quality Agreement may cover the following topics, but the inclusion of these or of other
topics is a matter for agreement between the two parties <5.7>:
1. Compliance
• Excipient specifications, including,
a. Additional functional tests,
b. Altered ranges of tests already in the excipient suppliers standard
specification,
c. Alternative test methods either for parameters already in the manufacturers’
specification or for additional parameters, and
d. Microbial test limits.
2. Sourcing,
• BSE/TSE, GMO, allergens, etc. risk assessments,
• Acceptability (as appropriate) of excipient from multiple manufacturing locations,
• Restriction, or allowance, of contract operations such as manufacturing; packaging
and laboratory testing,
• Identification of the country of origin and restriction to specified locations,
• Importation restrictions, and
• Special certifications such as Kosher or Halal approval.
3. Auditing,
• The right of the customer to audit supplier’s facilities and systems at a mutually
agreeable time,
• Confidentiality agreement as required,
• User to issue a written report within a specified timeframe, and
• Supplier to respond to report with a specified timeframe.
4. Notification of changes,
• Conformance to designated quality system,
• Conformance to specified compendia such as USP-NF, Ph.Eur., and JP, and
• Disclosure of regulatory agency inspections and findings.
5. Provide an understanding of the intended use including:
• Route of administration and
• Geographical region.
6. Communication
• Nonconformance
a. Out-of-Specification (OOS),
o Test results to be investigated and documented according to procedure.
• Other Quality Issues,
a. Deviations,
• Documentation of investigation of significant process deviations.
b. Complaints,
• Investigation of complaints involving product quality according to
procedure and communication to the customer,
• Promptly reporting complaints and provision of samples by the customer
as appropriate, and
• Cooperation between both parties in the investigation.
7. Manufacturing, Packaging and Labeling,
44
IPEC Quality Agreement Guide (in development)
• Qualification of manufacturing and packaging processes,
• Validation of cleaning and analytical methods, where appropriate,
• Sample retention, and
• Special labeling requirements.
8. Documentation and Records,
• Certificate of Analysis (COA) to be supplied with each lot,
• Content of the COA,
• Additional information to be included on the COA,
• Use of electronic signatures, and
• Retention period for applicable records.
9. Storage and Distribution
• Documentation in support of recommended storage conditions and retest interval,
• Recommended storage and transportation conditions,
• Storage and shipment in conformance to recommendations, and
• Use of reusable shipping containers.
10. Change Control,
• Handling of change notification such as following the guidance provided by the
Significant Change Guide40.
11. Recalls
• Prompt notification to the customer by the supplier,
• Cooperate of both parties in the recall, and
• Supplier will have a recall procedure that has been demonstrated as effective.
5.3 Modification of Requirements

If the supplier finds they are unable to meet either the customer specification and/or other
requirements, the customer should be promptly notified <5.8>. The supplier should clearly
identify specifications and requirements they cannot achieve and include an explanation as to
why <5.9>. The customer should review the correspondence and seek to clarify any points as
necessary.
Once the customer requirements and supplier capabilities are clearly understood, the parties can
determine what concessions can be made that are acceptable to both <5.10>. The customer
specification would only be modified if the changes are not expected to affect the functionality of
the excipient in the intended dosage form.
If the customer is unable to alter the specification or other requirements, they would then inquire
as to whether the supplier was in a position to make appropriate changes. If the user and/or the
supplier are able to reach agreement on the specification and other requirements <5.11>, an
agreement to supply excipient is achieved <5.4>.
It should be recognized that altering specifications and other requirements can be time
consuming. If the change is made by the user, they must ensure that the change will not alter their
ability to achieve the desired functionality and reliability of supply. If the supplier makes the
change, they must confirm their ability to reliably supply excipient of the specified quality and to
the specified requirements. There will often be considerable internal discussion and data
evaluation by both the supplier and the user before reaching an appropriate decision.
5.4 Identification of Potential Solutions

Where agreement through modification of specifications and other requirements cannot be readily
achieved, then other solutions should be explored <5.12>. The supplier will be requested to work
with the user to develop a solution <5.13>. It should be recognized that the supplier can decide
not to work with the user and exercises their option to walk away from the potential business
<5.39>. For technical and/or business reasons they may be unable to agree to the user
specification and/or other requirements. In that event, the process then proceeds to section 5.5,
Other Approaches.
If the supplier agrees to work with the user, the supplier will assess whether lot selection can meet
the user’s desired excipient quality <5.14>. The supplier identifies inventory that conforms to the
user’s specification <5.15>. This approach is discussed in some detail under Section 5.4.1.
A more suitable solution is custom manufacture, where the supplier either alters the
manufacturing process for the excipient to produce the excipient on demand to meet the user
specification <5.31> or further processes the finished excipient in a custom manufacturing
operation <5.33>. Further processing may be performed where unique solid state properties such
as particle size, particle size distribution, and bulk density are desired.
5.4.1 Lot Selection

Lot selection is the practice of comparing the test results for the material in the supplier’s
inventory against the user’s specification to identify those lots that conform. However, such
approaches do not guarantee continuity of supply from the excipient supplier since not
every lot may conform. Both parties should ensure that the process capability is sufficient
to ensure continued supply in a timely manner.
Lot selection should be the consideration of last resort due to the risks involved, including
inhomogeneity, continuity of supply, etc. The agreement to use lot selection should be
documented between the parties.
This discussion is meant to alert the user to the many issues that arise from relying on lot
selection for conforming excipient. For additional information on these issues, see
references under Appendix C Bibliography.
Evaluation of the suitability of lot selection begins with the identification by the customer
of the property, measurement method, and acceptance criteria <5.16>. The supplier then
evaluates the measurement method and their ability to perform the measurement at their
manufacturing location or otherwise identifies where the test can be performed <5.17>. A
potential test location is the user who would then use pre- or co-shipment samples provided
by the supplier.
Three important criteria should be met if lot selection is to be used to fulfill the user
requirements: intra-lot variability, inter-lot variability, and the stability of the property.
Lot selection should only be used when the excipient manufacturing processes operates in a
state of statistical control. Random variation associated with the property used for lot
selection is important to ensuring the sampling plan will adequately protect the customer
from receiving a non-conforming lot. With the process in statistical control and displaying
random variation, it is possible to gather data for intra-lot variability <5.18>. Generally this
is accomplished through statistical sampling of a lot so as to show with a high degree of
confidence (≥95% Confidence Interval), that the lot is homogenous. This allows for the
establishment of a routine lot sampling plan.
Lot selection relies on understanding the variation associated with the property being
measured in relation to the required range. As a basis for considering lot selection, it is
important to quantify the intra-lot variation of that property. Variation of this property in
the excipient results from the variability contributed by both the manufacturing process and
the measurement system.
Measurement variation is the result of the variability of the entire system from sampling
through testing. It includes such sources of variation as:
• Sampling technique,
• Sample non-uniformity,
• Sample preparation,
• Test equipment,
• Analyst technique, and
• Laboratory conditions.
Variability between the supplier’s measurement process and that of the user’s measurement
process should also be considered. Otherwise there can be a disagreement as to whether the
lot meets the requirements.
The second criterion for consideration is inter-lot variability. Sufficient data should be
gathered so as to measure the lot to lot variation of the excipient <5.19>. Ideally the
average value of the data for the property under evaluation will be midway between the
specified ranges. Also when this data is plotted, the shape of the histogram should approach
a Gaussian Curve (Normal Distribution).
Manufacturing process variation, resulting in lot-to-lot variability, arises from:

• Seasonal impacts due to such changes as:
o Raw materials,
o Water quality, and
o Environmental conditions.
• Effects of process aging such as:
o Catalyst life,
o Equipment wear,
o Filter efficiency, and
o Equipment cleanliness.
• Operational differences:
o Equipment,
o Personnel,
o Process control, and
o Raw material through storage and handling.
The final criterion is an assessment of the stability of the excipient <5.20> which is an
important factor that can affect the decision to provide excipient using lot selection. With a
stable excipient <5.21> and user concurrence to take inventory that has been held for a
prolonged interval, the supplier can set aside sufficient conforming excipient to meet the
anticipated needs of the user for an extended period. If the excipient does not possess
adequate stability to inventory material from lot selection, the user will need to re-assess
their options <5.23>. Among the options the user can consider are in-house modification
<5.43> of the excipient grade that is available (Section 5.5.1) and where this is not feasible,
reformulation of the drug product (Section 5.5.2) <5.44>.
The process capability of the specified property should be calculated to confirm it is

adequate for the purpose of lot selection <5.22>.
Cpk = minimum (USL-Avg or Avg-LSL)/3σ
Where USL = Upper Specification Limit,

LSL = Lower Specification Limit,
Avg = Average, and
σ = standard deviation.
It is noted that a process capability (Cpk) value of 1.0 indicates that 99.7% of material
would meet the specification. Depending on the mutually agreed level of risk, lower
process capability can be acceptable. The inherent risks should be thoroughly understood
and acknowledged by both the user and supplier.
Once quantified, the variability arising from manufacturing and measurement along with
the desired specification range can be used to determine the number of samples that are
needed from each lot to assure the entire lot conforms to the user specification45. Simply
stated, the more variation, whether it arises from manufacturing manifested as lot non-
homogeneity or lot-to-lot variation, or the measurement system, the greater the number of
samples needed to assure the accuracy of the measurement result, and the subsequent
acceptance decision. The determination of the proper number of samples needed to assure
the proper accept/reject decision, is determined from the Operating Characteristic (OC)
curve. This curve of a plot of the probability of acceptance vs. the true lot average
demonstrates the proper number of samples to achieve a statistical probability the lot
conforms to specification.
Briefly, an OC curve uses the customer risk (the risk that nonconforming lots are released
as acceptable), the producer risk, (the risk that conforming lots are rejected as
unacceptable), the specification range, and variation (both manufacturing process and
measurement system) and determines the appropriate acceptance sampling plan46. It should
be noted that the closer the measurement average for the property to the center point of the
specified range, the fewer samples that will be needed to achieve a constant level of risk.
The ability of the supplier to reliably provide excipient to the user’s specification is
dependent upon the quantity of material the user orders versus the quantity of material
produced during that time period that meets the user specification. There are many factors
to consider but at a minimum, it is desirable for the ratio of production to user order
requirements should be at least 3:1; allowing the supplier to select inventory to fill the
customer order <5.24>. Otherwise the user may find the supplier does not have sufficient
conforming material to meet their order quantity and delivery requirements.
Generally lot selection is viable <5.25> <5.26> when there is mutual agreement between
manufacturer and user concerning:
1. Cost of manufacture provides an adequate profit to the manufacturer at an
acceptable cost to the user,
2. The supplier can agree to provide a continuity of supply of conforming excipient.
3. The excipient is stable enough so that the user receives it with sufficient shelf life
for use in the manufacture of the pharmaceutical product.
4. The business objectives of both supplier and user have been met.
If there are no agreements on these issues <5.27>, then the user will have to re-assess their
options <5.23>.
With agreement the supplier and user will evaluate the ability of the supplier to test for
conformance to the user requirements <5.28>. If the supplier is capable of performing the
appropriate tests and can provide their results on a Certificate of Analysis (COA), then the
45
Specifications for the Chemical and Process Industries, A Manual for Development and Use, American Society
for Quality, 1996, 61-64.
46
Specifications for the Chemical and Process Industries, A Manual for Development and Use, American Society
for Quality, 1996, 75-90.
supplier can implement special inventory management and logistics as necessary <5.30>.
Otherwise, the user might request that the supplier provide pre-shipment samples so that the
user can test and identify those lots that meet user requirements <5.29>. The supplier
and/or user would then implement appropriate inventory and logistics management.
5.4.2 Manufacture to Order

Where the stability of the excipient is inadequate or where the process capability is
insufficient for lot selection <5.21> <5.22>, consideration should be given by the excipient
supplier to produce the excipient to order <5.31>. This often involves careful process
monitoring that result in the excipient with the property desired by the user. The excipient
is manufactured to fulfill the user order where the user will supply a forecast to the
manufacturer with an agreed to lead time <5.34>. The manufacturer will then assure there
is conforming material in inventory to meet the user demand forecast and there will be an
agreement to proceed <5.27> between supplier and user.
Where the excipient supplier cannot meet the user requirements by producing the excipient
to order, the manufacturer can consider custom manufacturing the excipient <5.32>.
Otherwise the user will need to reassess their options <5.23>.
5.5 Other Approaches

Where the supplier has declined the business <5.39>, the user should ascertain if there are any
other suppliers capable of providing the excipient quality desired. If there is another supplier
<5.41>, the user would return to Phase 2 <4.34> and evaluate that supplier’s excipient. If the user
cannot identify another supplier of the excipient, the user might then consider either
reformulating the dosage or modifying the excipient quality available in-house to meet the
requirements of the formulation.
5.5.1 In-House Processing

If there is no supplier <5.40>, the user is left with the option to consider in-house
modification of the excipient <5.42> <5.43>. This approach is practical in circumstances
where certain physical properties of the excipient are desired, such as finer or more uniform
particle size for powders and homogeneity of batches for liquids. Improvements to the
chemical properties of the excipient that might be feasible include increased purity,
removal of a specified impurity or concomitant component, alteration of the excipient pH,
or treatment to reduce the excipient activity. Other considerations for in-house processing
include modification of moisture content and reduction of bioburden. Finally, the user can
purchase a non-pharmaceutical grade of material and under appropriate GMP, can improve
the purity of the material so that it now meets the requirements for an excipient ingredient.
Such activities should be justified in the regulatory filing.
Where purification of a non-pharmaceutical grade of starting material is conducted, the user

should qualify the material and justify the steps used to improve its purity. It is not
acceptable to purchase a "technical" grade of material and simply test it to confirm it meets
compendial standards. Without production conducted in conformance to appropriate GMP
requirements, the material remains unsuitable for use as an excipient.
5.5.2 Reformulate
Where the stability of the excipient is inadequate and where the excipient cannot be made
to order, the user will not have an assured supply of excipient that meets their requirements.
In that case, the user will be left with no alternative but to reformulate <5.44>.

5.5.3 Supplier Custom Manufacture
If lot selection is not viable, then custom manufacture can be considered <5.33>. The data
from lot selection as discussed in Section 5.4.1 is assessed for intra-lot <5.18> and inter-lot
<5.19> variability. This information is used to make the determination as to whether the
process capability is sufficient <5.22>. Where process capability is insufficient for
manufacture to order (Section 5.4.2), process modifications can be considered <5.36> to
achieve the desired excipient quality <5.37>. If the process can be optimized, then data can
be developed to support the new process capability. If process optimization will not achieve
the target excipient quality, the user will have to re-assess their options <5.23>.
If the modified process shows adequate capability, then consideration can be given to
custom manufacture of the excipient <5.35>. Examples where custom manufacture might
be indicated were discussed under Section 5.5.1, In-House Processing. The important
difference is that the manufacturing improvement in custom manufacture occurs at an
excipient manufacturing facility whereas in-house processing occurs under the direction of
the user.
If custom manufacture is viable and the product is used exclusively for the user <5.38>,
there is an agreement to proceed <5.27>. Where the excipient is not produced exclusively
for the user and there is still an agreement with the user to proceed, the process returns to
Phase 1 for the introduction of a new excipient grade.
5.6 Concluding Agreements

Where there is mutual agreement to use a special excipient grade to meet the user specification, it
is important for the user to supply a forecast to provide the supplier with adequate lead time
<5.34>. The accuracy of the user forecast and the supplier’s desire for lead time are negotiated
prior to reaching final agreement.
With agreement to proceed, the supplier approves the user specification and other requirements.
If the user requires pre-shipment samples, the supplier makes arrangements to provide them
<5.29> (see Section 5.1).
If the agreement requires lot selection, the supplier and/or user should implement inventory
management procedures to assure there is appropriate inventory to meet the user forecast <5.30>
within the desired lead time <5.34>.

APPENDIX A: FLOW DIAGRAMS
<1.1> MANUFACTURING COMPANY

INDICATES INTEREST IN
MARKETING AN EXCIPIENT
<1.2> ID TARGET
MARKET AND ROUTES
OF ADMINISTRATION
<1.3> REGULATORY No
ASSESSMENT**
**REGULATORY ASSESSMENT:
· COMPENDIAL (GLOBAL) <1.4> DETERMINE
· REGULATORY (GLOBAL)
CONSTRAINTS AND
· GMP <1.5>
· ORIGIN (NATURAL, SYNTHETIC, ETC.) MINIMUM CONSTRAINTS
DISCONTINUE
· ADDITIVES? REQUIREMENTS FOR UNREASONABLE
· PRECEDENCE OF USE/SAFETY ASSESSMENT PROJECT
· DEGRADATION PRODUCTS
VIABLE PRODUCT IN
· IMPURITY PROFILE (INCLUDE PROCESS TARGET MARKET
RESIDUES, CATALYSTS, ETC.)
· RESIDUAL SOLVENTS
· RELATED SUBSTANCES
· EXCIPIENT MASTER FILE?
<1.17>
<1.7> DETERMINE <1.6> EVALUATE <1.12> DETERMINE
GMP COMPLIANCE MANUFACTURING & CAN ADJUST VIABILITY OF
Yes
ISSUES PACKAGING/LABELING PROCESS EXCIPIENT
OPTIONS PARAMETERS? (ENHANCE
STABILITY)
<1.8> ESTABLISH
MANUFACTURING &
PACKAGING/LABELING No
PROCESS
<1.9> <1.16>
<1.10> MODIFY PROCESS
IS PROCESS BROADEN
PARAMETERS AND No
CAPABILITY SPECIFICATION
ASSESS CONTROLS
ADEQUATE? ?
No
<1.11> ANALYTICAL Yes
METHODS ASSESSMENT
<1.15>
<1.13> DRAFT <1.14> ASSESS
STABLE FOR
COMPLIANCE-BASED STABILITY OF THE
INTENDED
SPECIFICATIONS EXCIPIENT
Yes USE?
Yes
<1.18> DETERMINE
<1.19>
<1.20> NEEDS FOR
DO NOT EVALUATE TARGET
DISCONTINUE PRODUCT
PROCEED MARKET POTENTIAL
PROJECT CONSISTENCY &
AND GMP
CONTROL
PROCEED
From page 2
<1.22>
To page 2 <1.21>

From Phase 2
<4.3> or <4.25>
<4.34> IDENTIFY
ALTERNATIVE
SUPPLIERS
SUPPLIER EVALUATION <4.36> SUPPLIER <4.35> CONTACT

· PRICE EVALUATION NEW SUPPLIERS
· CAPACITY
· SUPPLY CHAIN
· SPECIAL REQUIREMENTS
· HISTORY AS SUPPLIER
· PACKAGING
· COST SAVING
· TECHNICAL COMPETENCE <4.37> IS <4.43> GET <4.44> LAB/SMALL
· QUALITY SYSTEM
· GMP CONFORMANCE EVALUATION Yes SAMPLES FROM SCALE EVALUATION
OK? SUPPLIER COMPARISON
No
<4.38> CAN <4.47> <4.45>

PROBLEM BE REASSESS No EVALUATION
REMEDIED? OPTIONS OK?
Yes Yes
<4.46> PILOT SCALE

<4.42> <4.39> CAN COMPARISON PLUS
IMPLEMENT Yes SUPPLIER DESIGN SPACE
CHANGES MEET NEED?
No
<4.48>
EVALUATION
Yes
OK?
<4.40>
IS THERE
ANOTHER Yes
SUPPLIER?
<4.49> PIVOTAL
SCALE
No COMPARISON PLUS
DESIGN SPACE
<4.41>
CONSIDER
OTHER
OPTIONS <4.50>
EVALUATION
OK?
Yes GO TO PHASE 3
<4.53> VALIDATION <4.51> FULL SCALE

<4.52>
AND Yes COMPARISON PLUS
EVALUATION
COMMERCIALIZE DESIGN SPACE
OK?

APPENDIX B: DEFINITIONS AND GLOSSARY
Active Pharmaceutical Ingredient (API): Any substance or mixture of substances, intended to be used
in the manufacture of a drug product and that, when used in the production of a drug, becomes an active
ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other
direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure
or any function of the body of man or animals.
Additive: A substance added to the excipient to improve or maintain a characteristic such as a

preservative, flow agent, antimicrobial, etc.
Bill of Lading: A document used when shipping goods that describes the content of the shipment
and accompanies it.
Certificate of Analysis: A document listing the test methods, specification and results of testing a
representative sample from the batch to be delivered.
Certificate of Suitability to the European Pharmacopoeia (CEP): Certification granted to individual

manufacturers by the European Directorate for the Quality of Medicines (EDQM) when a specific active
ingredient or excipient is judged to be in conformity with a Ph.Eur. monograph.
Change Control: A process for management review of proposed changes that may impact the quality or
regulatory conformance of the excipient.
Component: Any material present in the excipient that arises as a consequence of the raw materials
and/or manufacturing process.
Composition Profile: A description of all of the components present in the excipient.
Concomitant Component: A material found in an excipient in addition to the major component(s) that is
necessary for assuring the proper performance of the excipient in the drug formulation.
Contaminant: An undesired material of a chemical or microbiological nature or foreign matter

introduced from a raw material, intermediate, or excipient during production, sampling, packaging,
storage or transport.
Co-processing: Any mixture of compendial or non-compendial excipients that has been designed to be
physically co-processed in a way which results in functional performance attributes when used in a drug
application and which are not seen if the excipients are combined using simple mixing.
Customer Risk: The probability that a lot is released by the manufacturer although the product is
nonconforming.
Date of Manufacture: A date indicating the completion of the final manufacturing process (as defined by
the supplier for the particular excipient and process).
Design of Experiments: A series of planned experiments that uses statistical principles to select variable
parameters with the objective of optimizing process performance.
Design Space: The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance of quality.

Document Control: The set of procedures to ensure documents can be identified as to their status e.g.
draft, revised, approved, obsolete, superseded, etc.
Drug Master File (DMF): Detailed information about the manufacture of an excipient that can be
submitted to the United States Food and Drug Administration, Health Canada, and the Japanese
Pharmaceutical and Medical Devices Agency.
Endotoxin: A toxin that is produced within certain bacteria that is released only when the bacteria are
destroyed.
Excipient: Substances other than the API which have been appropriately evaluated for safety and are
intentionally included in a drug delivery system.
Expiry (Expiration) Date: The date designating the time during which the excipient is expected to
remain within specifications and after which it should not be used.
Excipient Information Package (EIP): An IPEC initiative to provide standards for the exchange of data
between excipient suppliers and excipient users. The EIP is comprised of the Site Quality Overview,
Product Regulatory Datasheet, and Site and Supply Chain Security Overview. IPEC’s Standardized
Excipient Information Protocol User Guide provides information on the preparation of the EIP
documents.
Expiration Period: The duration, normally expressed in months or years from the date of manufacture,
within which the excipient can continue to be used.
Functionality: A desirable property of an excipient that aids and/or improves the manufacture, quality,
or performance of the drug product.
Good Distribution Practices: The general principles of good practices in the pharmaceutical starting
materials supply chain.
Good Manufacturing Practices: Requirements for the overall quality system under which drug products
and their ingredients are manufactured, tested, and released. Current Good Manufacturing Practices
(cGMP) is the applicable term in the United States. For purposes of this guide, the terms GMP and cGMP
are equivalent.
Impurity: A component of an excipient that is not intended to be present but arises as a consequence of
the manufacturing process.
Inactive Ingredient Database: An FDA database containing information on excipients present in FDA-
approved drug products.
Interchangeability: Functional equivalent in all respects to the original source material
Master Batch Record: Documentation of the steps necessary to produce a finished excipient by batch
processing.
Master Process Flow: Documentation that describes excipient manufacture from raw material to final
purification using continuous processing.
Master Process Log: Record of the operating conditions used for the manufacture of the excipient using
continuous processing

Master Production Record: Record of the manufacture of the lot/batch of the excipient from raw
material to completion.
Operating Characteristic (OC) Curve: A graphical technique for showing the performance of an
accept/reject plan.
Other Components: Materials present in an excipient that arise as a consequence of the raw materials
and/or manufacturing process and are not concomitant component.
Original Manufacturer: Person or company manufacturing a material to the stage at which it is

designated as a pharmaceutical starting material.
Packaging Material: A material intended to protect an intermediate or excipient during storage and
transport.
Pivotal Scale: A scale of cGMP pharmaceutical product manufacture less than full commercial scale but
greater than 1/10th commercial scale. Studies using such manufacture (e.g. product stability) may be used
to support the marketing application.
Pre-formulation: Those studies preceding formal formulation design that are used to investigate the
physical, chemical and biopharmaceutical properties of the API.
Process: The set of operating steps including synthesis, isolation, purification, packaging, etc. that
produce the finished excipient.
Process Capability: Measurement of the process variability for a specified property.
Process Parameter: A measurable operating condition.
Process Step: A documented instruction to the excipient manufacturing personnel directing that an
operation be done.
Process Validation: Documented evidence demonstrating assurance that a specific process will
consistently produce excipient meeting its specifications and quality characteristics.
Processing Aid: A material added to a manufacturing step for the purpose of facilitating the completion
of that step or subsequent step.
Producer Risk: The probability that a lot is rejected by the manufacturer although the product is
conforming.
Production Specification: A list of tests, references to analytical procedures, and appropriate criteria for
a material as manufactured.
Pyrogen-Free: A specification parameter stipulating the excipient is free of endoxin and any other fever
causing agents.
Quality Agreement: A formal agreement between the excipient manufacturer and their pharmaceutical
customer that stipulates the responsibilities of each party in meeting the regulatory requirements for sale
and use of the excipient in a dosage form.

Quality by Design: The development of the design space, specifications, and manufacturing controls that
result from pharmaceutical development studies using Design of Experiments, process analytical
technology (PAT) and or prior knowledge.
Random Variation: Variation in the measured property whose distribution of results shows no
predictable pattern.
Re-evaluation Interval: The duration, normally expressed in months or years, from the date of
manufacture, throughout which the excipient should continue to conform to the specification and after
which should be tested to confirm it continues to meet specification.
Retest Interval: (Re-evaluation Interval)
Sales Specification: A list of tests, references to analytical procedures, and appropriate criteria for a
material as offered for sale.
Shelf Life: The length of time during which the excipient meets specification (see also expiration period,
re-evaluation interval and retest interval).
Significant Change: Any change that alters an excipient physical or chemical property from the norm, or
that is likely to alter the excipient performance in the dosage form.
Specification: A list of tests, references to analytical procedures and appropriate acceptance criteria that
are numerical limits, ranges or other criteria for the tests described for a material.
Statistical Control: A process that results in product that exhibits random variation of its property.
Sterile: Completely free from microorganisms such that, after inoculation of a suitable nutrient medium
under aseptic conditions with the material, and followed by incubation at an appropriate temperature for
14 days, no growth of microorganisms is seen.
Supplier: Used here to denote the company providing the excipient ingredient to the pharmaceutical
customer. May be either the excipient manufacturer or distributor.
Validation: A documented program that provides a high degree of assurance that a specific process,
method, or system will consistently produce a result meeting predetermined acceptance criteria.
Worst Case: A set of conditions encompassing processing limits, circumstances, equipment, etc., which
pose the greatest chance of a failure in a process, to a product, or in a procedure, when compared to ideal
conditions or those stipulated in a procedure. Such conditions do not necessarily induce product, process,
or equipment failure.

APPENDIX C: BIBLIOGRAPHY
General
1. Engel, Jan and DeVries, Bert, Evaluating a Well-Know Criterion for Measurement Precision, Journal
of Quality Technology, 29/4, 469-476, October 1997.
2. European Pharmacopoeia
3. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems,

Katdare, A and Chaubal, MV, (Eds), Informa Healthcare, New York, 2006.
4. U.S. FDA, Nonclinical Studies for Development of Pharmaceutical Excipients (final version May
2005)
5. Food Chemical Codex
6. International Conference on Harmonisation Documents:

• ICH Q1A: Stability Testing of New Drug Substances and Products
• ICH Q2: Validation of Analytical Procedures: Text and Methodology
• ICH Q3A: Impurities in New Drug Substances
• ICH Q3C: Impurities, Guideline for Residual Solvents
• ICH Q5A: Viral Safety Evaluation of Biotechnology Products derived from Cell Lines of Human
or Animal Origin
• ICH Q5C: Stability Testing of Biotechnological / Biological Products
• ICH Q6A: Specifications, Test Procedures and Acceptance criteria for New Drug Substances and
New Drug Products: Chemical Substances
• ICH Q6B: Test Procedures and Acceptance Criteria for Biotechnological / Biological Products
• ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
• ICH Q8: Pharmaceutical Development
• ICH Q9: Quality Risk Management
• ICH M4, Organisation of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use, Step 4, 2004.
7. International Pharmaceutical Excipients Council Documents:

• The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006
• Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshita, F.K., Loper, A., Mitchell, D.B.,
Tamulinas, C.B., and Weiner, M.L., A New Approach to the Safety Assessment of
Pharmaceutical Excipients, Regulatory Toxicology and Pharmacology, 24, 2, 1996.
• IPEC Europe Safety Committee, The Proposed Guidelines for the Safety Evaluation of New
Excipients, European Pharmaceutical Review, November 1997.
• IPEC-Americas Standardized Excipient Information Protocol User Guide, 2005
• IPEC-Americas Significant Change Guide, 2005
• IPEC-Americas Excipient Master File Guide, 2004
• IPEC-Americas Certificate of Analysis Guide for Bulk Pharmaceutical Excipients, 2000
• IPEC The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, 2006
• The Joint IPEC-PQG Good Manufacturing Practices Audit Guide for Pharmaceutical Excipients,
2007.
• IPEC Excipient Composition Guide (in development)
• IPEC-Americas Stability Guide (in development)
• IPEC QbD Guide (in development)
• IPEC Quality Agreement Guide (in development)
8. Japanese Pharmacopoeia
9. Japanese Pharmaceutical Excipients
10. Japanese Pharmaceutical Excipients Dictionary
11. Juran’s Quality Control Handbook, J.M. Juran and Frank M. Gryna, 5th edition, McGraw Hill, NY
1999.
12. Specifications for the Chemical and Process Industries, A Manual for Development and Use,
American Society for Quality, Milwaukee, 1996
13. United States Pharmacopeia-National Formulary
14. Virus Validation Studies: CPMP/BWP/268/95: The Design, Contribution, and Interpretation of
Studies Validating the Inactivation and Removal of Viruses.
15. Dictionaire Vidal – ISBN-13 978-0320075759
16. Die Rote Liste – ISBN-13 978-3540219309
17. Electronic Medicines Compendium; http://www.medicines.org.uk/emc.aspx
Foreword
i. ICH Q9, Quality Risk Management, http://www.ich.org/LOB/media/MEDIA1957.pdf
Main Text
1. The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006
2. The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, 2006
3. IPEC Excipient Composition Guide (in development)
4. ICH International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use: http://www.ich.org
5. Instructions: http://www.fda.gov/cder/iig/iigfaqWEB.htm,
6. Database: http:www.accessdata.fda.gov/scripts/cder/iig/index.cgm
7. Maximum dosage information is only contained in the Japanese language version of the JPED.
8. Electronic Medicines Compendium; http://www.medicines.org.uk/emc.aspx
9. Draft: Specific Conditions of the Application of the Principles and Guidelines of Good
Manufacturing Practice for Certain Excipients,
http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/docs/doc2006/12_2006/2006_12_21_e
xcipientsgmp.pdf , & EC-Directive 2001/83/EC, as amended by EC-Directive 2004/27/EC
10. ICH M4, Organisation of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use, Step 4, 2004.
11. U.S. FDA, Nonclinical Studies for Development of Pharmaceutical Excipients (final version May
2005)
12. Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshita, F.K., Loper, A., Mitchell, D.B.,
Tamulinas, C.B., and Weiner, M.L., A New Approach to the Safety Assessment of
Pharmaceutical Excipients, Regulatory Toxicology and Pharmacology, 24, 2, 1996.
13. USP-NF General Chapter <1074> Excipient Biological Safety Evaluation Guidelines
14. The Proposed Guidelines for the Safety Evaluation of New Excipients (European Pharmaceutical
Review, November 1997)
15. USP-NF General Notices subsection Ingredients and Processes, second paragraph.
16. USP-NF <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients
17. USP-NF General Notices subsection Official and Official Articles, fourth paragraph.
18. USP-NF <1225> Validation of Compendial Methods
19. Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, page
67 October 8, 2003
20. Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, pp 57-
64 October 8, 2003
21. The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for
Human Use, Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in
the Dossier for Application for Marketing Authorisation of a Medicinal Product, (DRAFT)
CPMP/QWP/419/03, February 2003
22. The European Agency for the Evaluation of Medicinal Products, Guideline on The Chemistry of
New Active Substances, CPMP/QWP/130/96/Rev 1, February 2004
23. FDA Guideline for Drug Master Files, September 1989.
24. IPEC-Americas, Excipient Master File, 2004.
25. ICH Q3A, Impurities in New Drug Substances, http://www.ich.org/LOB/media/MEDIA422.pdf
26. ICH Q3C, Impurities, Guideline for Residual Solvents,
27. See EMEA Note for Guidance Guideline on the Specifications Limits for Residues of Metal
Catalysts or Metal Reagents, EMEA/CHMP/SWP/4446/2000
28. The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006,
p3
29. IPEC-Americas Certificate of Analysis Guide for Bulk Pharmaceutical Excipients, 2000.
30. A document used when shipping goods that describes the content of the shipment and
accompanies it.
31. ICH Q2, Validation of Analytical Procedures: Text and Methodology,
32. IPEC Stability Guide (in development)
33. ICH Q1A, Stability Testing of New Drug Substances and Products
34. IPEC QbD Guide (in development)
35. IPEC-Americas Standardized Excipient Information Protocol User Guide, 2005
36. ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
37. See ICH Q8, Pharmaceutical Development. http://www.ich.org/LOB/media/MEDIA1707.pdf
38. The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006,
p. 3
39. Moreton, RC, Excipient Interactions, in Excipient Development for Pharmaceutical,
Biotechnology, and Drug Delivery Systems, edited by Katdare, A and Chaubal, MV, (EDs),
Informa Healthcare, New York, 2006, 93-108
40. IPEC-Americas Significant Change Guide, 2005
41. The Joint IPEC-PQG Good Manufacturing Practices Audit Guide for Pharmaceutical Excipients
2007
42. IPEC Excipient Composition Guideline (in development)
43. GMP paper audits or EIP Site Quality Overviews alone are insufficient for this purpose.
44. IPEC Quality Agreement Guide (in development)
American Society for Quality, 1996, 61-64.
American Society for Quality, 1996, 75-90.

24579 IPEC cover CX2:113114_IPEC Cover 4-1 PGS 10/3/08 12:46 PM Page 1
INTERNATIONAL PHARMACEUTICAL EXCIPIENTS COUNCIL
Qualification of
Excipients for
Use in
Pharmaceuticals
Printed in the USA by IPEC-Americas

1655 N. Ft. Myer Drive, Suite 700 Copyright © 2008 International Pharmaceutical Excipients Council
Arlington, VA 22209
AUDITING OF STERILE PREPARATIONS
INTRODUCTION
AUDIT: A systematic, independent examination of the manufacturer’s quality

system that is performed at defined intervals and at sufficient frequency to determine
whether both quality system activities and the results of such activities comply with
quality system procedures, that these procedures are implemented effectively and
that these procedures are suitable to achieve quality system objective.
STERILE PRODUCT: Sterile products are the dosage forms of therapeutic agents
that are free of viable microorganism, example parenteral dosage forms, eye drops,
surgical dressings etc.
The terms aseptic and sterile are not synonymous. Sterile means having a complete
absence of viable microorganisms or organisms that have the potential to reproduce.
In the purest microbiological sense, an aseptic process is one that prevents
contamination by the exclusion of microorganisms. In contemporary aseptic
healthcare-product manufacturing, aseptic describes the process for handling
sterilized materials in a controlled environment designed to maintain microbial
contamination at levels known to present minimal risk.
STERILE MANUFACTURING:
The manufacturing of sterile products takes place in a number of stages, and the
exact sequence depends on a number of variables, including the nature of the product
and the type and material of the primary container. In general terms, the sequence of
events will be as follows:
• The preparation stage for the bulk batch of drug, the primary packaging
components and ancillary items, such as filling machine parts.
• The filling and sealing stage.
• The inspection stage.
• The final packaging stage.
In addition, there will be the sterilization stage, which will vary in position. For some
dosage forms, there will also be a leak-test stage after filling and sealing.
There are two types of sterile manufacturing-

• Terminal sterilization usually involves filling and sealing product containers
under high-quality environmental conditions. Products are filled and sealed in
this type of environment to minimize the microbial and particulate content of
the in-process product and to help ensure that the subsequent sterilization
process is successful. In most cases, the product, container, and closure have
low bioburden, but they are not sterile. The product in its final container is
then subjected to a sterilization process such as heat or irradiation.
• In an aseptic process, the drug product, container, and closure are first
subjected to sterilization methods separately, as appropriate, and then brought
together. Because there is no process to sterilize the product in its final
container, it is critical that containers be filled and sealed in an extremely high-
quality environment. Aseptic processing involves more variables than
terminal sterilization. Before aseptic assembly into a final product, the
individual parts of the final product are generally subjected to various
sterilization processes. For example, glass containers are subjected to dry
heat; rubber closures are subjected to moist heat; and liquid dosage forms are
subjected to filtration.
GMP FOR STERILE PRODUCTS:
• Premises
• Quality control
• Sanitation
• Manufacture of sterile preparations
• Sterilization
• Terminal sterilization
• Aseptic processing and sterilization by filtration
• Isolator technology
• Blow/fill/seal technology
• Personnel
• Equipment
• Finishing of sterile products
BUILDING AND FACILITY REQUIREMENTS FOR PREPARATION OF

STERILE PRODUCTS:
There shall be separate or defined areas or such other control systems for the firm’s
operations as are necessary to prevent contamination or mixups during the course of
the procedures. Aseptic processing, which includes:
(i) Floors, walls, and ceilings of smooth, hard surfaces that are easily
cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through high-efficiency particulate air filters under
positive pressure, regardless of whether flow is laminar or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions.
(vi) A system for maintaining any equipment used to control the aseptic
conditions.
LAYOUT
CLEANROOMS:
Cleanroom is a facility ordinarily utilized as a part of specialized industrial
production or scientific research, including the manufacture of pharmaceutical items
and microprocessors. They are designed to maintain extremely low levels of
particulates such as dust, airborne organisms, or vaporized particles.
The clean room is divided into; Critical Area and General Area.
The cleanrooms are classified as-
AIR FILTRATION
1.Membrane: A compressed gas should be of appropriate purity (e.g., free from oil)
and its microbiological and particle quality after filtration should be equal to or better
than that of the air in the environment into which the gas is introduced. Compressed
gases such as air, nitrogen, and carbon dioxide are often used in cleanrooms and are
frequently employed in purging or overlaying.
2. High-Efficiency Particulate Air (HEPA): An efficiency test is a general test

used to determine the rating of the filter. An intact HEPA filter should be capable of
retaining at least 99.97 percent of particulates greater than 0.3 µm in diameter.
HEPA filter integrity should be maintained to ensure aseptic conditions. Leak
testing should be performed at installation to detect integrity breaches around the
sealing gaskets, through the frames, or through various points on the filter media.
Thereafter, leak tests should be performed at suitable time intervals for HEPA filters
in the aseptic processing facility.
An aseptic process is designed to minimize exposure of sterile articles to dynamic

conditions and potential contamination hazards presented by the operation. Limiting
the duration of open container exposure, providing the highest possible
environmental control, and designing equipment to prevent entrainment of lower
quality air into the Class 100 zone are essential.
The sterile product and container-closures should also be protected from activities
occurring adjacent to the line. Carefully designed curtains, rigid plastic shields, or
other barriers should be used in appropriate locations to partially segregate the
aseptic processing line.
Airlocks and interlocking doors facilitate better control of air balance throughout the
aseptic processing area. Airlocks should be installed between the aseptic processing
area entrance and the adjoining uncontrolled area. Other interfaces such as
personnel entries, or the juncture of the aseptic processing room and its adjacent
room, are also appropriate locations for air locks.
EQUIPMENTS:
Processing equipment and systems should be equipped with sanitary fittings and
valves. Drains are not considered appropriate for rooms in classified areas of the
aseptic processing facility.
When applicable, equipment must be suitably designed for ease of sterilization . The
effect of equipment layout and design on the clean room environment should be
addressed. Flat surfaces or ledges that accumulate dust and debris should be
avoided. Equipment should not obstruct airflow and, in critical zones, its design
should not perturb airflow.
In order to ensure the sterility of products purporting to be sterile, both sterilization

and aseptic filling/closing operations must be adequately validated . The goal of
even the most effective sterilization processes can be defeated if the sterilized
elements of a product (the drug, the container and the closure) are brought together
under conditions that contaminate those elements. Similarly, product sterility is
compromised when the product elements are non-sterile at the time they are
assembled.
The validation of an aseptic processing operation should include the use of a

microbiological growth nutrient medium in place of product. This has been termed
a “media fill” or “process simulation.” The nutrient medium is exposed to product
contact surfaces of equipment, container systems, critical environments, and process
manipulations to closely simulate the same exposure that the product itself will
undergo. The sealed containers filled with the media are then incubated to detect
microbial contamination. The results are interpreted to determine the potential for
any given unit of drug product to become contaminated during actual operations
(e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing).
Environmental monitoring data is integral to the validation of an aseptic processing
operation.
SANITATION: The sanitation of clean areas is particularly important. They should

be cleaned frequently and thoroughly in accordance with an approved written
programme. Monitoring should be regularly undertaken to detect contamination or
the presence of an organism against which the cleaning procedure is ineffective.
Fumigation of clean areas may be useful for reducing microbial contamination in
inaccessible places.
PERSONNEL TRAINING, QUALIFICATION, & MONITORING
The quality control unit shall have the responsibility for approving or rejecting all
procedures or specifications impacting on the identity, strength, quality, and purity
of the drug product.
Appropriate written procedures, designed to prevent microbiological contamination

of drug products purporting to be sterile, shall be established and followed.
Each person engaged in manufacture, processing, packing or holding of a drug

product shall have education, training and experience, or any combination thereof,
to enable that person to perform the assigned functions. Each person responsible for
supervising the manufacture, processing, packing, or holding of a drug product shall
have the education, training, and experience, or any combination thereof, to perform
assigned functions in such a manner as to provide assurance that the drug product
has the safety, identity, strength, quality, and purity that it purports or is represented
to possess. Adequate number of qualified personnel to perform and supervise the
manufacture, processing, packing or holding of each drug product. Continuous
training in CGMP “shall be conducted by qualified individuals on a continuing basis
and with sufficient frequency to assure that employees remain familiar with CGMP
requirements applicable to them. The training “shall be in the particular operations
that the employee performs and in current good manufacturing practice (including
the current good manufacturing practice regulations in this chapter and written
procedures required by these regulations), as they relate to the employee's functions.
General Gowning procedure in aseptic area:
Step 1:
❖ Hair net – contain all hair.

❖ Shoe covers
❖ Wash hands thoroughly using bactericidal soap and dry thoroughly
❖ Don first pair of sterile gloves following aseptic technique by touching only the
inside of the gloves.
❖ Sanitize gloves after donning each article, if required.
Step 2:
❖ Put sterile boots (high- top shoe covers) on using aseptic technique.
The first boot donned can now be placed in the “clean side” of gowning
area. Don second boot and place the other foot in the “clean side” of
gowning area.
Step 3:
❖ Sterile hood – Ensure snug fit and proper neck seal.

❖ Sterile mask – Adjust for a snug facial fit. May be worn over or under
hood
❖ Sterile coveralls – Carefully remove coverall from package by holding the
inside neck area. Unfold garment while preventing it from touching the
floor, your clothes or bench. Don using aseptic technique. Tuck coverall
legs into boots.
❖ Goggles – Adjust for a snug facial fit.
Step 4:
❖ Perform a final inspection in gowning room mirror prior to the entry
into the sterile clean room.
❖ Complete gowning steps by aseptically donning second pair of sterile
gloves over the first pair, making sure the cuffs are securely over the
sleeves.
Removal of sterile Garments:
❖ Enter gowning area from clean room and head directly to the “exit
gown room”.
❖ If no “exit gown room” is available, go directly to the “non-clean side”,
usually divided by a bench and/or line. Remove items in reverse order
of gowning procedure and discard.
COMPONENTS AND CONTAINER/CLOSURES:
A drug product produced by aseptic processing can become contaminated by

use of one or more components (e.g., active ingredients, excipients, Water for
Injection) that are contaminated with microorganisms or endotoxins. It is
important to characterize the microbial content of each component liable to
contamination and establish appropriate acceptance/rejection limits based on
information on bioburden. Knowledge of bioburden is critical in assessing
whether the sterilization process is adequate. In aseptic processing, each
component is individually sterilized or several components are combined,
with the resulting mixture sterilized.
STERILITY TESTING:
• To assure batch uniformity and integrity of drug products, written

procedures shall be established and followed that describe the in-
process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate the
performance of those manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material and
the drug product.
• For each batch of drug product, there shall be appropriate laboratory
determination of satisfactory conformance to final specifications for the
drug product, including the identity and strength of each active
ingredient, prior to release. For each batch of drug product purporting
to be sterile and/or pyrogen-free, there shall be appropriate laboratory
testing to determine conformance to such requirements. The test
procedures shall be in writing and shall be followed.
AUDITING OF CLEANROOMS:
Many aspects of a cleanroom are designed to ensure contamination control,
including control of air movement, air filtration, cleanroom practices, cleaning and
disinfection schemes. The auditor should assess what control measures are in place
to protect the process and product from contamination.
Quality auditing is the systematic examination of a quality system and audits form
an important part of Good Manufacturing Practice (GMP). Auditors need to be
knowledgeable about cleanroom operations, and have an understanding of microbial
contamination as well as being trained specifically as auditors. Ideally, they should
have complete independence from the functions they are auditing. The audit
approach within GMP is designed to verify objective evidence of processes and to
provide evidence of action to eliminate or reduce problem areas. Quality auditing
should not only report non-conformances and corrective actions, it should also
highlight areas of good practice. Risk assessment plays an important part because
one aim of the audit is to assess vulnerability. Risk assessment tools are available to
the auditor to help structure the audit. These include approaches such as Failure
Modes and Effects Analysis (FMEA) and Hazard Analysis and Critical Control
Points (HACCP).
AUDITING A STERILE PRODUCTION AREA:
1.Inspect the component preparation area.
• Ensure that sterilization equipment (autoclave, dry heat oven, sterilizing

tunnel) has been validated and is properly maintained.
• Ensure that equipment used to wash/rinse containers and closures has been
properly validated and maintained.
• Ensure the required water quality is used for washing/rinsing
• Ensure that there are approved procedures for departmental processes,
operation of/and maintenance of equipment. Verify that operating procedures
reflect those used during validation.
• Observe personnel to determine if they are appropriately gowned.
• Ensure that there is a documented training program in place for operators in
this area.
2. Inspect the microbiology laboratory.
• Review sterility testing program, performance and test results.

• Review all investigations for completeness and lot disposition decisions.
• Determine if there are any trends regarding false positive test results and the
root cause
3. Review the Media Fill Procedure.
4. Review the Environmental Monitoring Program.

• Ensure that there is a defined, approved program.
• Review training records for staff performing program sampling and testing.
• Ensure that the program is compliant with all worldwide regulatory and site
policy/guideline requirements.
• Ensure that there are established alert and action limits that are appropriate.
• Review test results and associated investigations.
• Ensure that the program requires review of test results prior to release of
product batches.
• Ensure that data is tracked for trends and reviewed by QC unit on a regular
basis.
AUDIT CHECKIST FOR STERILE AREA:
XYZ COMPANY
DATE OF AUDIT: TIME:
AUDITOR NAME: SIGNATURE:
DOCUMENT CODE: APPROVED BY:
S NO. AUDIT ITEM YES NO REMARKS
I STERILE AREA LAYOUT AND CONSTRUCTION
1.
Whether the building is devoid of cracks especially in the Aseptic
solutions preparation rooms, Filling rooms, Sealing rooms
2.
Is the area differentiated into class 100,1000 and class 10000 rooms.
3. Whether water lines pose any threat of leakage to the aseptic area
4.
Whether the walls are flat, smooth and devoid of Recesses

5.
Sterile area layout validation
6.
Whether the aseptic areas have separate exit and Entrances

7.
Are the rest room, canteen and toilets outside the sterile
manufacturing area
8.
Are the animal houses outside and away from the sterile product
manufacturing area with separate AHU.
9. Is the change rooms entrance provided with air locks before entry to
the sterile product manufacturing areas and then to the aseptic areas
ii.
HVAC system qualification and maintainance
Iii.
ENVIRONMENTAL MONITORING
1. Humidity ,temperature and pressure control records are present or

not
2. Cleaning validation records
3. HEPA filters integrity testing records
4. Are the microbiological results recorded
iv. GARMENTS
1.
Whether Outdoor clothing is allowed in the sterile areas
2. Are the garments made of non-shedding and tight weaving material?

3. Are periodic inspections of the garments carried out by responsible
staff
4. Specify garment sterilization procedure and its entry to the aspetic
area
5. Whether the garments washed in clean area

V. SANITATION
1. Whether written procedures available for sanitation of sterile

processing facilities
2. Whether more than one sanitizing agent is used and its concentration
used is as specified by the regulatory agency
3. Are the sanitizing agents used in rotation and records maintained
4. Whether records maintained thereof
5. Whether fumigation carried out in aseptic areas. If yes, specity

fumigating agent and its conc.
6. Whether an SOP exist for the purpose of Fumigation
7. Whether air particulate count monitored on a regular basis
vi. EQUIPMENTS
1. DQ, IQ and PQ reports of all the equipments used in sterile production

area
2. SOP for operating equipments
3. Weather written procedures for cleaning of equipment are available
4. Whether SOPs available for each equipment for its calibration,

operation and cleaning
5. Whether calibration status documented and displayed on the of the

equipment and the Gauges
6. Whether the measuring devices attached to equipment calibrated at
suitable intervals
7. Whether a written calibration program is Available
vii. MANUFACTURING PROCESS
1. Whether the bulk raw materials and bulk solutions monitored for
bio-burden periodically
2. BMR and MFR is maintained
3. IPQC test and results
viii. STERILIZATION
1. Whether the sterilizing processes have been validated( Dry heat,

Moist heat, filtration, ETO, ionizations whichever applicable.
2. Whether the validity of the process verified at regular intervals (at

least annually)
3. Whether significant changes made to the equipment and / or the

prodcut. Whether the records of such changes maintained.
4. Whether biological indicators used in monitoring of sterilization.
5. Whether the biological indicators stored and used as per

manufacturers instructions.
6. Whether the label on the basket/tray or other carrier of

product/component clearly states:
• Name of the material
• Its batch number

• Its Sterilization status
• Indicator (in case it has passed through
• sterilization process)
7. Whether sterilization records including thermographs and

sterilization monitoring slips attached with the Batch Production
Record
ix PRODUCT AND CONTAINER CLOSURES
1. Whether the containers and closures used comply to pharmacopoeia

or other specific Requirements
2. To assure suitability of the containers / closures and other

component parts of drug packages, whether they have: Suitable
sample sizes, Specifications , Test methods, Cleaning procedures,
Sterilizing procedures
3. Whether a written procedure exist for washing process. Do they

follow the written schedule for cleaning of the glass bottles
4. Whether the material quality of the stoppers and closures ensures

that it does not affect the quality of the product and avoids the risk
of Toxicity
5. Sterilization test for the containers and closures
X DOCUMENTS
1. Leak test records
2. SOPS
3. Records and reports
4. Inspection records
REFERENCES -
Introduction
Sterile manufacturing Process
GMP for sterile products
Building and facility requirements
Auditing of Sterile preparations
Conclusion
References
Preparation Stage
Filling and sealing stage
Inspection stage
Final packaging stage

Terminal
Sterilizaton
Sterile
Manufacturing
Aseptic
Processing
Premises
Quality Control
Sanitation
Manufacture of sterile preparations
Sterilization
Terminal Sterilization
Filteration
Isolator technology
Blow/Fill/Seal technology
Personnel
Equipment
Finishing of sterile products

• Heat a plastic polymer resin • Inflate it to the shape of
• Extrude it to form a parison (a tubular form of the mold walls
the hot resin) • Fill the formed container
• Cut the parison with a high-temperature knife with the liquid product
• Move the parison under the blow-fill needle • Remove the mandrel
(mandrel) • Seal
Building and facility requirements for
manufacturing sterile products
Membrane
HEPA
HVAC
Auditing of Sterile Preparations
(Checklist)
❖ Name of the material ❖ Its Sterilization status
❖ Its batch number ❖ Indicator (in case it has passed through

❖ sterilization process
Auditing Of Solid Orals
1
Table of contents:
contents Page no.
what is audit? 3
Typical layout of solid orals 4
GMP requirements of warehouse 4
CQA tablet process parameters 7
Audit checklist 8
References 13
2
Audit is a systematic, independent and documented process for obtaining audit
evidence (records, statement of fact or other information which are relevant and
verifiable) and evaluating it objectively to determine the extent to which audit
criteria ( a set of policies, procedures or requirements) are fulfilled.
Dry production includes the oral solid manufacturing unit such as tablets and
capsules.
Typical manufacturing flow:
Solid Blending
dispensing
orals:Tablets,
capsules
dosage form formation

packaging Coating and polishing
compression and filling
Area required for manufacturing of tablets:

▪ Raw material warehouse
▪ Receiving quarantine
▪ Approved raw material section
▪ Dispensary
▪ Production room
▪ Mixing, Granulation and Drying Section
▪ Tablet Punching Section
▪ Coating Section
▪ Quality control section
▪ Packaging Section.
The most commonly used dosages in capsules form hard gelatin capsules. In the
manufacturer of hard gelatin capsules following process operations are used:
✓ Mixing / blending and granulation
✓ Capsules filling
3
✓ Capsules packing
Typical layout of solid orals:
Auditing sequence:
Warehouse Dispensing area granulation tablet
compression
packaging process quarantine coating
GMP requirements for warehouse

✓ Good solid construction, vermin and weather proof
✓ No windows
✓ Suitable floor construction
✓ No open drains
✓ Temperature
✓ humidity control
✓ Rack storage
✓ Status labelling &Quarantine area
4
➢ Auditing of granulation, compression, coating, in process quarantine is mostly
based on the critical quality attributes, process parameters and should include
an examination of the all of the six GMP Systems:
o Quality
o QA Laboratory
o Production
o Facility and Equipment
o Material Handling
o Packaging and Labelling
➢ The instruments should result in an investigation. Measuring, weighing,

recording and control equipment should be of the appropriate range and
precision for the intended operation.
➢ Controls should be established to assure the integrity of the punches and dies
used in compressing tablets.
➢ All equipment and containers used to manufacture a drug should be labelled
at all times.
➢ The label should identify the contents of the container or equipment including
the batch number and the stage of processing.
➢ If the equipment is "in use" the tags and charts associated with the equipment
should indicate the product number, product name and strength and batch
number.
➢ For reusable equipment/containers, previous labels must be removed or
defaced.
➢ If reusable filters are part of the equipment, ensure they are product specific if
needed. Equipment used during the manufacture of a batch should be
identified in the batch record.
➢ Equipment and utensils must be cleaned at appropriate intervals to prevent
contamination and malfunction. Time limits for cleaning of production
equipment after use must be established and followed. There should also be
requirements established for re-cleaning of processing equipment after a
specific period of disuse. Equipment and containers not in use should be
tagged.
Material handling:
5
Raw materials should be weighed in a separate area to prevent cross
contamination. To prevent cross contamination, air pressure differentials should
assure that materials do not migrate outside of weighing area. The air pressure
differentials should be documented. Daily balance checks should be performed
on balances used to weigh raw and in-process materials. Pay attention to cleaning
procedures between products.
Components and product containers:
Written procedures describing how components, drug product containers, and

closures are received, identified, stored, handled, sampled, tested, and approved
or rejected must be adhered to and available for review. If the handling and
storage of components is computer controlled, the program must be validated.
Receiving records must provide traceability to the component manufacturer and
supplier.
Materials Receiving Area:
Ensure that approved procedures are in place for inspection, sampling, testing and
release of incoming materials (raw materials, packaging components, excipients,
etc.). Confirm, through observation that procedures are being followed.
• Determine if raw materials, intermediate products, or final products require
special storage conditions or handling procedures.
• If special storage is needed, confirm that controls are in place to ensure
these conditions are met throughout the holding, manufacturing,
packaging, and distribution process.
Utility systems:
➢ Determine what type of water is used in the process and in equipment

cleaning.
➢ Determine if any compressed gases or other utilities are used in the
manufacturing process.
➢ Ensure that if any utilities contact the product they have been qualified.
➢ Ensure that if filters are used in the process they have been qualified or
validated according to the established approved facility procedures
CQA tablet process parameters:
6
Unit operation Process parameters Quality attributes
Mixing 1. Order of addition ➢ Particle size
2. Mixer load level distribution
3. Impeller speed and time ➢ Bulk/tapped density
4. Chopper speed and time ➢ Moisture content
➢ Flow properties
Milling 1. Impact/ cutting/ screening ➢ Particle size
mills direction ➢ Particle shape
2. speed of mill ➢ Flow properties
3. screen size ➢ Polymorphic form
Wet granulation 1. pre-binder addition mix ➢ Blend uniformity
time flow
2. impeller speed ➢ Moisture content
3. chopper speed ➢ Particle size
4. binder fluid temperature ➢ Particle size
distribution
Spray granulation 1. spray nozzle type & ➢ Blend uniformity
location flow
2. binder addition rate & ➢ Moisture content
time ➢ Particle size
3. bowel temperature ➢ Granule size
4. fluid bed granulation ➢ Residual solvents
mixing time
5. inlet air flow rate
Drying (FBD) 1. Inlet airflow rate, volume, ➢ Granule size
temperature, dew point ➢ Granule strength
2. Exhaust air temperature ➢ Particle size
3. Shaking intervals ➢ Moisture content
4. Product temperature ➢ Residual solvents
Drying (tray dryer) 1. Trays per chamber ➢ Granule size
2. Quantity of product per ➢ Granule strength
tray ➢ Particle size
3. Drying time & ➢ Moisture content
temperature ➢ Residual solvents
4. Air flow
Roller compaction 1. Roll speed ➢ Appearance
2. Gap setting ➢ Density, strength &
3. Roll pressure thickness of solid
4. Auger screw rate form
Compression 1.) Compression speed ➢ Target weight
2.) Force pre-compression ➢ Content uniformity
3.) Force main compression ➢ Weight uniformity
4.) Force feed frame type & ➢ Hardness
speed
Coating 1.) Product temperature ➢ Moisture content
2.) Total pre-heating time ➢ Weight of core
3.) Spray nozzle (type/ ➢ Tablet appearance
quantity/ pattern/ ➢ %weight gain
configuration) ➢ Film thickness
7
4.) Individual gun spray rate ➢ Colour uniformity
5.) Total spray rate ➢ Hardness
6.) Pan rotation speed
7.) Atomization air pressure
pattern
8.) Air pressure
9.) Inlet air flow,
temperature, dew point
10.) Exhaust air temperature,
air flow
11.) Product temperature
12.) Total coating time
Audit checklist:
S.no Check list point Yes No Remarks
Warehouse
1 Whether storage area is adequately
designed for better storage
conditions?
2 Whether cleaning record is
maintained or not?
3 Is there adequate space for orderly
storage of all materials,
intermediates, finished products,
and also a product in quarantine,
released, rejected, returned or
recalled
4 Whether separate sampling area for
active Raw Materials and Excipients
is provided and maintained.
Whether log book for sampling
booth maintained.
5 How highly hazardous, poisonous
and explosive materials, narcotics,
and psychotropic drugs are handled
and stored.
6 What provisions have been made to
prevent the entry of rodents, insects,
birds.
Dispensing area
7 Whether dispensing of sop is
followed
8
Do the personnel receive updated
training?
8 Are the dispensed materials with
proper status labelled?
9 Is the dispensing activity is carried
out under RLAF or not
10 How containers are cleaned before
and after dispensing. Who carries
out the dispensing?
11 What is the control on entry of
material and men into the
dispensing area?
Does this identification include:
1.the name of the raw material or
component
2. the batch and another control
number of raw material
3.the batch number of drug product
to be manufactured
4.the quantity that was weighed
5. the signature of checker
Granulation
12 Are the characteristics of initial
powder blend wet/dry granulation
and the final blends mentioned?
13 Is the particle size distribution
determined?
14 Is the density of wet granulation and
dry powder compared?
15 Granulating agent used is proper or
not?
Compression
16 pressure used is proper or not?
17 Compression speed is in specified
limit or not
18 hardness and friability of tablets
correct or not
Coating
19 Coating apparatus is cleaned or not
20 Coating speed is in specified range
or not
21 Total coating time is recorded or not
9
22 Air pressure is maintained or not
23 Moisture content is checked or not
Production area
24 specify the design of the
manufacturing area which allow
uniflow and logical sequence of
operations so as to prevent product
contamination/ mix ups.
25 Specify the position of IPQC lab in
the manufacturing area .
26 Is the optimal blending time based
MFR
Qc area
27 Whether QC carries out its own:
• physico-chemical testing,
• biological testing,
• microbiological testing &
sterility testing and
• Instrumental testing.
Whether firm is outsourcing
testing. If yes names of the testing
laboratories contacted or approved.
28 Is there separate area for humidity
chambers for stability studies
29 Whether separate AHU's are
provided for biological,
microbiological and radio iso-topes
testing areas with HEPA filter
arrangement.
Are the operating ranges defined?
30 Are the tests used to assess the
uniformity of the final product
determined?
Content uniformity ,weight
variation testing?
31 For colour uniformity ,is there a
provision for colour uniformity test?
32 Is Validation Master Plan available?
33 For colour uniformity ,is there a
provision for colour uniformity test?
Documentation and record
10
34 Whether documents are approved
signed and dated by appropriate and
authorized person.
35 Whether master formula and
detailed operating procedures are
maintained as hard copy.
36 Do the complaint records include
the
following:
• name and address of
complaint
• name and phone number of
person
submitting the complaint
• complaint nature (including
name
and batch number of API)
• date complaint is received
• action taken (including
person
taking the action)
• any follow-up, if applicable
• response provided to the
originator
of complaint including date
of
response
• final decision on API
How master formula records are
prepared authorized and controlled
Whether following information are
recorded in BPR
a. The name of the product,
b. The number of the batch being
manufactured,
c. Date and time of commencement,
sign,
d. The batch number and analytical
control no. as well as quantities of
each starting material actually
weighed,
11
e. The record of IPQC and the
initials of the person(s) carrying
them out.
f. The amount of product obtained
after different and critical stages of
manufacture (yield)
37 Are the records of complaints
retained? For how long? Are trends
or recurring complaints evaluated?
38 Whether data is recorded by
electronic means or any other
means.
Mixing
Specify the following points:
a. Instrument used for mixing
b. Type and geometry of mixing
c. Blend uniformity
d. Number of rotations e. Particle
size distribution
Packaging
Specify the following :
1. Type of packaging
2. Label details
12
References :
1.
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Smal
lBusinessAssistance/UCM456367.pdf .
2. auditing an oral solid solution area [Internet]. www.gmpsop.com. .
https://www.gmpsop.com/sample/Audit-022-Auditing-an-Oral-Solid-
Solution-Area-sample.pdf .
3. http://pharmapathway.com/critical-quality-attributes-tablet-process-
parameters/
4. https://www.pharmaguideline.com/2017/09/checklist-to-review-tablet-
process-validation.html
5. https://www.pharmaguideline.com/2017/09/checklist-for-audit-in-
warehouse.html
13
Auditing of Solid orals
1
Contents
• What is audit?
• Typical manufacturing flow
• Typical layout of solid orals
• GMP requirements of warehouse
• CQA tablet process parameters
• Audit checklist
2
What is Audit?
• Audit is a systematic, independent and documented process for
obtaining audit evidence (records, statement of fact or other
information which are relevant and verifiable) and evaluating it
objectively to determine the extent to which audit criteria ( a set of
policies, procedures or requirements) are fulfilled.
• Dry production includes the oral solid manufacturing unit such as
tablets and capsules.
3
Typical manufacturing flow
Solid orals:Tablets,
capsules dispensing Blending dosage form formation
compression and filling
packaging Coating and polishing
4
Typical layout of solid orals
5
GMP requirement of warehouse
• Good solid construction, vermin and weather proof
• No windows
• Suitable floor construction
• No open drains
• Temperature
• humidity control
• Rack storage
• Status labelling &Quarantine area
6
• Auditing of granulation, compression, coating, in process quarantine is
mostly based on the critical quality attributes, process parameters and
should include an examination of the all of the six GMP Systems:
• Quality
• QA Laboratory
• Production
• Facility and Equipment
• Material Handling
• Packaging and Labelling
7
Material handling
• Raw materials should be weighed in a separate area to prevent cross
contamination.
• To prevent cross contamination, air pressure differentials should
assure that materials do not migrate outside of weighing area.
• The air pressure differentials should be documented.
• Daily balance checks should be performed on balances used to weigh
raw and in-process materials.
• Pay attention to cleaning procedures between products.
8
Components and product containers
• Written procedures describing how components, drug product
containers, and closures are received, identified, stored, handled,
sampled, tested, and approved or rejected must be adhered to and
available for review.
• If the handling and storage of components is computer controlled,
the program must be validated.
• Receiving records must provide traceability to the component
manufacturer and supplier.
9
Materials Receiving Area
• Ensure that approved procedures are in place for inspection,

sampling, testing and release of incoming materials (raw materials,
packaging components, excipients, etc.). Confirm, through
observation that procedures are being followed.
• Determine if raw materials, intermediate products, or final products
require special storage conditions or handling procedures.
• If special storage is needed, confirm that controls are in place to
ensure these conditions are met throughout the holding,
manufacturing, packaging, and distribution process.
10
Utility Systems
• Determine what type of water is used in the process and in
equipment cleaning.
• Determine if any compressed gases or other utilities are used in the
manufacturing process.
• Ensure that if any utilities contact the product they have been
qualified.
• Ensure that if filters are used in the process they have been qualified
or validated according to the established approved facility procedures
11
CQA tablet process parameters
Unit operation Process parameters Quality attributes
Mixing 1. Order of addition ➢ Particle size distribution
2. Mixer load level ➢ Bulk/tapped density
3. Impeller speed and time ➢ Moisture content
4. Chopper speed and time ➢ Flow properties
Milling 1. Impact/ cutting/ screening mills ➢ Particle size

direction ➢ Particle shape
2. speed of mill ➢ Flow properties
3. screen size ➢ Polymorphic form
Wet granulation 1. pre-binder addition mix time ➢ Blend uniformity flow

2. impeller speed ➢ Moisture content
3. chopper speed ➢ Particle size
4. binder fluid temperature ➢ Particle size distribution
12
Spray granulation 1. spray nozzle type & ➢ Blend uniformity flow
location ➢ Moisture content
2. binder addition rate & ➢ Particle size
time ➢ Granule size
3. bowel temperature ➢ Residual solvents
4. fluid bed granulation mixing time
5. inlet air flow rate
Drying (FBD) 1. Inlet airflow rate, volume, temperature, ➢ Granule size

dew point ➢ Granule strength
2. Exhaust air temperature ➢ Particle size
3. Shaking intervals ➢ Moisture content
4. Product temperature ➢ Residual solvents
Drying (tray dryer) 1. Trays per chamber ➢ Granule size

2. Quantity of product per tray ➢ Granule strength
3. Drying time & temperature ➢ Particle size
4. Air flow ➢ Moisture content
➢ Residual solvents
Roller compaction 1. Roll speed ➢ Appearance

2. Gap setting ➢ Density, strength & thickness of solid
3. Roll pressure form
4. Auger screw rate
13
Compression 1.) Compression speed ➢ Target weight
2.) Force pre-compression ➢ Content uniformity
3.) Force main compression ➢ Weight uniformity
4.) Force feed frame type & speed ➢ Hardness
Coating 1.) Product temperature ➢ Moisture content

2.) Total pre-heating time ➢ Weight of core
3.) Spray nozzle (type/ quantity/ ➢ Tablet appearance
pattern/ configuration) ➢ %weight gain
4.) Individual gun spray rate ➢ Film thickness
5.) Total spray rate ➢ Colour uniformity
6.) Pan rotation speed ➢ Hardness
7.) Atomization air pressure pattern
8.) Air pressure
9.) Inlet air flow, temperature, dew
point
10.) Exhaust air temperature, air flow
11.) Product temperature
12.) Total coating time
14
Audit Checklist:
• Warehouse
• Dispensing area
• Mixing
• Granulation
• Compression
• Coating
• Production area
• QC area
• Documentation and record
• packaging
15
Conclusion
• Auditing helps any organization to recognize the deficiencies in their
processes and quality systems.
• Regular internal and external auditing will promotes great confidence
and communication between organization and regulatory bodies as
well as between organization and customers.
16
References
1.https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Sm
allBusinessAssistance/UCM456367.pdf
2. auditing an oral solid solution area [Internet]. www.gmpsop.com. .
https://www.gmpsop.com/sample/Audit-022-Auditing-an-Oral-Solid-
Solution-Area-sample.pdf
3. http://pharmapathway.com/critical-quality-attributes-tablet-process-
parameters/
4. https://www.pharmaguideline.com/2017/09/checklist-to-review-tablet-
process-validation.html
5. https://www.pharmaguideline.com/2017/09/checklist-for-audit-in-
warehouse.html
17
18
Auditing Of Vendor
1|Page
Table of Contents
S.no Topic Page no.
1 Introduction 3
2 Vendor audit 4
3 Audit process 6
4 Checklist for 13
vendor audit
2|Page
Introduction:
Audits are an effective means of evaluating compliance with the objectives of the
quality system and providing feedback to management as part of a continuous
improvement program.
In simplistic terms, the "vendor" or "supplier" is the seller to a manufacturer of

finished dosage forms.
Selection of vendor:
It is the process whereby the vendor is approved by the finished dosage form
manufacturer for given material that will be used in specific product.
Qualification of vendor:
This is accomplished by demonstrating that the materials meets all of the

established specifications consistently, with test results that show comparability
between the API and dosage form laboratories and with established GMP
compliance of the API plant.
In this qualification process, the vendor will be determined to be acceptable to

supply the API that meets the established specifications.
Certification of an API vendor occurs after qualification.
Vendor audit is one of the steps in vendor qualification.
Audit:
An audit is a two-way process in which compliance (or otherwise) is reviewed
and discussion takes place on how improvements can take place.
Companies that are manufacturing in the pharmaceutical industry become

accustomed to being audited on a regular basis, and also need to be able to
organize and run inspections themselves.
Auditing of manufacturing facilities tend to go through a number of stages, which

together build towards a cohesive programme. Starting from the base, there is the
3|Page
informal self-inspection that takes place on a daily basis by operators and
managers alike. If something is seen to be wrong, it is immediately put right.
Next there is the formal self-inspection process that takes place on a regular basis,
and is a specified requirement of GMP.
Finally, there is the external inspection. This will come from a number of sources.
Vendor audit:
Conducting internal audits (self inspections) and external audits of suppliers and
outsourcing operations are key elements of a good quality system. All CGMPs
require that materials only be purchased from approved suppliers.
Auditing of suppliers is a key part of ensuring that the supplied material are being
produced according to GMPs and ensuring product is produced (product
realization) using materials meeting the required quality characteristics. 2
Auditing plays a key role in three objectives: Achieve product realization,

establish and maintain a state of control, and facilitate continual improvement. In
order to achieve product realization, appropriate quality materials must be
purchased from approved suppliers; supplier approvals may involve supplier
audits
Within the EU code of GMP, it states that materials should only be purchased
from approved suppliers and that all aspects of the manufacture and distribution
of materials should be reviewed with the supplier and with the manufacturer, if
they are not one and the same company. By implication, this means that, wherever
possible, an audit of the suppliers’ premises should be carried out as part of the
approval process.
Who conducts the supplier audits?

A supplier audit will involve more than one function within the company. The
process will generally be lead by the quality assurance department, but will
also concern the purchasing department, as well as production and possibly
engineering, depending on the material being purchased. Not all these
departments need to be represented during the audit, but all should be involved
in the preparatory work and the decision on whether to approve the supplier or
not.
4|Page
Audit team:
Auditing is performed by qualified and trained personnel that are capable of

using certified auditing guidelines and practices. Selection of auditors mainly
depends on the type and criticality of the audit.
On what basis vendors are audited:
Many companies have a long-established list of suppliers. Supplier audits are not
performed for all the suppliers. It is performed for those suppliers who are new
in market or those who failed to provide quality products. Any supplier audit
should be conducted based on the risk they have to your business
If this were the case, then the first step in preparing for an audit would be to
review the history of the relationship between the company and the supplier.
What is their performance on deliveries, in terms of accuracy and timeliness?

How does the material perform during processing; does it cause problems within
production? What other information is already on file about the supplier?
When carrying out the audit, the team should focus on any major issues
highlighted by the questionnaire, but also review the systems and premises
against requirements of GMP.
EU GMP Annex 8 provides the following useful items to include

when evaluating a supplier:
• The nature and status of the manufacturer and of the supplier or
outsourcing operation and their understanding of the GMP requirements of
the pharmaceutical industry
• The quality management system of the supplier or outsourcing operation
• The conditions under which the material is produced and controlled
• The nature of the material and the products in which it will be used.
• Check out the suppliers capabilities against company's needs
• See if supplier has the capacity to handle company’s requirements and how
quickly they can deliver
5|Page
Once a supplier has been approved, it will be necessary to monitor their
performance over time and occasionally revisit the premises. However, it is
unlikely that an annual visit will be required, as would be expected for regulatory
inspections of manufacturers’ facilities.
Performing audit:
It is important to clearly establish the reason for performing the audit (e.g. new
supplier; outsourcing; defect/recall investigation; routine re-audit; remedial
action follow-up; etc.) in order to determine the type, scope and specific
objective(s) of the audit
For a potential new supplier, there is less information available; although analysis
of a sample of material to ensure it complies with the purchase specification
should be a first step.
Supplier audit is not performed for all the suppliers. It is performed for those
suppliers who are new in market or those who failed to provide quality products.
Any supplier audit should be conducted based on the risk they have to your
business.
It is useful to send the supplier a pre-audit questionnaire, to be completed in

advance of the visit. From experience, it is better to keep this questionnaire to just
a few pages and to provide it to the supplier at least one month before the date of
the audit, in order to guarantee receiving the completed form in good time. 3
The person conducting the audit may want to use a checklist developed for this
purpose for two main reasons.
(1) The checklist will include all areas of the audit to be covered so that nothing
will be forgotten.
(2) Boxes on the checklist can be marked, with brief comments that can be added
by the auditor, obviating the need for much time spent writing, and allowing for
more time to be spent observing the facility and asking plant personnel questions
in a dialogue.
An example of the framework for such a checklist is shown
6|Page
It is always best to start at the beginning, i.e., at the raw material storage area, and
follow through the process in the manufacturing sequence to the final dispatch to
the customer, covering all aspects of GMP at each stage.
GMP requirements for
• Raw material storage:

Aim ensure that the raw materials are stored correctly, do not deteriorate, and are
not contaminated prior to use, special storage conditions may be required for
some material
• A building of good, solid construction and design to minimize vermin

infestation, i.e.,
• birds, insects, mice, etc. The Large access doorway to the storage area is
usually the main entry point for such infestation, therefore, this should be
kept closed as much as possible.
• The building should preferably have no windows, as sunlight can
deteriorate, discolor, or fade materials.
• It should have a sealed concrete floor or similar material that minimizes
dust generation
7|Page
• Open drains must not be present in the warehouse. This would be a
potential bacteriological risk that might contaminate the raw materials.
• Extremes of heat, cold, and dampness should be avoided. Air conditioning
may be necessary to prevent the deterioration of some materials.
• Adequate segregation of different materials to prevent possible mix-ups,
damage, or contamination (eg: material with a strong odour) is necessary.
Liquids should be stored at the ground level, with a catchment area in
case of spillage. No items should be stored in direct contact with the
ground. High rack storage should be used to make the most efficient use
of space available and to prevent damage of materials from placing one
full pallet on top of another. An overcrowded storage area can create the
above mentioned problems and can make access difficult. Stock rotation
may not always be possible as a result.
• Status labelling and quarantine areas should be set aside for storage of
materials awaiting testing and rejection. This is sure way of ensuring that
such materials are not used by mistake.
GMP REQUIREMENTS FOR THE FORMULATING AREA:

• A dedicated clean area must be available for weighing and mixing
materials.
• Authorized formulation procedures must be available and followed.
• Only one formulation is to be weighed and mixed at a time in any one area
to prevent mix-ups and cross-contamination.
• The container into which each material is weighed must be clearly
labelled.
• Weighing equipment must be calibrated regularly with standard weights
and should have a calibration certificate that is traceable to the National
Bureau of Standards (or the relevant country equivalent for overseas
suppliers). Ensure that the weighing equipment is calibrated over the
whole of its weighing range. A record must be kept of these checks.
• Each operator and supervisor must be fully trained with a full appreciation
of the GMP aspects of the job.
GMP REQUIREMENTS FOR PRODUCTION OF COMPONENTS:
• Each machine must be separated by a barrier or at least sufficient space

to ensure that neither materials nor staff overlaps can occur. Ideally there
should be a separate room for each machine. This is to prevent cross-
8|Page
contamination between machines, i.e., rogues. Primary components
should be produced in a clean area.
• Staff allocated to one machine must not be allowed to wander freely
between machines.
• Prior to the start of production, a check must be made to ensure that
everything is correct. The machine and area must be thoroughly cleaned
and completely free from materials used or produced on the machine
previously.
• Each batch produced from a machine must be quarantined until
considered suitable for passing by quality assurance. With a good IPC
system, this will probably be when the production run has finished, and
hence it can be passed immediately. Otherwise the batch must be placed
in a quarantine area or at least be labelled quarantined.
FINISHED PRODUCT STORAGE AREA:

• This must be of the same standard as the raw material storage.
• Each order must be kept separate, and preferably each batch in an order
should be kept separate, e.g., on a separate pallet.
• Rack storage should be used.
• Loaded pallets should not be stacked on top of one another unless the
component packaging has been designed to take the weight.
Documentation:
An API manufacturing operation must utilize written procedures that are

followed to describe the manufacturing and control operation.
These SOPs should be assembled into a manual that is available for personnel
in performing their assigned functions.
Other documentation includes raw material and packaging component

specifications, in-process and finished product specifications, process controls,
laboratory test methods, master manufacturing formulas and batch records,
stability records, validation records, and so on-to cover the areas of GMP.
• Is there proper documents or records for incoming goods, does it include

following information,
a) Receiving document number?
b) Date of receipt?
c) Date of releasing?
9|Page
d) Date of expiry, if any?
Personnel:
"People" are one of the major elements in a manufacturing operation. It is
very important that personnel be trained in the duties and responsibilities
that they are expected to perform.
If personnel training are not conducted, following an explicit procedure,

then there will not be assurance that a manufacturing and control process
will be performed properly and consistently
Further, these procedures may not be clear or in sufficient detail and this
may not be discovered unless people are trained properly.
 Number and qualification of personnel in manufacture and quality control?
 Is there a company training scheme?

 How personnel clothing and health monitoring are controlled?
 Do personnel receive up-date GMP training? How often?
Storage and packaging
 Are the storage areas properly cleaned and well equipped?

 Are there proper procedures and system for storage and preservation of
products?
 Are the stored products inspected regularly for deterioration?
Non conformance
 Is there a separate area for non conforming substances or products to avoid

there use?
 Is the re procedure material retested to check its conformance to recognized
standards?
 Has the company formed a system to notify customers about a non
conforming product that has been shipped already?
10 | P a g e
Manufacturing procedure
 Are written process instructions in force?

 Are the substances/materials used specified?
 Is documentation done?
 How are deviations dealt with?
Quality Assurance Program
An API manufacturer must have an ongoing quality assurance program in

order to comply with the basic concept of GMP.
Production personnel should build quality into the manufacturing operation

and the products they manufacture;
The manufacturing process for a product should include process controls

and in process tests, in addition to finished product testing, in order to
assure that the manufacturing process is in control and to provide a higher
level of assurance that the finished product will meet its established
specifications.
Furthermore, a manufacturer must have a quality unit
Following GMP principles, this unit has the basic responsibility and
authority to approve or reject all manufacturing components, products, and
procedures.
It should be described in sufficient detail so that all manufacturing and

control personnel understand clearly that the function of the quality unit is
to test and issue disposition; the function of production personnel is to
manufacture products that utilize written procedures and that incorporate
quality principles.
11 | P a g e
Quality control
 Has the company established an inspection team to inspect quality and

conformance of incoming materials with set standards?
 Is the Quality control staffs adequately trained?
 Has the company established a separate area for inspection of incoming raw
materials?
 Does the organization maintain quality control records efficiently?
 Has the company established the manufacturing plan before starting the
operation?
 Is suitable analytical apparatus available?
 Is the analytical apparatus maintained and calibrated?
 Do written analytical procedures exist?
 Does a sampling plan exist?
Observations and Report of Audit:
An important point to check during the audit is how the supplier handles
changes. This applies to changes initiated by the pharmaceutical
manufacturer and to those made by the supplier.
The single most important product of an audit is the audit report
After vendor audit a vendor audit report classifying the observations as critical,
major and minor with recommendations shall be issued to the vendor within
specified period.
Upon making observations, classify them as minor, major, or critical. The

vendor/supplier must understand the level of importance of the observation.
A minor observation is any non-conformance or non-compliance that if

allowed to continue has a low risk of affecting product quality. The
observation represents limited or minor gaps in one or more quality systems.
A major observation is any non-conformance or non-compliance that if

allowed to continue has a moderate risk of adversely affecting product
12 | P a g e
quality. The observation represents significant gaps in one or more quality
systems.
A critical observation is any non-conformance or non-compliance that

already has or if allowed to continue presents high risk of adversely affecting
product quality. The observation represents the complete absence or
systematic lack of one or more quality systems. The observation is a
repeated major observation or one that fails to meet a commitment of a
regulatory authority.
The vendor shall reply to the audit report with the action plan on CAPA along
with the expected date of completion of CAPA items.
The quality function shall follow up with supplier on the implementation and
compliance of CAPA items suggested in the CAPA plan.
CHECKLIST FOR VENDOR AUDIT:
Company: Auditor(s):
Location, Country: Date of audit:
S.NO AUDIT QUESTIONS YES NO REMAR

KS
Does the supplier’s assurance system ensure
1. that all purchased product or material
conforms to defined specifications of
applicable regulatory or customer
requirements?
2. Is the storage area designed as per the GMP
requirements or not?
3. Any appropriate pest control measures are
taken to prevent pest infestations?
4. An organised storage (High rack storage) and
stock control system is followed or not?
13 | P a g e
5. Whether storage area has adequate lighting
and air quality?
6. Did all the records for storage, material flow

and pest control inspections are maintained?
7. Whether weighing equipment used is

calibrated regularly?
8. Whether the formulation procedures are

authorised or not?
9. All weighing and mixing operations are
recorded or not?
10. Whether sufficient space is there between
machines to prevent cross contamination?
11. Whether the storage area, manufacturing
facilities and equipment are clean or not?
12. Any pre-production checks are there to

ensure that everything is correct?
13. Did each production line have an effective

Inprocess control system (IPC)?
14. Did all the In process control (IPC) checks

are recorded or not?
15. Whether all the staffs are fully trained by

experienced personnel?
16. Are suitable methods used to verify training

effectiveness?
17. Are suitable records of all types of training

are maintained?
14 | P a g e
18. Records for issue of tooling and equipment
are maintained or not?
19. Did the manufacturing process/equipment

are validated or not?
20. Any records of secured disposal of specified
materials (printed) are maintained?
21. Whether supplier transportation system can

supply the quality product within delivery
time?
22. Is a corrective action system in place that
provides root cause analysis and takes timely
and effective action to prevent recurrence?
23. Whether customer needs and requirements

incorporated into product designs and/or
manufacturing processes? And/or
manufacturing processes?
24. Does customer notification/approval occur

for changes to control plans, manufacturing
site, product transfers, raw material or
product obsolescence?
25. Is there any effective complaint handling

system?
26. Whether the vendor has sufficient equipment

and labour to supply bulk orders?
27. Vendor is financially capable?
28. Is packaging stored to prevent cross

contamination?
15 | P a g e
29. Is the facility’s use restricted to the storage of
packaging materials?
30. Are packaging materials rotated using FIFO
policy?
31. Are packing operations segregated from
production?
Conclusion:
Vendor evaluation or supplier audits should be done once in a year. In this kind
of audit, the vendor's location, the products and his manufacturing unit should be
audited and checked well. The kind of audit and how many times it should be
done depends on the kind of products and service the company is using or buying
from the vendor. It also depends on how important is that vendor and his products
for company's business. Based on that, one can decide on the kind and times an
audit should be done.
A supplier audit checklist is really necessary part for a successful audit and is
defining what to cover during the audit. It also helps as support to ensure areas
don’t get neglected during the audit..
A quality audit determines whether a new supplier is basically suitable for

producing components to the standard required or whether an existing supplier is
continuing to produce at the standard required.
References
1. Fields, T.I.M. Auditing as a Component of a Pharmaceutical Quality
System. Journal of GXP Compliance. 2008;12(5): 61-68.
16 | P a g e
2. . Berry, VENDOR QUALIFICATION . In: Berry, I.R.A.R (ed.) Validation of
Active Pharmaceutical Ingredients . : CRC Press; 2001. p. 343-364.
3. Supplier qualification & management guideline by active pharmaceutical
ingredients committee;retrieved from:
https://apic.cefic.org/pub/guidelinesupplierqualification
and edit info Copy to Clipboard
17 | P a g e
Auditing Of Vendor
1
INTRODUCTION
❖ Vendor: In a supply chain, a vendor is an enterprise that
contributes materials
❖ Audits: An audit is a two-way process in which compliance (or

otherwise) is reviewed and discussion takes place on how
improvements can take place.
❖ Auditing of suppliers/vendors is a key part of ensuring that the

APIs/excipients/packaging materials are being produced
according to GMPs and ensuring product is produced using
materials meeting the required quality characteristics.
2
Purpose
Vendor audits are used to verify on-site whether the

supplier/vendor is in the position to manufacture and supply
materials of the desired quality.
The EU GMP Guideline does not give any more precise

specifications regarding the scope of the inspection.
3
VENDOR AUDITS
❖ A drug product comprises of an API, Excipient and the

Packaging material (Primary & Secondary) and all these play
an important role in the quality and efficacy of the product.
❖ Auditing of suppliers is a key part of ensuring that the all these

materials are being produced according to GMPs.
❖ Events such as the recalls due to contaminated heparin, have

focused attention on ensuring that the controls are in place for
the entire supply chain.
4
WHEN TO EVALUATE SUPPLIER
❖ New material from new /existing vendor
❖ Existing material from a new vendor (alternate vendor)
❖ Change in manufacturing location of vendor
❖ Routine periodical requalification
❖ Resumption of supplies after a gap of 2 years or more
❖ Resumption of vendors after suspension/disqualification

5
WHO CONDUCTS
❖ The process will generally be lead by the quality assurance

department, but will also concern the purchasing department
as well as production.
❖ Audit team:
Auditing is performed by qualified and trained personnel that

are capable of using certified auditing guidelines.
6
Items To Include When Evaluating
Supplier:
❖ The quality management system of the supplier or outsourcing
operation
❖ The conditions under which the material is produced and

controlled
❖ Check out the suppliers capabilities against company's needs
❖ See if supplier has the capacity to handle company’s

requirements and how quickly they can deliver
7
VENDOR AUDIT PROCESS
An audit cycle includes:
i. The preparation of an audit

ii. Performing the audit
iii. Reporting the results
iv. Audit closure/ follow up
8
❖ Step 2: Performing audit
❖ This begins with introductory meeting wherein all parties are

introduced and agenda is discussed.
❖ The inspection is carried out on the basis of a checklist
❖ Collection of evidence and verification of information.
9
❖ Vendors can be audited for
1. GMP requirements:
i. raw material storage
No open Temperature
Suitable floor
construction drains humidity
control
No Rack storage
windows Stock rotation
Good solid RAW Status labelling

construction , MATERIAL &
vermin and weather STORAGE
proof Quarantine area
10
ii. Formulation area
One batch to
be mixed at a
time in an
area Clearly
Dedicated labelled
clean room containers
FORMULATION
Calibrated Authorized
formulating
Weighing
equipment procedure
Trained
staff
11
iii. Production area
Separated machines with defined working areas

Restricted staff movement between machines
Check materials are correct for production

Check machine and area are clean before starting production
Check first samples produced

Quarantine each production batch until passed by QA
12
Finished product storage area
❖ This must be of the same standard as the raw material

storage.
❖ Each order must be kept separate, and preferably each batch
in a order must be kept separate.
❖ Rack storage should be used.
13
2. Personnel:
✓ Number and qualification of personnel in manufacture and
quality control?
✓ Is there a company training scheme?
✓ How personnel clothing and health monitoring are controlled?
✓ Do personnel receive up-date GMP training? How often?
14
3. Quality control
❖ Is the Quality control staffs adequately trained?

❖ Has the company established a separate area for inspection of
incoming raw materials?
❖ Does the organization maintain quality control records
efficiently?
❖ Is suitable analytical apparatus available?
❖ Is the analytical apparatus maintained and calibrated?
❖ Do written analytical procedures exist?
15
4. Non conformance
✓ Is there a separate area for non conforming substances or

products to avoid there use?
✓ Is the material retested to check its conformance to recognized
standards?
✓ Has the company formed a system to notify
customers(manufacturing premises) about a non conforming
product that has been shipped already?
16
• Are the supporting sales documents relating to the customer
and the batch retained?
• How are the accuracy of the delivery and adherence to delivery
dates guaranteed?
17
❖ Step 3:Reporting of results:
❖ Audit report should present a summary of findings.

❖ Written summary prior to leaving the vendor’s facility
❖ After vendor audit a vendor audit report classifying the
observations with recommendations shall be issued to the
vendor within specified period.
18
Step 4:Corrective action and Follow up
❖ After audit, vendor is responsible for developing a corrective

action plan to address any weaknesses identified
❖ It is sponsor's responsibility to ensure that the corrective

actions are effective and implemented in timely manner.
❖ The sponsor must verify all commitments through Routine

monitoring
19
Frequency of audit
❖ Supplier should be audited for every 1-2 years, or whenever a

serious problem is encountered.
20
Company: Auditor(s):
Location, Country: Date of audit:
S.NO AUDIT QUESTION YES NO REMARKS

1 Are all the areas in the premises are
designed as per the GMP requirements or
not?
2 A organised storage (High rack storage) and
stock control system is followed or not?
3 Whether storage area has adequate lighting

and air quality?
4 Does the supplier assurance system ensure

that all purchased product or material
conforms to defined specifications
5 Any appropriate pest control measures are
taken to prevent pest infestations?
6 Are all the records of storage, material flow 21
and pest control inspections are maintained?

7 All weighing and mixing operations
are recorded or not?
8 Whether sufficient space is there

between machines to prevent cross
contamination?
9 Whether the storage area,
manufacturing facilities and
equipment are clean or not?
10 Any pre-production checks are there
to ensure that everything is correct?
11 Whether all the staff are fully trained

by a experienced personnel?
12 Are suitable methods used to verify

training effectiveness?
13 Whether weighing equipment used are

calibrated regularly? 22
14 Are suitable records of all types of
training are maintained?
15 Records for issue of tooling and
equipment are maintained or not?
16 the manufacturing process/equipment
are validated or not?
17 Any records of secured disposal of
specified materials (printed) are
maintained?
18 Whether supplier transportation system
can supply the quality product with in the
delivery time?
19 Is a corrective action system in place
that provides root cause analysis and
takes timely and effective action to
prevent recurrence?
20 Whether customer needs and 23
requirements incorporated into product
21 Is there any effective complaint handling

system?
22 Whether the vendor has sufficient

equipment and labour to supply bulk
orders?
23 Vendor is financially capable or not to
handle multiple orders?
24 Are packing operations segregated from

production?
24
Conclusion
❖ The quality of product is also important for maintaining the drug
quality.
❖ If company has to grow and flourish in the business, then it is

always best to do proper checks of the equipment and raw
material that the vendor is supplying for the said business.
25
References
❖ Fields, T.I.M. Auditing as a Component of a Pharmaceutical
Quality System. Journal of GXP Compliance. 2008;12(5): 61-68.
❖ Berry, vendor qualification . Validation of Active Pharmaceutical

Ingredients . : CRC Press; 2001. p. 343-364.
❖ Supplier qualification & management guideline by active

pharmaceutical ingredients committee;
❖ Retrieved from:
https://apic.cefic.org/pub/guidelinesupplierqualification
26
Auditing of Microbiological laboratory
Syllabus: Auditing the manufacturing process, Product and process

information, General areas of interest in the building raw materials,
Water, Packaging materials.
Auditing the manufacturing process
Why audit?
Microbes have a proven ability to contaminate both product and process.
Widely distributed in the general environment, often in considerable numbers,
they are extremely versatile and can thrive in hostile environments. Not
surprisingly, the pharmaceutical industry goes to great expense to minimize
the risk of microbiological contamination. As discussed elsewhere, this is
achieved through good-quality raw materials and components, control of the
production environment, design of facilities and utilities, contamination
control procedures and a well-trained work-force with a good understanding
of the importance of basic hygiene, basic microbiology and why
contamination control measures are so important. Any audit of the production
environment provides an ideal opportunity to challenge the
suitability of contamination control practices. Throughout any such audit, the auditor
has the following key questions in mind:
• Is there a potential source of microbiological contamination?
• Is the process vulnerable?
• Is there a risk of contamination reaching the product?
• What is the ultimate risk to the safety, quality and efficacy of the product. In other
words, is the patient at risk?
Since there is always a source of microbiological contamination, the auditor must
make a balanced judgement as to its significance to the process and, ultimately, to the
product.
As with any audit, time is limited and the auditor is duty-bound to make best use of
the time available. In deciding where effort should be concentrated, the following
information should be gathered at the earliest opportunity.
Product information
Here, relevant factors are the microbiological status of the product (sterile or
non-sterile), the physical nature of the dosage form (dry, liquid, cream,
ointment), and whether the product supports microbial growth.
Process information
Factors to be considered here include: the raw materials used in the
manufacturing process; whether the process is vulnerable to contamination
(i.e. open) or whether the product is well protected (i.e. a closed process);
whether the product is exposed to recontamination sources and how the
contamination risk is controlled; whether there is any storage of intermediate
materials; and the total duration of the manufacturing process.
General areas of interest in the building
Walls and ceilings
Moulds are the most commonly encountered microbes on walls and ceilings,
particularly when poor ventilation, temperature and relative humidity control
lead to high levels of moisture. Contamination may be excessive where
damaged surfaces expose the underlying plaster. Surfaces should be smooth,
impervious and cleanable; damaged surfaces should be repaired promptly.
Floors and drains
Floors should be impervious to water, cleanable and resilient to day-to-day
wear and tear. Floors should be laid flat to minimize the risk of excessive
surface water (e.g. washing bays) or, ideally should slope towards a drain. The
auditor should pay particular attention to joints, seals and floor-to-wall coving
to ensure that surface integrity is maintained. Where floor drainage channels
are needed, they should be open, shallow, easy to clean, and drain effectively.
The auditor must be aware that any ‘static’ water can act as reservoirs for
Gram-negative organisms, particularly Pseudomonas species.
Doors, windows and fittings
These should be flush-fitting whenever possible. Wood readily absorbs
moisture and can generate high numbers of moulds; where present, it should
be sealed with a high-gloss paint and any surface damage repaired
immediately.
Equipment
The ability of bacteria to attach to surfaces such as stainless steel and
plastic and survive should not be under-estimated. Every piece of
equipment has its own particular nooks and crannies where microbiological
contamination can reside; internal threads and deadlegs cause particular
problems (see Chapter 8). Equipment should have smooth continuous
surfaces, free from pits; it should be easily dismantled and cleaned. Pumps
and valves should be of sanitary design.
Cleaning of equipment
Cleaned equipment can be readily recontaminated before use. The auditor
should review: the quality of water used in final rinsing stage; and how
equipment is dried and stored to minimize the risk of contamination by
Pseudomonas and other Gram-negative bacteria.
Pipelines
Pipelines must be completely drainable to ensure that trapped fluid does not
provide a hospitable environment for the growth of bacteria. Internal surfaces
should be smooth and polished to minimize pits where microbes may lodge.
Joints and welds should be kept to a minimum, since they may provide a
protective haven for micro-organisms. Of note, pipelines are often insulated
with sealed lagging material. If the protective outer seal is damaged, the
exposed lagging may provide a rich source of mould contamination.
Raw materials
Raw materials pose a major contamination threat to the product and the
production environment, and warrant special attention from the auditor.
Untreated raw materials of natural origin contain an extensive and varied
microbial population, including potentially pathogenic organisms, such as
E.coli and Salmonella species. In cases of excessively high bioburden, pre-
treatment may be needed to reduce the bioburden to an acceptable level, using
processes such as heat filtration, irradiation, recrystallization from a biocidal
solvent or, where compatible, ethylene oxide gas. In contrast, manufacturing
processes for synthetic raw materials are usually hostile towards bacteria. As
such, their bioburden is considerably lower. Irrespective of the type of raw
material used, the auditor should confirm that the material is provided by an
‘approved’ supplier. Confidence in the quality of raw materials comes from
confidence in the
supplier’s manufacturing processes and their quality systems, which have been
challenged through audit. Likewise, the sampling programme used should be
satisfactory, based upon the nature of the raw material (natural/synthetic), the
history and performance of the supplier, and the end use of the raw material.
Sampling procedures should also be reviewed. Appropriate environmental
conditions should be used to reduce the risk of contamination of both sample
and bulk. Sampling equipment should be dedicated and clean. Samplers should
be properly trained in aseptic techniques. Warehouse storage conditions should
also be reviewed: temperature control should be satisfactory; pest control
should be effective; and containers should be positioned so that they do not
come into contact with damp, cold surfaces such as walls and floors.
Water
Water is the principal raw material used in the pharmaceutical industry. When
reviewing water systems, usually as part of a ‘product-based’ audit, the auditor
must establish quickly an understanding of the system and how it performs.
Key facts to know include whether water is used directly in manufacture, and
what grades of water are used. Management and operational issues include who
owns the system, its complexity (one or multiple plants), its age and any
substantial modifications made, and whether the system provides water for
facilities that operate shifts or operate through weekends. A schematic of the
system should be provided.
Microbiological results
In establishing whether an adequate system of control operates, data from
samples taken from user points over the past 6–12 months should be reviewed
noting user points sampled, the range of results and underlying trend, whether
action and alert limits are visible and appropriate, and whether trend analysis
has been applied to improve interpretation and reporting of results. The time
of monitoring should also be noted with reference to when the system was
sanitized. Even in the event of zero counts, the microbiological sampling
practices and test procedures should be challenged.
Essential documents
Validation documents relating to design qualification, installation qualification,
operational qualification and performance qualification (DQ, IQ, OQ and PQ)
should be complete, available and current for the water system concerned. As
with all equipment and operating systems (including that of the air handling
system), it is futile to contemplate any microbiological testing programme
unless appropriate DQ, IQ, OQ and PQ documentation exists to prove that the
system meets all the required specifications. Only when this has been
thoroughly reviewed and approved may any microbiological
considerations be addressed. In all cases it should be confirmed that protocols
were prepared and approved (with all acceptance criteria justified), detailed
tasks were completed, results were formally reviewed and approved, and all
test acceptance criteria were achieved.
Final reports should have been completed, reviewed and approved
highlighting areas of non-compliance together with any justifications and
recommendations for corrective action. In the case of design qualification, the
following items require confirmation: specified
water requirements (quality and quantity); defined design principles; defined
operation and control levels; defined critical instruments; specified system
components; comprehensive system drawing; and pre-delivery inspections
(welding, degreasing, passivation). Likewise, for installation qualification, the
following should be checked: equipment protocols; pipe slopes; absence of
dead-legs; material certificates; equipment tagging; wiring check; calibration
certificates;
and welding certificates and sample welds. Additionally in operational
qualification, the following should have been documented: calibration on site;
equipment function; set points and alarms; flow rates (maximum/minimum);
hydraulic balancing; and sanitization.
Performance qualification should have been spread over an extended period
divided into phases. In phase 1, all parameters should have been reviewed and
approved at all sample and user points during every day of a 20 to 30-day
period. During phase 2, all user points and worst-case locations should have
been examined using a reduced sampling scheme over a 2-to 3-month period.
The final phase should have investigated similar sample points on a rotational
basis for a period of 6–10 months.
Besides these validation documents, the auditor should review the status of
other essential documents relating to the water systems. As before, these
should be complete, available and in current use. With regard to operation of
the system, these should include:
sanitization procedures and records for pipework and specific items of
equipment (e.g. carbon beds, reverse osmosis membranes); alarms and action
to be taken; equipment log books and specific SOPs; and the planned
preventative maintenance policy, schedules
and records.
In the case of sampling policy for physical, chemical and microbiological
parameters, sampling procedures and practices should be reviewed. These
should document what is to be done, when and by whom; limits and standards
should be defined. Likewise, the management policy should state who has
defined responsibilities and how often the system should be reviewed. The
role and control of contractors should be clearly documented. Accurate
training records should be kept in all cases. Finally, microbiological
procedures to be reviewed include the following: media preparation and
fertility testing; media type used; methods used (filtration, plate count, etc.);
incubation conditions (temperature/time); identification policy and
procedures; action and alert limits; trend analysis procedures; and finally the
reporting of data.
Packaging materials
Cardboard, paperboard and pulpboard, unless sealed or treated, can provide a
rich source of contamination, particularly moulds and Gram-positive bacteria,
often as resistant spores. If these materials become moist through poor storage,
levels of microbiological contamination can increase significantly. Materials
such as glass, synthetic rubbers, plastics and laminates have minimal surface
microbial counts. However, if stored with limited protection in dusty or damp
conditions and packed for transportation in cardboard boxes, often on damp,
dirty wooden pallets, they may contain moulds and bacterial spores.
Effective ventilation
The aerial route of contamination is common and can be significantly
reduced by an effective heating, ventilation and air-conditioning system. For
non-sterile products, the provision of coarse-filtered, humidity-controlled air
can effectively remove dust particles from vulnerable stages of the process.
Humidity and temperature control is important, since this not only provides a
pleasant working environment, but also reduces the risk of mould
contamination.
Cleaning and disinfection
Although routine sanitization of surfaces is key to controlling environmental
contamination, its importance is often over-looked. Since poor sanitization
practices can contribute to environmental contamination, this area is certainly
worthy of audit time. The sanitization programme and procedure should be
reviewed to confirm the frequency and precise method of cleaning and their
scientific basis. The cleaning records should confirm procedural compliance
(when, where and by whom). The activity of any disinfectant used should be
appropriate for the wide range of environmental contaminants likely to be
present.
It is good practice to rotate disinfectants on a regular basis. Disinfectants only
work effectively if made up correctly; the manufacturer’s instructions should
be followed and fresh disinfectant solutions should be made up before use.
Mops, sponges and cloths can provide an ideal environment for rapid and
extensive growth of water-borne organisms such as Pseudomonas species.
They should be washed regularly, dried thoroughly and inspected for signs of
wear and damage and replaced if necessary. Inadequately stored and
maintained cleaning equipment can be highly efficient vehicles for spreading
micro-organisms throughout the environment. An auditor can quickly gauge
how seriously environmental control is taken by the standard of housekeeping.
Untidy, cluttered and dirty work areas leave a lasting impression.
Clothing disciplines and personal hygiene
From the microbiologist’s perspective, clothing is worn for one purpose: to
protect the product from a major source of contamination, the operator. The
auditor should assess the standard of dress; clean clothing correctly worn
should be seen at all times, including that worn by contractors and engineers. A
high standard of personal hygiene is the single most important means of
reducing the potential for product contamination by the operator. People with a
pride in their personal appearance should therefore be selected at employment.
Pharmaceutical companies should thereafter provide them with training in the
importance of personal hygiene and, importantly, provide them with
appropriate facilities and clothing to maintain acceptable levels of cleanliness.
Summary
The role of the auditor is immensely rewarding, but not easy. A thorough
knowledge of the product and manufacturing process, complemented by a
range of good inter-personal skills are essential in making sound judgements
throughout the audit. Good judgement comes from experience, and experience
comes from making mistakes! Therefore each audit should always be
critically reviewed.
AUDITING OF EFFLUENT TREATMENT PLANT (ETP)
1
Sr. No. Contents Pg. No.
1 INTRODUCTION 3
2 DEFINITION 4
3 NEED OF ETP 6
4 DESIGN, SIZE & AREA DIAMENSIONS OF ETP 7
5 CETP (COMMON EFFLUENT TREATMENT PLANT) 8
6 CETP IN INDIA 9
7 PHYSIOCHEMICAL PARAMERTERS MEASURED OF EFFLUENTS 10
8 EFFLUENT TREATMENT PROCESS 19

9 TREATMENT PROCESS IN PHARMACEUTICAL INDUSTRIES 20
10 GENERAL CHEMICALS USED IN CHEMICAL EFFLUENTS 31
11 HANDLING OF CHEMICALS IN ETP 32

12 SAFETY IN ETP OPERATION 36
13 PERSONNEL PROTECTIVE EQUIPMENT (PPE) FOR ETP 37
14 RECORD KEEPING 38
15 AUDITING OF ETP 39
16 AUDIT CHECKLIST FOR EFFLUENT TREATMENT PLANT 40
2
INTRODUCTION
 ETP / Waste water Treatment Plant is a process assign for treating the industrial / waste
water for its reuse or safe disposal to the environment.
 Waste water generated by pharmaceutical and personal care industries and drug
manufacturing units contain various solvents, ingredients and other solid, hazardous
wastes.
 Pharmaceutical wastewater contains about 99.99% of water and 0.01% of other

materials in the form of dissolved solids. Generally, the pharmaceutical wastewater
contains pharmaceutical drugs (API & Excipients) from production, chemicals and
solvents from quality control and oil and grease from utility and maintenance.
 It is necessary to treat the wastewater and purify to a recommended level because

pharmaceutical wastewater pollutants are the great source of water pollutant.
3
EFFLUENT TREATMENT PLANT (ETP)
 Effluent is defined by the United States Environmental Protection Agency as
"wastewater - treated or untreated - that flows out of a treatment plant, sewer, or
industrial outfall.
 The ETP plant works at various levels and involves various physical, chemical,
biological and membrane processes to treat waste water from different industrial sector
like chemicals, drugs, pharmaceutical plants etc for its reuse or disposal to the
environment.
4
TREATMENT
INFLUENT EFFLUENT
ETP
SLUDGE
5
NEED OF ETP
 To clean industry effluent and recycle it for further use.
 To reduce the usage of fresh / potable water in Industries.
 To cut expenditure on water procurement.
 To meet the Standards for emission or discharge of environmental

pollutants from various Industries set by the Government and avoid hefty
penalties.
 To safeguard environment against pollution and contribute in sustainable

development.
6
DESIGN, SIZE & AREA DIAMENSIONS OF ETP
Design and Size of the ETP depends upon:

 Quantity and quality of the industries discharge effluent.
 Land availability.
 Monetary considerations for construction, operation & maintenance.
Area dimension depends on:

 Quality of wastewater to be treated.
 Flow rate.
 Type of biological treatment to be used.
7
CETP (COMMON EFFLUENT TREATMENT PLANT)
 CETP concept helps small and medium scale industries to dispose of their
effluents. Otherwise it may not be economical for these industries to treat their
wastewater or there may be space constraints.
 For operation and maintenance of CETP, small scale industries formed a co-
operative society. The expenses for operation and maintenance of CETP are
being shared by participating industries.
 Some of these industries may require to give preliminary treatment (for removal
of solids) so that the receiving sewers can be maintained free flowing.
 It may be required to correct pH or removal of specific pollutant before the

industries discharges in CETP.
8
CETP IN INDIA
 A total of 130 CETPs have come-up in the country, either established or in the process of
establishment, to cater to the needs of the industrial clusters / group of industries of which, 91 CETPs
are in operation.
 The status of zone-wise CETPs in the country is given in Table:
Zone Number of CTP

Northern Zone
{UP - 3,
Haryana - 1,
16
Punjab - 2,
Delhi - 10 complete,
2 under construction,
3 kept in abeyance}
Western Zone
{Gujarat - 19, 31
Maharashtra - 12}
Eastern Zone 1
{WB - 1}
Central Zone
{Rajasthan - 5, 6
MP - 1}
South Zone
{T.N - 33,
37
AP - 2,
Karnataka – 2} 9
PHYSIOCHEMICAL PARAMERTERS
MEASURED OF EFFLUENTS
1. pH
2. Total Solids
3. Total Dissolved Solids
4. Total Suspended Solids
5. Biological Oxygen Demand
6. Chemical Oxygen Demand
7. Oil and Grease
8. Temperature
10
pH
The pH is determined by measuring the emf by pH meter. 100 ml of the sample was
taken in a beaker and the electrodes were dipped in it and pH was recorded.
ACCEPTABLE RANGE
6.5 to 8.5.
Total Solids
Total solid is determined as a residue left after evaporation of unfiltered samples.
The total solids concentration is equal to the difference between the weight of the
beaker with the residue and the weight of the beaker without it.
11
.
Total solids
(Fixed and volatile)
Solid retrieved after evaporation &
subsequent drying of the sample between
1030 & 1050C
Total Suspended Solids Total Dissolved Solids

(TTS) (TDS)
Solids retained by filter of 2.0 micrometer Solid that pass through a filter of 2.0
(or smaller) nominal pore size under micrometer (or smaller) nominal pore size
specific conditions under specific conditions
12
Total Dissolved Solids
 TDS is determined by taking a well-mixed sample was filtered through glass
fiber filter.
 The filtrate was transferred to a empty weighed crucible and evaporated on a hot
water bath.
 The crucible was transferred into hot air oven for dryness at 1050 C.
 The crucible was cooled and weighed which gives the amount of total dissolved
solid.
ACCEPTABLE CRITERIA
The treated effluent value of TDS after treatment should approx. 2100 mg/L.
13
Total Suspended Solids
Filtering a known volume of a sample, drying the filter and captured solids, then
weighing the filter to determine the weight of the captured suspended solids in the
sample.
ACCEPTABLE CRITERIA
The treated effluent value of TSS after treatment should 100 mg/L.
Biological Oxygen Demand

 Biochemical oxygen demand is the amount of dissolved oxygen needed by the
aerobic biological organisms to break down organic material present in a given
water sample at certain temperature over a specific period of time.
 The BOD value is most commonly expressed in milligrams of oxygen consumed per
liter of sample during 5 days of incubation at 200c.
14
Procedure:
 The BOD test takes 5 days to complete and is performed using dissolved oxygen test
kit.
 The BOD level is determined by comparing the dissolved oxygen level of water
sample that has been taken immediately with the water sample that has been
incubated in dark location for five days.
 After five days take another dissolved oxygen reading using test kit.
 The BOD level is determined by subtracting the day five reading from the day one
reading.
 The difference between the two dissolved oxygen level represent the amount of
oxygen required for the decomposition of any organic material in the sample for
five days.
ACCEPTABLE CRITERIA
The dissolved oxygen concentration after 5 days must be at least 30 mg/L.
15
Chemical Oxygen Demand
 It is the amount of oxygen required by organic matter for its oxidation by strong COD
substance in water.
 COD measures all organics that were biochemically digestible.
 application of COD is quantifying the amount of oxidizable pollutant found in waste
water.
Procedure:
 Sample reflux in strong acid solution with a known excess of potassium dichromate.
 After digestion the remaining un reduced potassium dichromate is titrated with FAS to
determine the amount of potassium dichromate consumed.
ACCEPTABLE CRITERIA
For domestic sewage the allowable range 100 mg/L.
16
Temperature
 A pyrometer is a type of remote-sensing thermometer used to measure

the temperature of a surface.
 A modern pyrometer has an optical system and a detector. The optical system
focuses the thermal radiation onto the detector.
ACCEPTANCE CRITERIA
NMT 30◦C.
17
Standards of ETP
PARAMETERS PERMISSIBLE LIMITS
USA INDIA
pH 6.5-8.5 5.5-9.0
Total Dissolved Solids Approx. 2100 mg/L 2100 mg/L
Total Suspended Solids 100mg/L 100 mg/L
Biological Oxygen Demand 30 mg/L 30 mg/L
Chemical Oxygen Demand 100 mg/L 250 mg/L
Oil and Grease 10 mg/L 20 mg/L
Temperature NMT 30◦C 45◦C

18
EFFLUENT TREATMENT PROCESS
Preliminary Treatment Primary Treatment
 Screening.  Flocculation
 Grit Chamber  Coagulation
 Sedimentation  Neutralization
 Clarifiers
Secondary Treatment Tertiary Treatment

 Aerobic Processes  Alum
 Anaerobic Processes  Chlorination
 Filtration
 Adsorption
 Reverse osmosis
 UV disinfection
19
TREATMENT PROCESS IN
PHARMACEUTICAL INDUSTRIES
1. Screening
2. Equalization Tank
3. Flocculation and Clarification
4. Neutralization
5. Anaerobic Digestion and Clarification
6. Aerobic Digestion and Clarification
7. Chlorination
8. Filtration & adsorption on Activated Carbon
9. Sludge Management
20
Screening
 It has the goal to separate coarse and fine matter at the inlet of the plant, avoiding
sedimentation and clogging in the successive stages.
 Raw effluent from the source is received into the bar screen chamber by gravity.
 Screen provided will remove all floating and big size matter such as plastic bottles,
polythene bags, glasses, stones etc., which may otherwise choke the pipeline and pumps.
Bar Screen Continuous Screen
21
Equalization Tank
 The raw waste from the main plant is first collected in the equalization
tank through a bar screen.
 Air blowers are used for achieving uniform and homogeneous mixture.
 The equalization tank is designed for a hydraulic retention time of around
10 hours and is provided with air grids connected to air blowers for
maintaining the solids in suspension.
22
Flocculation and Clarification
 The equalized effluent water is then pumped into the
flocculation tank, where coagulant and polymer is dosed in the
flocculation compartment to air in the process of settling.
 Alum, Lime and Polyelectrolyte are added by means of dosing

with pumping or gravity force to reaction tank for sludge
formation.
 The chemicals are injected in the pipeline feeding and controlled

by valve.
 suspended solids reduce in this stage by nearly 50%.

23
Neutralization
 The waste water will have acidic pH and base dosing will be
required for bringing up pH to level (6-9).
 The raw effluent contains average pH 3.3.
 The suitable pH of Anaerobic Microorganisms is 8 to 9 and the

suitable pH of Aerobic Microorganism is 7 to 8.
 The biochemical reactions of the Anaerobic Microorganisms

reduce pH minimum by 0.5-1.5 by producing organic acids, so
when the effluent pH decreases then for plant safety neutralize
pH to 8.0 by controlled alkali dosing.
24
Anaerobic Digestion and Clarification
 Effluent from the high polluted equalization tank is
pumped to anaerobic digester for Bio-Chemical reaction.
 Normally Cow dung can be used as nutrient of anaerobic

microorganism at primary stage (up to 5 days).
 COD & BOD will be reduced & pH also reduced by

biochemical reaction at this area and formed CH4 gas,
organic acids, N2 and CO2.
 Anaerobic digestion process ultimately reduces total

sludge quantity.
25
Aerobic Digestion and Clarification
 Aerobic bacteria are very sensitive about pH, temperature, dissolved oxygen and
nutrients.
 Aeration provides oxygen by means of air diffuser in the form of fine air bubble which
will oxidize the organic compound and oxidizable inorganic compound by
Biochemical reaction.
 Some sulfate reducing bacteria plays an important role to removal of heavy metals in
the effluent.
 This tank is divided into two parts, Oxygen will be provided in tank by air diffuser. This
process results in the formation of Biogenic Sulfide, these Sulfides form highly
insoluble precipitate with heavy metals such as Cd, Cu, Zn, Cr, etc. and be removed.
 After oxidation effluent comes to clarifier with suspended sludge & for new cell settled
at the bottom of the clarifier unit.
 There is also a provision to return the activated sludge into the distribution tank and a
part of it to carry at sludge drying bed or filter press & a part to carry at anaerobic pond
as nutrients.
26
Chlorination
 The overflow from the secondary lamella clarifier is collected in the clear
water tank where chlorine in the form of sodium hypochlorite is dosed
to aid in the process of disinfection.
 The disinfected water is then treated through filtration to achieve desired
treated water quality.
 Possible disadvantages of chlorine disinfection are the toxicity of the
chlorine residual to aquatic life and the potential of the chlorine combining
with organic material in the effluent or the receiving stream to form
cancer-causing compounds.
 For some chlorination systems additional detention time, addition of a
reducing agent (sodium bisulfite or sulfur dioxide), or passage through
activated carbon may be required to reduce chlorine residuals prior to
discharge.
27
Filtration & Adsorption on Activated Carbon
 Chlorinated waste water is then pumped into the Multi grade
filter for removal of suspended solids.
 Filtered water is then passed through Activated Carbon

Filter(ACF) for further polishing and removal of excess chlorine.
 ACF treated water is collected in the treated water tank from

where it is pumped for backwash of the filters.
 Dirty backwash water is taken back to the equalization tank.
 Filtered water can be used for low end applications like toilet
flushing, gardening etc.
28
Sludge Management
 The concentrated sludge is then taken to sludge bed or
filter press.
 The dried up sludge is manually cleared for disposal as

land filling.
 Very minimum sludge will be produced from aerobic

digester as dry form and anaerobic sludge will be cleaned
from anaerobic digester once a year and these will be
disinfected by Sodium hypo Chloride.
 It can be used as fertilizer or as land filling.

29
Flow Chart of ETP
30
GENERAL CHEMICALS USED IN
CHEMICAL EFFLUENTS
1. Neutralization / pH correction: Hydrochloric acid, Sodium
Hydroxide.
2. Coagulant / Settling Aids: Aluminium Sulphate, Ferric

Aluminium Sulphate, Ferric Sulphate, Ferric Chloride.
3. Disinfectant: Chlorine, Bleaching Powder, Ozone.
4. Adsorption / Absorption: Activated carbon.

31
HANDLING OF CHEMICALS IN ETP
Use and Storage of Corrosives:
 Always store acids separately from bases.
 Also, store acids in acid storage cabinets away from flammables

since many acids are also strong oxidizers.
 Do not work with corrosives unless an emergency shower and

continuous flow eyewash are available.
 Never store corrosives above eye level. Store on a low shelf or

cabinet.
32
 Handling of Chlorine:
 Chlorine gas has a disagreeable, sharp, pungent, penetrating odor. In airborne

concentrations above 1000 parts per million (ppm) it has a greenish-yellow color. In
smaller concentrations it is colorless.
 Chlorine is corrosive. It can burn moist body surfaces such as the eyes, nose, throat,
lungs, and wet skin because it forms harmful acids when it reacts with moisture.
 Repeated exposure to chlorine does not produce an immunity or tolerance.
 Long term exposure to low concentrations of chlorine may cause a gradual decrease in
lung efficiency. A single exposure to a high concentration can cause the same effect.
33
Concentration of Chlorine and its Effect
Concentration Effect
0.03 – 0.1 ppm Range of odor threshold (many specify this
as 0.08 ppm).
1 – 3 ppm May cause mild irritation of the eyes, nose,

and throat.
Stinging or burning in eyes, nose, and

throat; may cause headache, watering eyes,
3 – 5 ppm sneezing, coughing, breathing difficulty,
bloody nose, and blood tinged sputum.
5 ppm or more Severe irritation of the eyes, nose, and

respiratory tract.
14 – 25 ppm May be fatal after 30 minutes of exposure.
Immediate breathing difficulty resulting in
pulmonary edema (fluid build-up in lungs),
25 ppm or more possibly causing suffocation and death
1000 ppm or more Fatal after a few
breaths.
1000 ppm or more Fatal after a few breaths.
34
Exposure Limits of Chlorine
Concentration Effect
0.5 ppm Maximum allowable concentration
averaged over an eight-hour period.
1 ppm Maximum allowable short-term exposure

(15 minutes).
Immediately Dangerous to Life and Health

as published by National Institute for
10 ppm or more Occupational Safety and Health in the
United States (NIOSH).
35
SAFETY IN ETP OPERATION
Do and Don’ts in ETP Operation for Safety:
 Use safety shoes or boots with non-slip soles.
 Wear personal protective equipment and chemical resistant clothing to avoid exposure of
skin or eyes to corrosive and/or polluted solids, liquids, gases or vapors.
 Do not smoke, eat or drink in areas where chemical or biological contamination may be
expected.
 All workers should undergo periodic examinations by occupational physician to reveal
early symptoms of possible chronic effects or allergies.
 Take extreme care when handling highly corrosive agents such as liquid or gaseous
chlorine, concentrated acids or alkalis, or when toxic gases may be emitted from the
reagents, etc.
36
PERSONNEL PROTECTIVE EQUIPMENT
(PPE) FOR ETP
 Safety Boots with non-skid soles.
 Electrical Hazard safety Toe shoes.
 Gas Masks and Face Shields.
 Oxygen meters for ascertaining type of atmosphere in a confined area.
 Safety Goggles.
 Helmets / Hard Hats.
 Latex Rubber / Butyl Rubber / Fabric / Chemical Resistant Gloves.
 Overall Clothing.
 Aprons for laboratory Personnel.
 First Aid Box.
 Fire extinguishers.
 Respiratory Protective mask with man pack cylinders.

37
RECORD KEEPING
 Running records are required to be kept for various operating machines such as Mechanical
Screens, Mechanical Grit Removers, Pumps, Motors, Scrapers, Aerators.
 The records of effluent quality and other laboratory tests are kept in the laboratory as per daily
sample collection and testing schedules.
 The daily log sheet is passed to the Plant Manager on the subsequent day duly signed by the
operator in the first shift.
 The Plant Manager shall verify the daily record as well as the calculations and shall be
responsible to generate further data using these.
 All operators shall be responsible to fill up their part of observations and calculations.
 Record has to be prepared for each chemical detailing the consumption of the respective
chemical.
38
AUDITING OF ETP
 The auditor should be well experienced and skilled who are conducting on effluent treatment plant
because each process activities, safety requirements ,personal protection should be properly verified
and audited.
 validated SOP for personal protective equipment procedure are provided.
 The chemicals which are used and released in the ETP, material waste and other processes sewage and
which are used for testing should be audited.
 Effluent treatment plan and laboratory records should be verified by the auditors.
 Visual audits have to be conducted to check whether the flow meters are working properly.
 Maintenance record and calibration records of equipment should be audited.

39
AUDIT CHECKLIST
40
REFERENCE
1. https://ehs.ncpublichealth.com/oswp/docs/forms/3703InspectionOfWastewaterTreatmentPlant.pdf
2. https://www.pharmaguideline.com/2013/07/wastewater-effluent-treatment-procedure.html
3. http://web.iitd.ac.in/~arunku/files/CVL100_Y16/Lecture%201%20ETP%20Textile_verII.pdf
4. Technical EIA Guideline manual for Common Effluent Treatment Plants;

http://environmentclearance.nic.in/writereaddata/Form-
1A/HomeLinks/TGM_CETP_010910_NK.pdf
41
42
HVAC
• Heating, ventilation, and air system encompasses heating, ventilation, and air conditioning, which is integral
component of pharmaceutical facility functionality.
• The system is needed for maintenance of a suitable temperature, for continuous flow of air, which ultimately
prevents cross-contamination and accumulation of air and to ensure the cooling of air in the premises.
• The three core facets of HVAC system validation comprises of installation qualification (IQ), operational
qualification (OQ), and performance qualification (PQ).
• Validation of HVAC system is an essential subject to provide documented evidence about the accuracy of results
produced by it. The validation of HVAC system involves systemized and assembled documents of functional
specifications; design drawings, plans, and specifications; validation master plan; testing, adjusting, and balancing
(TAB); and startup reports.
• The various parameters to be evaluated for the validation of HVAC system include air flow pattern, air flow
velocity, air changes per hour, filter leak test, particle count, viable monitoring, filter integrity test, pressure
difference, recovery test for temperature and humidity, temperature and humidity uniformity, and fresh air
determination.
Pharmaceutical AHU and HVAC Components
“Validation is a very vast topic in the field of pharmaceutical sciences. It ensures about the accuracy of
results being produced by any system. Maintenance of quality of products is of great importance,
especially in the field of pharmacy as this field deals with drugs which directly affect the human body.”
• The heating, ventilation, and air conditioning (HVAC) system is an extremely vital concern, which aids to
enhance and maintain the quality of drug products. It assists in achieving an adequate temperature,
ventilation, and air conditioning in the premises.
• The HVAC system design has an immense impact on the prevention and control of cross contamination and
for the achievement of a hygienic condition at the work place. Temperature and ventilation are very
important parameters to be perpetuated during the processing as well as storage of the various drug
substances and drug products, which ultimately influence their standard.
• Air conditioning not only mean cooling of air but also embrace temperature, moisture in the air (humidity),
supply of outside air for ventilation, filtration of airborne particles, and air movement in the occupied space.
• The American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) defines air
HVAC system as “a system that must accomplish four objectives simultaneously, namely; control of air
temperature; control of air humidity; control of air circulation; and control of air quality”.
IMPORTANCE OF HVAC SYSTEM
HVAC systems are of great importance to architectural design efforts for four main reasons.
• Firstly, these systems often require substantial floor space and/or building volume for equipment and
distribution elements that must be accommodated during the design process.
• Secondly, HVAC systems constitute a major budget item for numerous common building types.
• Thirdly, the success or failure of thermal comfort efforts is usually directly related to the success or failure
of a building’s HVAC systems (when passive systems are not used), even though the HVAC systems should
be viewed as part of the larger architectural system.
• Last, but not least, maintaining appropriate thermal conditions through HVAC system operation is a major
driver of building energy consumption.
High-efficiency particulate air
To achieve an appropriate cleanliness in the premises, High efficiency particulate air (HEPA) filters are used.
The HEPA filters are employed to ensure the aseptic condition. The integrity of the filters should be checked at
regular intervals by performing leak test. HEPA filters are a part of the air handling unit (AHU). In the AHU, the
outside fresh air, combined with the return air from the cubicles, is treated by AHU and supplied to the
laboratory area. A part of the air exiting from the laboratory rooms is directly exhausted into the atmosphere by
an exhaust fan, while the remaining air is recirculated to the AHU as return air by a return fan. The air entering
into the AHU is filtered by prefilters and medium filters and then air conditioned for humidity and temperature
control, and is supplied to the laboratory area by a supply fan at desired pressure. The supply air is terminal
filtered by HEPA filers at the entrance to the clean rooms.
HVAC - Freudenberg Filtration Technologies
Heating, ventilation and air conditioning (HVAC) in intensive care unit
VALIDATION OF EQUIPMENT
• Equipment is one of the basic components of the pharma processing and hence, a
critical validation issue also.
• If one wants a pharmaceutical process to be validated then the equipment used plays
a very major role in the whole process.
• The equipment validation process generally covers the following steps:

1. Customer requirements or user requirementspecification (URS)
2. Preparation of design qualification (DQ) and its certification
3. Installation qualification (IQ)
4. Operational qualification (OQ)
5. Performance qualification (PQ).

HVAC Validation; Design, Installation, Operational, Performance Qualification
User requirement specifications
Customer of the equipment has certain expectations about the equipment which he wants to use. Some of the general requirements
may be stated in the form of certain parameters like:
1. Size of the equipment
2. Speed of the equipment
3. Effectiveness of the equipment
4. Availability of spares, change parts, and prompt services
at reasonable cost
5. Ease of operation, cleaning, and maintenance
6. Low dust and sound generation
7. Lesser breakdowns8. Materials of construction
9. Auto control system
10. Easy change over
11. Overall good construction and workmanship, etc.
These requirements are generally discussed with the equipment manufacturer or supplier and based on that discussion; the
selection of the equipment is done. In case of standard items, user accepts the standard specifications of the manufacturer.
Preparation of DQ and its certification
If particular equipment is to be fabricated as per the user requirements, then it is very essential to design detailed
qualification document. It is advisable to work out the detailed equipment specification by sitting together with
the manufacturer. Once this is ready, it should be agreeable to both the parties, that is, the purchaser and
manufacturer. At this stage it may be advisable to identify the stages during the fabrication of the equipment,
where visual, instrumental, or even physicochemical testing may be performed in the presence of the purchaser.
Generally, the factory acceptance test (FAT) is performed at the manufacturer’s premises before dispatch of the
equipment to the purchaser. DQ should provide documented evidence that the design specifications were met.
HVAC Design and Qualification for Solid Pharmaceuticals
Installation qualification
It may be defined as: “Documented verification that all key aspects of the installation adhere to manufacturer’s
recommendation, appropriate codes, and approved design qualification”. The simple meaning of this statement
is that the equipment in question can be installed when it is qualified for installation, that is, when it passes the
IQ test. IQ should provide documented evidence that the installation was complete and satisfactory. The
purchase specifications, drawings, manuals, spare parts lists, and vendor details should be verified during IQ.
Control and measuring devices should be calibrated.
Operational qualification
It may be defined as: “Documented verification that the system or subsystem performs as intended throughout
all specified operating range”. The equipment should be operated only when it passes the OQ Test. OQ should
provide documented evidence that utilities, systems, or equipment and all its components operate in accordance
with operational specifications. Tests should be designed to demonstrate satisfactory operation over the normal
operating range as well as at the limits of its operating conditions (including worst case conditions). Operation
controls, alarms, switches, displays, and other operational components should be tested. Measurements made in
accordance with a statistical approach should be fully described.
Performance qualification
PQ is considered by many as synonymous with OQ. Some experts consider OQ as verification of performance
of the system or subsystem without load and PQ is the same with load. However, these two terms always go
hand in hand and no water tight distinction can be made. PQ should provide documented evidence that utilities,
systems or equipment and all its components can consistently perform in accordance with the specifications
under routine use. Test results should be collected over a suitable period of time to prove consistency.
VALIDATION OF HVAC SYSTEM
The validation of HVAC system usually involves the compilation of the documents like functional specifications (the
conceptual design); design drawing, plans, and specifications; validation master plans; contractor documents; testing,
adjusting, and balancing (TAB); startup reports; commissioning reports (the actual execution of validation protocols); and
validation (IQ, OQ, and PQ).
IQ may be defined as: “Documented verification that all key aspects of the installation adhere to
manufacturer’s recommendation, appropriate codes, and approved design qualification”. The goal of IQ is to
verify and document the quality, installation, and integrity of HVAC system components. Design documents
and literatures are used to design installation protocols.
OQ may be defined as: “Documented verification that the system or subsystem performs as intended
throughout all specified operating range”. The equipment should be operated only when it passes the OQ
Test.
PQ should provide documented evidence that utilities, systems, or equipment and all its components can
consistently perform in accordance with the specifications under routine use. Test results should be collected
over a suitable period of time to prove consistency.
In general the various parameters to be evaluated for the validation of HVAC system comprise of air flow pattern or
smoke pattern, air flow velocity and changes per hour, filter leak test, particle count, viable monitoring, filter integrity
test (dioctyl phthalate (DOP)/polyalphaolefin (PAO) test), pressure difference, recovery test (temperature and humidity),
temperature and humidity uniformity test, and fresh air determination.

METHODOLOGY
The methodology for the validation of the HVAC system embrace:
• Air flow or smoke pattern

• Air flow velocity and changes per hour
• Filter leak test
• Particle count
• Viable monitoring
• Filter integrity test (DOP/PAO test)
• Pressure difference
• Recovery test
• Temperature and humidity uniformity test
• Fresh air determination
METHODOLOGY
The methodology for the validation of the HVAC system embrace:
Air flow or smoke pattern
For the evaluation of this parameter, a titanium tetrachloride stick is taken and burnt and the burning stick is placed in front
of the AHU. The distribution of smoke is observed. It should be uniform.
Air flow velocity and changes per hour
For this test, the area of HVAC is divided into four hypothetical grids and the air velocity is measured at each grid and then
the average air velocity (V) is calculated. The area of the HEPA filter inlet (A) is calculated in feet and the total air volume
(T) is then calculated by multiplying the average velocity of air and the area of the inlet (T = A × V). After this, the volume
of the room is calculated and the air changes per hour are obtained by dividing the total air change by the volume of the
room.
Filter leak test
For the leak test of the HEPA filter, a velometer is placed at the front of the AHU system and the air velocity is checked at
all the corners. The air velocity should be within the higher limit of the HEPA filter. In case it is found to exceed the upper
limit, a gas cut (silicon) is used to decrease the leakage.
Particle count
A particle counter is used to conduct the test. Particle count is taken before the operation as well as during the working
condition. The particle count should be within the range as per the standards of Grade A, B, C, and D area.
Viable monitoring
Viable monitoring is performed on daily basis by employing the swab test and using nutrient agar medium for the incubation of
microorganisms. The different media plates are exposed in every manufacturing section including the reverse air duct of the
HEPA filter at the back of the cubicle. The microorganism count should be within the range and if it is found out of
specification for consecutive two times, an effective corrective and preventive action is taken.
Filter integrity test (DOP/PAO test)
The HEPA filter integrity is tested by generating a PAO aerosol by an aerosol generator and allowing the upward flow of the
aerosol. The 100% upward flow of the aerosol is ensured and then the receptor probe of the HEPA is monitored to know the
amount of the aerosol reversed. It should not exceed the higher limit of the HEPA filter. Earlier to carry out this test, DOP was
used. But nowadays, it is replaced by the PAO taking into consideration the carcinogenicity of the DOP.
Pressure difference
It is calculated by making use of the manometer attached at the walls of the adjacent area. The pressure difference is generally
kept between 5 and 20 mmHg pressure.
Recovery test
The recovery of temperature and humidity is checked. For this, the humidity and temperature are checked at the off position of
the HVAC system. Then the humidity is increased to 75% and temperature to 400°C and again the temperature and humidity
are measured after switching on the HVAC system, and the time required to stabilize the temperature and humidity is noted.
Temperature and humidity uniformity test
The uniformity of temperature and humidity are monitored by employing a calibrated thermometer and manometer,
respectively. The two parameters are monitored on daily basis, documented in the format and stabilization is ensured within
the specified limit.
Fresh air determination
The fresh air intake is observed at the inlet on the fresh air dumper. The total air change is calculated. The intake fresh air is
divided by the total air change in the room and multiplied by 100 to obtain the percent fresh air intake on each cycle by the
HVAC system in all the individual rooms.
What is a Cleanroom?
• A cleanroom is defined as a room in which the concentration of airborne particles is
controlled.
• The cleanrooms have a defined environmental control of particulate and microbial
contamination and are constructed, maintained, and used in such a way as to minimize the
introduction, generation, and retention of contaminants.
• Cleanroom classifications are established by measurement of the number of particles 0.5
micron and larger that are contained in 1 ft3 of sampled air. Generally class 100 to 100,000
rooms are used in the pharmaceutical industry. [Note - rooms may be classified as clean at
class 1 or 10 for other applications, particularly in the microchip /semiconductor industry].

Cleanrooms classified in the United States by Federal Standard 209E of September 1992 and by the European
Economic Community (EEC) published guidelines “Guide to Good Manufacturing Practice for Medical Products
in Europe, which are more stringent than U.S. FDA regulations.
REFERENCES
1. Quality Assurance of Pharmaceuticals, A Compendium of Guidelines and Related Materials. 2nd ed., Vol. 2. 2007.
2. Guideline on General Principles of Process Validation, May 1987, FDA, CDRH/CDER.
3. Potdar MA. Pharmaceutical Quality Assurance, Nirali Prakashan, Pune, Edition II, 2012.
4. FDA/Global Harmonization Task Force (GHTF; medical devices), Quality Management Systems-Process Validation. 2nd ed.
Guidance; 2004.
5. Guidance for Industry, Process Validation: General Principles and Practices, U.S. Department of Health and Human
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation
and Research (CBER), Center for Veterinary Medicine (CVM), January 2011, Current Good Manufacturing Practices
(CGMP), Revision 1.
6. FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center
for Veterinary Medicine (CVM), Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice
Regulations, guidance for industry; 2006.
7. Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice, U.S.
Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER) Office of Regulatory Affairs (ORA), Pharmaceutical CGMPs; 2004.
8. Guidelines for the Validation of Chemical Methods for the FDA Foods Program, Department of Health and Human
Services, Public Health Service Food And Drug Administration; 2012.
9. Scott B, Hargroves J, Bauers J. Validation of HVAC systems in pharmaceutical and biotechnology facilities-Part 1.
10. Goldschmidt N. First steps for sustainable bio/pharma

Introduction Merged

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Introduction Merged

Uploaded by

Copyright:

Available Formats

UNIT-1

PHARMACEUTICAL QUALITY AUDIT

 Instead of considering the audit as an intrusive and potentially threatening

 Internal audit is a professional activity that consists of advising organizations on

 The internal audit involves the use of a systematic methodology to analyze

 Although there are no strict legal requirements for this control.

 It is always advisable to evaluate the competence of the contractors in which we

 International regulatory bodies such as MHRA,UK, USFDA, Therapeutic goods

 There is a team to perform the audit, it must be composed of audit inspectors

 Evaluating conformity of documentation to ISO 9001.

 Judging conformity of implementation to documentation.

 Meeting any contractual or regulatory requirements for auditing.

 Permitting registration and inclusion in a list of registered companies.

 To determine the conformity or non-conformity of the quality system in meeting

 To determine the effectiveness of the implemented

 To meet the regulatory requirement .

 To permit listing of the audited organizations Quality systems in a register.

 Management of an audit program includes all the activities necessary for

1. Plan, establish, implement, monitor, review and improve the audit

2. Identify the necessary resources and ensure they are provided.

 Every product manufactured by a pharmaceutical company has characteristics

 Responsibility to plan and manage all phases of the audit.

 Make decisions about audit issues and the quality system.

 Establishing the intended means of achieving the objectives of the audit.

 Assisting in the direction and control of the work.

 Helping to ensure that attention is devoted to

 Ensuring that the work is completed expeditiously.

 Facilitating review of the audit work.

 Helping to assign the proper tasks to members of

 Interim financial statements are analyzed to identify accounts and

The performance of such analytical procedures is mandatory in the planning of an

 Outside assistance needs should be determined, including the use of a

 Pronouncements on accounting principles and audit guides should be read or

 Scheduling with the client is needed to coordinate activities.

 Only verifiable information can be audit evidence which must be recorded.

 It is any information used by the auditor to determine if the audited information

 Interviewing is a powerful data collection technique, which works well on its

 The most important thing to remember when interviewing is to always talk to

 The simplest way to check how a process works is to observe it in action.

 This method is also referred to as “vertical auditing” and consists of following a

 Doing so is likely to have negative consequences as unannounced actions may

The key stakeholders of internal audit are:

 While internal audit reports functionally to the Audit Committee, it is important

 Organisations today, recognize the advantages in making the Head of Internal

 Audit Committees play an integral role in the governance framework of

b.Direct or coordinate work programs relating to internal and external audits.

c. Review the adequacy of responses to reports of internal and external audits.

d.Utilize the internal audit function to undertake secretariat compliance.

 To effectively fulfill its responsibilities, it is important that internal audit has a

 Thus, a constructive relationship between both sets

 Protocols can be particularly important in situations where internal audit needs

 a condition adverse to Quality.

 The non-fulfillment of a requirement.

The number of nonconformities that can arise during an audit can be

 Critical defects have a high probability of resulting in a product recall or in an

 Critical deficiencies found in internal audits that usually produce significant

 Cross-contamination of materials of the product.

 Product manufactured according to obsolete or unapproved procedures.

 Untrained operators working in the sterile filling area.

 Contaminated purified water or water for injection system.

 Inadequate segregation of quarantine components.

 Inadequate evaluation of production process outside of action levels.

 Process deviations not properly documented or investigated.