GMP 3001

AAPS
COURSE OUTLINE
CLASS 1 REVIEW OF GMP2001
CLASS 2 COMPLAINTS AND RECALLS
CLASS 3 STABILITY
CLASS 4 ANNUAL PRODUCT QUALITY REVIEWS
CLASS 5 HEALTH CANADA GUIDE 0069, and a high level overview of Temperature
Mapping
CLASS 6 PHARMACEUTICAL WATER SYSTEMS/PHARMACEUTICAL AIR SYSTEMS
CLASS 7 NATURAL HEALTH PRODUCTS AND COSMETICS
CLASS 8 INTRODUCTION TO MEDICAL MARIJUANA
CLASS 9 INTRODUCTION TO HEALTH CANADA ANNEXES
CLASS 10 EUROPEAN GMP’s
CLASS 11 MRA, PIC, ICH, A COMPARISON BETWEEN HEALTH CANADA, FDA AND
EUROPEAN GMP’S

GMP 3001 will cover more advanced topics and will require you
to read a number of documents in order to reinforce specific
details.
CLASS 1 – REVIEW OF GMP 2001

QUALITY MANAGEMENT
QUALITY SYSTEM CONTROLS-QUALITY LABORATORY
QUALITY SYSTEM - OUT OF SPECIFICATION (OOS) INVESTIGATIONS
QUALITY SYSTEM - CHANGE CONTROLS AND DEVIATIONS
QUALITY SYSTEM - COMPLAINTS AND ADVERSE DRUG REACTIONS
STERILE PRODUCTION
QUALITY SYSTEM –AUDITS
THIRD-PARTY AUDITS
HEALTH CANADA REGULATORY INSPECTIONS
FDA REGULATORY INSPECTIONS
 Quality Management
• Quality Management is a principle that is important in ISO standards, and is
gaining importance in the pharmaceutical industry
• Section 4.0 of the Canadian GMP Guidelines contains a section on Quality
Management
• Quality Management is a principle that ensures that quality is designed into the
product and that the quality of the product is ensured via various quality systems
within the organization
• Every person within the organization must have a commitment to quality,
including everyone from senior management to sales
 Quality Management
A simple
definition of
This means as well quality: “Totality of features
that the product SISPQ and characteristics of
when sampled and a product or service
tested, is and its ability to
representative of I
satisfy stated or
the details implied needs”
indicated on the S
label or product S
monograph/insert

P In the pharmaceutical
industry, this means that
Q the product has the Safety,
Integrity, Strength, Purity
and Quality
 Quality Management
Examples of Quality Systems are the Change Control System, SOP
System, Validation System, Complaint System, Deviation System,
Training System, OOS System, Document Management System

All of these Systems and others not mentioned in this training are
audited to verify if they are compliant to the Regulations and
Company Procedures
Pharmaceutical Companies involved in the activities of fabrication,
packaging/labeling, wholesaling, distribution or importing are
required to conduct its activities under a state of “GMP” control
 Quality Management
• Management is responsible for putting the quality plan in place,
and ensuring that it is followed.
• This should be documented and the effectiveness of the quality
system should be monitored.
• Management is also responsible for ensuring that there is
adequate staff to perform the duties necessary for ensuring
quality (provide resources such as time, money, people).
• They must also provide sufficient premises, equipment and
facilities.
The management team must show that it is committed to quality.
The management team should never put profits before quality.
 Quality Management
• Support for all Quality Systems within the organization must have
visible and ongoing support from top management.
• At the same time, each individual in the organization must be
aware of their roles and responsibilities for ensuring quality
• Quality systems are all of the organizational structures,
procedures, processes and resources needed to implement the
quality policy and GMPs.
• Quality Management is performed by the use of various Quality
Systems within the organization.
 Quality Management
• Responsibilities should be reflected in organization charts and job
descriptions.
• It is very important to ensure that the quality function is
independent of production, to avoid conflicts of interest.
• All staff whose activities influence quality should be appropriately
qualified through education, training and experience.
• At defined intervals, a review of the adequacy and performance of
the quality program should be done to ensure that it is
satisfactory.
• The review should be based on information gathered from audits,
product reviews, trend analysis, investigations of deviations,
customer complaints, and any other source of relevant
information.
Quality System Controls –
Quality Control Laboratory
Quality System Controls

• The quality control lab (QC lab) is involved in ensuring

the quality of raw materials, packaging components,
in process bulks and finished product. The QC lab also
ensures that the drug product meets its quality
specifications throughout the shelf life of the product
(stability testing).
• This is achieved by the performance of chemical tests,
physical evaluations and microbiological testing to
ensure that these materials meet pre-determined
specifications.
Quality System Controls

►The Quality Control Laboratory is regulated by Good

Manufacturing Practice (GMP and cGMP) regulations.
This is the lab where all analytical testing is performed
to ensure the quality of the drug product.
►The toxicology (animal testing) laboratory is
regulated by Good Laboratory Practice (GLP).
►In both cases, the goal of the regulations is to ensure
the accuracy of the data that is generated in the lab.
Quality System Controls

• The Canadian GMPs and US cGMPs specify that each

batch of drug product shall have appropriate
laboratory determination that it meets the
specifications, prior to release.
• All sampling plans and testing procedures must be
described in written procedures. In the
pharmaceutical industry, this is usually in the form of
Standard Operating Procedures (SOPs).
Quality System Controls

• Proper documentation is extremely important in a GMP regulated

environment. Lab records are covered under the US cGMP
regulations, 21CFR Part 211.194.
Laboratory documentation includes;
• Specifications
• Certificates of Analysis
• Standard Operating Procedures
• Test Methods
• Instrument Logs, Calibration, maintenance and repair logs
• Raw Data
• Electronic Records
• OOS Records
• Canadian GMP references for Records being maintained C.02.020-C.02.021, C.02.024,
C.02.014, C.02.015, Quality Management, 4.2.3 Quality Control…..
QUALITY SYSTEM - OUT OF SPECIFICATION
(OOS) INVESTIGATIONS
OUT OF SPECIFICATION INVESTIGATIONS

• An important part of the Quality Assurance program

involves the Quality Control laboratory testing of raw
materials, packaging components, bulk, and finished
products, including stability testing.
• The physical, chemical and microbiological attributes
that are deemed to be important factors in the quality
of the drug are tested against specifications set by the
manufacturer or a pharmacopoeia. This information
is used to decide whether the batch is safe to release
and to be used by the public.
OUT OF SPECIFICATION INVESTIGATIONS

• If a result is Out of Specification (OOS), then a procedure for

handling this OOS result must be followed.
• As always, this procedure must be outlined in a Standard
Operating Procedure (SOP).
OUT OF SPECIFICATION INVESTIGATIONS

• Health Canada and the FDA are very concerned about how a
pharmaceutical company or contract testing laboratory handles
OOS results because this will ultimately determine if the batch in
question is released for use by the public.
• (or continues to be released – i.e. when considering the results
from ongoing stability testing)
• Health Canada GMPs C.02.015 section 7.9-7.9.5
• The FDA has published a draft guideline on Investigating OOS test
results
OUT OF SPECIFICATION INVESTIGATIONS

• The FDA guidance on OOS/OOT results advises that there are 3

possible reasons for an OOS result:
1: The chemist made a mistake during the testing; (OOS NOT VALID)
2: An operator performing one of the steps during the manufacturing process
made an error; (OOS IS VALID)
3: The manufacturing process itself is faulty. (OOS IS VALID)
OUT OF SPECIFICATION INVESTIGATIONS

• A formal investigation must be conducted to determine which of

these 3 possibilities has caused the OOS result.
• As always, this investigation process must be well documented
and controlled, and have final approval by management and QA.
Most companies use a controlled template which allows for easy
documentation of the investigation.
• If an analyst generates an OOS result, the supervisor MUST be
notified.
OUT OF SPECIFICATION INVESTIGATIONS
The OOS investigation report should, at a minimum, include:
1: The reason for the investigation (including the OOS result, a
reference to the lab book, the batch or lot affected);
2: A summation of the findings of the investigation;
3: The corrective actions necessary and preventive actions to
prevent a reoccurrence as well;
4: A list of other batches and other products possibly affected
along with their investigational results;
5: Comments and signatures of any production and quality
personnel regarding approval of any material reprocessed
after additional testing.
OUT OF SPECIFICATION INVESTIGATIONS

Health Canada and the FDA also requires that this

investigation be closed off in a timely manner.

Ensure that the investigation includes all details

required and is signed off.
QUALITY SYSTEM - CHANGE CONTROLS AND
DEVIATIONS
CHANGE CONTROL

►OVERALL PROCEDURE
• Change Request Initiation
• Internal & External Requests
• Preconditions Identification
• Approval in Principle
• Preconditions Completion
• Approval to Implement Change
• Implementation of Change
CHANGE CONTROL

►The first step of change is initiation of the change via a Change

Control Request Form (CCRF, or CCF).
►Review the Change Control Process Flow:
CHANGE CONTROL

►The CCF could be initiated by anyone who sees the need for a
change (example, the user of an SOP may determine that there is
a mistake in the SOP, or that the SOP is possibly misleading, etc.).
►The CCF is controlled by the Quality Assurance (QA) team. The
entire change process is facilitated by QA, and final approval is by
QA.
►The initiator of the CCF requests a CCF tracking number from QA.
►The CCF number would be entered into a database by QA for
tracking purposes. The CCF will be tracked through the entire
process and there should be time limits imposed on the process
CHANGE CONTROL

►The initiator of the CCF would then add a full explanation of what
the proposed change is and justify why it is necessary.
►The initiator of the change would then sign and date the CCF and
then send the form to QA. Some companies require that the
change be reviewed by the department manager before it is sent
to QA.
►QA should do an initial evaluation of the change. All changes
should be evaluated based on the possible risk to the quality of
the product.
CHANGE CONTROL

►A distribution list would then be made. The CCF

would then be passed to various
supervisors/managers of various departments,
depending on the nature of the change.
►Any department that would be impacted by the
change MUST be made aware of the proposed
change(s) so that they may contribute any
information for or against this change.
►Regulatory Affairs MUST be included in the
distribution list (discussed in detail later).
CHANGE CONTROL

►Once the CCF has been circulated to everyone on the

distribution list, the CCF would then be returned to
QA (Note: If you incorporate a time limit for this step,
make it an internal policy only and NOT part of the
SOP – otherwise it must be tracked and audited.).
►QA would then evaluate the change based on the
comments and recommendations of the various
departments. Sometimes a meeting may be called.
CHANGE CONTROL

►Once it is determined that the change should be made, the

Change Control Form is used to initiate the change.
►This could include a formal plan, work orders, drawings,
diagrams, etc.
►It is very important to have all required documentation filed with
the Change Control Form, these will be reviewed by the Change
Control Team as part of the assessment stage.
►These will also be reviewed by Auditors.
CHANGE CONTROL

►Regulatory Affairs MUST be notified of any changes so that they

may notify the regulatory bodies if necessary!!
►Minor changes may not need to be reported to the regulatory
bodies until the Annual Product Quality Review document is
submitted.
►Major changes may need to be reported to the regulatory bodies
immediately – Implementation time delayed!!
QUALITY SYSTEM – DEVIATIONS
DEVIATIONS
A proper deviation reporting system allows QA to track and trend
deviations. Trending should be done to ensure that deviations will
not repeat themselves in the future.
If a trend is noticed, an investigation into the
process/equipment/person should be extended in order to
determine whether more corrective/preventive actions are
necessary.
The ultimate goal is to reduce the number of deviations. A
company with numerous deviations each year may be considered
a high risk company. The FDA and Health Canada will assess the
number of deviations during their inspection.
However, deviations should never be ‘hidden’. Anyone who
discovers a deviation must report it immediately.
QUALITY SYSTEM - COMPLAINTS AND ADVERSE
DRUG REACTIONS
COMPLAINTS AND ADVERSE DRUG REACTIONS

Complaint System:

Classification of Complaints as Quality or Clinical:

• Product Complaint – Quality
– Quality: Product specific (i.e., packaging problems, lack of
effectiveness of product after use, etc.) and/or

• Product Complaint – Clinical (AE/ADR)

– Clinical: Patient related (i.e., Adverse Event (AE), Adverse
Drug Reaction (ADR) after use of product
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Investigation of Complaints:

• All product quality complaints must be responded to as quickly as

possible.
• QA decides what investigative action(s) are required.
– Is lab testing required?
– batch document review
– Circulation of the Complaint Report to other departments for
feed-back
– Etc.
• The proposed investigative actions are recorded on a formal
document, a Complaint Report
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Investigation of Complaints (Cont’d):

• The Investigation is conducted by all previously identified parties.

– Results are to be clearly recorded on a formal document
• Goal: To assess the complaint and determine
– The validity of the complaint
– The need for further follow-up corrective &/or preventative
actions
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Investigation of Complaints (Cont’d):

• If further follow-up corrective &/or preventative actions are

required, details are to be clearly recorded on a formal document
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Investigation of Complaints (Cont’d):

• QA must review the final report and provide sign-off.

• A final outcome of the investigation is sent to the complainant.
– This can be carried out in stages to let complainant know that
action has been taken.
– DON’T TAKE A LONG TIME TO RESPOND INITIALLY
– Further communications of status updates / final outcomes
can come when resolved.
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Important Note:
• There may be sufficient information to provide the
complainant PRIOR TO completing required follow-up
corrective &/or preventative actions.
• If this this the case, QA can review the COMPLAINT
INVESTIGATION REPORT, provide sign-off, and issue a
final response to the complainant.
• Required follow-up corrective &/or preventative
actions are INTERNAL and completion of such actions
can occur following the final response to the
complainant.
COMPLAINTS AND ADVERSE DRUG REACTIONS
Complaint System:

Analysis and trending of Complaints:

Regulation: Complaint records are regularly reviewed for any

indication of specific or recurring problems that require
attention.

• QA must monitor all product complaints for frequency and

severity.
– Use of Statistical Analysis and Trending

• Any necessary follow-up action(s) must be documented and

executed
COMPLAINTS AND ADVERSE DRUG REACTIONS
ADR Systems:

• A complaint that involves a patient with an Adverse Event (AE) is

considered as Medical or Clinical in nature.

• Each complaint that falls into this category must be processed in

a manner that is consistent with current agency regulations.

• Parallel to this “Clinical” procedural investigation is the execution

of the “Quality System” Evaluation as described earlier.

– This is carried out to assure that the AE (and potential ADR)

was not due to a product quality issue (i.e wrong amount of
active, product too hard to dissolve, high level of impurities
present, etc.).
COMPLAINTS AND ADVERSE DRUG REACTIONS
ADR Systems:

• Once the information about the AE has been collected and

documented, a formal Evaluation of the AE must take place.

– The Medical Director assesses whether or not the reported

AE is a drug related effect.

– The Medical Director determines whether or not any product

literature or labeling (i.e. product monograph, product insert,
prescribing information or product label / carton) makes
reference to the AE as an anticipated or expected adverse
effect.
COMPLAINTS AND ADVERSE DRUG REACTIONS
ADR Systems:

• All serious ADR’s or new literature reports must be reported to

the ADR Reporting Section, D.P. HPB, within 15 calendar days of
receipt of the report.
• Format - A “CIOMS FORM”
COMPLAINTS AND ADVERSE DRUG REACTIONS
ADR Systems:

• After the investigation is completed, a final response is sent to

the complainant (exactly as stated in the previous Quality
complaint process), outlining investigative actions, final results
and any required corrective and/or preventative actions.
• Adverse Events that are still being investigated will be processed
in a similar manner, but submitting a “Follow-up Report FORM”.
COMPLAINTS AND ADVERSE DRUG REACTIONS
ADR SYSTEMS:

• A summary report is prepared annually and upon request by

Health Canada

• A summary report consists of three sections

– Summary Line Listing – includes all ADR’s received during a

12-month period

– Critical Analysis of the ADR reports

– Recommended actions
STERILE PRODUCTION
 STERILE PRODUCTION
The GMPs, C.02.029 outline special requirements when
dealing with sterile products for:
• Premises
• Equipment
• Personnel
• Sanitation
• Water Systems
• Manufacturing Control
• Quality Control
• Products may be sterilized by dry heat, moist heat, radiation, or gas
(ethylene oxide) or filtration etc.
 STERILE PRODUCTION

The Canadian GMP Guideline defines sterile as “free from viable

microorganisms”

Some synonyms for “viable” are: Feasible, practical, possible

• Sterile products have special quality needs because they are susceptible
to particulate, pyrogenic and microbiological contamination.
Pyrogens are substances that cause a fever reaction when injected into
people
 STERILE PRODUCTION

• Special precautions must be made in the production area where

sterile products are manufactured.
• The raw materials that are to be used in sterile products must
meet stringent requirements and specifications
One of the most widely used raw materials in pharmaceutical
manufacturing is water
Control of the microbiological quality of water is important because
proliferation of microorganisms present in water may occur during the
purification, storage, and distribution of this substance
QUALITY SYSTEM -AUDITS
COMMON CLASSIFICATIONS OF QUALITY
AUDITS
AUDIT TYPES

*INTERNAL AUDITS/SELF-INSPECTIONS EXTERNAL AUDITS

FIRST PARTY AUDITS

(Auditor and Auditee are

within the same Organization) SECOND-PARTY AUDITS THIRD-PARTY
(Supplier/Vendor Audit)Independent Audit Free from conflict
of interest
Subject to rules of Contract Law Results in Certification,
Registration, Recognition, Award,
Survey/Off-site Audit or Onsite Audit Citation, fine, penalty, License
(Audit of another party)
approval:
Example: Regulatory, ISO,
Customer
(Outside audit of your Organization)

An internal audit measures an organization’s strength and weakness against business goals, internal procedure,
and external standards (GMP, FDA & HPFBI guidelines)
 DRUG COMPANY STATE OF CONTROL

State of Control:
a drug Company is considered
to be operating in a state of
control when it can guarantee
a finished drug product Equipment Personnel
for which quality, strength and
purity has been assured Drug
throughout production and meeting
that the product is compliant requirements
with its registration

Premises Methods
Definition of conditions under
which drugs are manufactured,
packed, tested, held
SUMMARY DEFINITION OF AN AUDIT

• Summary definition: a documented, systematic examination,

• periodically done by independent, qualified personnel to
• determine:

• What the firm does to develop and produce a quality

product;
• If the activities are scientifically sound, rationally based
and properly defined;
• If the activities are integrated into a system;
• If the activities are implemented and documented; and
• If the activities are effective
HPFBI DEFINITION OF A SELF-INSPECTION

“The purpose of self-inspection is to evaluate the fabricator’s,

packager’s/labeler’s, distributor’s, wholesaler’s or importer’s
compliance with GMP in all aspects of production and quality
control. The self-inspection programme is designed to detect
any shortcomings in the implementation of GMP and to
recommend the necessary corrective actions” (Canadian GMP
C.02.012(1)(b))
FDA DEFINITION OF AN AUDIT

“an established, systematic, independent, examination of a

manufacturer’s quality system that is performed at defined
intervals and at sufficient frequency to ensure that both
quality system activities and the results of such activities
comply with specified quality system procedures, that
these procedures are implemented effectively, and that
these procedures are suitable to achieve quality system
objectives.”
OVERVIEW OF THE AUDIT SYSTEM
Preparation

Conduct Analysis Report

audit

Follow-up,
closure
AUDIT PREPARATION
General steps for quality audit preparation (source: Quality audits for
improved performance by Dennis R. Arter):
1. Define the purpose of the audit
2. Define the scope of the audit
3. Determine the audit resources to be used
4. Identify the authority of the audit
5. Identify the performance standards to be used
6. Develop a technical understanding of the processes to be used
7. Contact those to be audited/Confirm
8. Perform an initial evaluation of lower-tier documents to higher level
requirements
9. Develop written checklists of the data needs (REMEMBER CHECK
LISTS GUIDE ACTION, NOT CONTROL IT)
 AUDIT PREPARATION

Adopt the mindset

We will be prepared and compliant all the time,
NOT just at the time of the inspection

Conduct Inspection Readiness Training and Self-Inspections at regular intervals (per

the SOP)

Integrate the audit program with an overall system based GMP program.
AUDIT PLAN AND AGENDA
• Document the Audit plan and Agenda. This should include:

 Tentative date and place of the audit

 Auditee and organizational units to be audited
 Names of audit team members
 Scope and purpose of the audit
 Standards being audited against
 Overall schedule of the audit
 Expected (maximum) duration of the audit
 Expected date of issue of the audit report

Additional information on the audit plan:

 Language of the audit
 Confidentiality requirement audit report distribution and the
expected date of issue.
 SELF INSPECTION PROGRAM
• GMP C.02.012
• The GMPs require that each fabricator, packager/labeler, distributor,
importer and wholesaler of a drug have a program of self-inspection.
• The self-inspection team should include personnel who are suitably
trained and qualified in GMP
• Periodic self-inspections should be carried out
• Reports on the findings of the inspections and on the corrective actions
should be reviewed by the appropriate Senior Management
• Corrective actions should be implemented in a timely manner
• During Regulatory Inspections, Health Canada and the FDA
will verify if the Self-Inspection Program is being followed.
 SELF INSPECTION PROGRAM

• The purpose of the self inspection program is to

find deficiencies in GMPs and other defined
Standards and to correct them as soon as possible.
• These findings and corrective measures must be
reviewed by appropriate senior management.
 SELF INSPECTION PROGRAM

• The program must be carried out on a periodic

basis, based on a rationale set by the company.
Once defined, this timeline should be respected

• Self inspections may also be carried out due to

product complaints, adverse events, non-
conformities/failures, or recalls
 SELF INSPECTION PROGRAM
• A first-party, internal audit or self-inspection audit measures an
organization’s strength and weakness against business goals, internal
procedures, and external standards (GMP, cGMP)
• Internal audits are performed within an organization by auditors who are
employed or hired by the organization
• The Organization is the Auditee
• Auditors must be independent of the area being audited (e.g. do not report to
the head of the area under review). You should not audit your own area
• Senior Management should support the Audit Team and not influence the
results of the audit report or how this is documented
• Internal auditors can be borrowed from different departments within the
organization and brought together for the purpose of the audit. Example
Engineering, Quality, Manufacturing, Packaging/Labeling, Warehouse.
• Cross-functional Team with Subject Matter Experts (SMEs)
 SELF INSPECTION PROGRAM

• Create an audit checklist using the information below:

• Department
• GMP Area to be audited
• Details of the applicable Standards or Regulation
• Documents, Records reviewed
• Complies ? (Yes/No)
• Comments / SOPs Reviewed
• Additional details of Inspected Area
• Required Follow Up Activities
THIRD-PARTY AUDITS
CONDUCTING A THIRD PARTY AUDIT

• A third party audit is performed by an independent Audit

Organization.
• Third party audits may result in:
• Recognition, Certification, registration eg. ISO Audits
• An award, eg. an award of a contract by a Customer
• License approval, a citation, a fine or a penalty e.g.
Regulatory Audit by Health Canada or the FDA
THIRD PARTY AUDITS

• It is very important that a pharmaceutical company

be ready for inspections/audits by FDA, HPFBI, EU
inspectors, or Third Party Clients.

• Companies must pass an inspection by the

regulatory authorities that shows they are in
compliance with GMPs in order to manufacture,
test, package/label, wholesale, distribute or import
drugs legally.
THIRD PARTY – REGULATORY AUDIT

• When regulatory authorities come to conduct an

inspection, the scope may not only encompass GMP
related issues, but it may also cover support
documentation for Product Registrations and R&D
activities.
THIRD PARTY – REGULATORY AUDIT
• Before the Auditors arrive, a pharmaceutical company should:

• Have a list of all changes and Change Control documentation since the last inspection: (Example:
Personnel, Equipment, Facility, Products, Raw Materials, Procedures)

• Have a complete list of all products, raw materials, packaging components used in manufacturing drug
products,
• A list of all drug products imported, distributed and wholesaled

• Ensure that the observations from the last inspection have been corrected and audit closure evidence is
available

• Ensure that all SOPs are up to date

• Ensure that the training records and job descriptions for all personnel are up to date and available

• Have a list and documentation for all Releases, Rejections, Destructions, Items in Quarantine,
Investigations, Deviations, CAPAs, OOS’, Trending Reports, Complaints, Recalls, Rejections, Quality Holds,
Change Control, Validation documentation, Equipment List, Calibration and Maintenance Schedules etc.

• Ensure that all of these files are closed off where required/ or are on track to being closed off
THIRD PARTY – REGULATORY AUDIT
• Make the ENTIRE facility is sanitary (immaculate) and organized. This sets the stage for the
inspection

• Ensure that the Quarantine areas are labeled, items scheduled for Destruction,
Discrepancy areas are organized and accounted for with rationale

• If Physical labels are used, ensure that products are labeled as required and that
system Holds are implemented where required

• Ensure that the inventory counts in the system matches the physical counts

• Ensure that only authorized personnel have access to the Quarantine areas of the
facility and designated areas requiring limited access (stability rooms, retain rooms,
production rooms etc.)

• Determine who will be responsible for what during the inspection (someone to accompany
the inspectors at all times {Escort}, someone to document everything, someone to retrieve
requested documents {Runner}).

• Train personnel on how to act during an inspection

THIRD PARTY – REGULATORY AUDIT

• At minimum, the Regulatory authorities will look at the “important”

SOPs, such as general documentation SOP, SOPs on SOP, Training SOPs,
Change Control SOP, Validation SOPs, Facility Sanitation, Pest Control,
Self-Inspections, Releasing Materials, Rejecting Materials, Equipment
Cleaning and Sanitation, and SOPs on handling Deviations and OOS
results, specific Manufacturing and Packaging SOPs, Lab Methods etc..

• BE PREPARED FOR MORE!!

• You should expect to have the TOC (Tracking of Changes/Change Control

History) of ALL company SOPs reviewed for verification of completeness
and required approvals
THIRD PARTY – REGULATORY AUDIT
• The Auditors will ensure that the SOPs are clear, concise and
specific, define responsibilities, include all of the required
details and are signed off by QA and signed off in a timely
manner

• The Auditors will also ensure that relevant people have been
trained on the SOP, if training was completed in a timely
manner, if the SOPs are followed, revisions are approved by
the designated Departments and Quality controlled, and
that outdated SOPs are not used

• They may also request to review archived SOPs. To verify

revisions made and also if the archived copies can be located
THIRD PARTY – REGULATORY AUDIT
• The Auditors will determine if an adequate and formal investigation
program is in place to address Incidents/deviations.

• Are the outcomes of Incidents/deviations determined adequately?

• Is “trending” used for assessments and analysis?

• Are Corrective Action (CA) decisions determined adequately?

• Are investigations performed and concluded in a timely manner?

• Are Preventive Actions (PA) carried out to prevent deviations from

occurring again?

• Is the correct root cause determined?

 THIRD PARTY –REGULATORY AUDIT
• The regulatory authorities will almost always look at the
validation program.

• The following will be determined:

• if the validation protocols are clear, detailed and
approved
• if the final reports have been reviewed and approved
• if the protocols are followed
• if operation limits are set
• if there is a proper change control system in place
THIRD PARTY –REGULATORY AUDIT
• During the inspection, all personnel should be responsive and courteous,
act professionally, and respond quickly and accurately.

• Personnel should always listen carefully to questions asked of them and

should never guess at the answer. It is OK for someone to ask the
inspector for more time to answer the question or contact someone who
could better answer the question.

• There are times when the Inspector is asking a particular employee to

answer a question because it is in their area of job responsibility. If that
is the case, another employee should not answer the question.

• The question should be answered. No more information should be

provided than was asked for.
THIRD PARTY –REGULATORY AUDIT

• Personnel should never act confrontationally and

they should work with the regulatory authorities,
not against them.

• Act Professional and courteous at all times.

• Follow up in a timely manner to provide documents

requested.

• Always be truthful
 HPFBI /FDA INSPECTIONS

The Canadian Health Products and Food Branch

Inspectorate (HPFBI) and the United States Food and
Drug Administration (FDA) conducts inspections of
pharmaceutical manufacturers, distributors,
wholesalers, packagers/labelers, and testers of drugs
to ensure that they are in compliance with
GMPs/cGMPs and are operating in a state of control
 HPFBI /FDA INSPECTIONS
Preparation:
1. Senior Management’s presence is important
2. Establish agenda at opening meeting
Keep initial presentation short (1 hour or less)
3. Use SOPs where required to answer questions
4. Ensure the appropriate knowledgeable person is available to respond to
questions
5. Ensure rapid document retrieval
6. Don’t volunteer information, but present complete story, always be truthful
7. Request daily summary meeting (Do Not Insist)
8. Debrief daily; plan for the next day. (CRITICAL)
9. Where possible implement Corrective Actions during the inspection
HEALTH CANADA
REGULATORY INSPECTIONS
 HEALTH CANADA INSPECTIONS

• During an establishment inspection, Health Canada

and FDA Inspectors look for areas of risk, including
deviations against the Regulations (GMPs and
cGMPs).

• These deviations are documented as Observations

or Citations in the Inspection Exit Notice according
to the Risk Level.
 HEALTH CANADA INSPECTIONS

Health Canada has issued a guideline called the Risk

Classification of GMP Observations-GUI-0023.

• This is a good reference on what the HPFBI will

look for when performing an inspection and
how these are classified based on the risk
level.
 HEALTH CANADA INSPECTIONS
• Assignment of the Risk to an Observation
• The risk assigned will be in relation to the nature of the deviation as well as the number of
occurrences.

• Generally, when only low risk products are involved, a risk 1 will not be assigned to
observations, except for extreme situations such as fraud or widespread cross-
contamination, infestation or unsanitary conditions.

• *Where a risk 2 observation is re-evaluated as a risk 1 (risk 2 observation with an arrow),

this situation is immediately brought to the attention of the company’s officials, proper
explanation will be provided to the establishment and this explanation should be captured
in the Inspector’s Comments field of the Inspection Summary in the Inspection Reporting
System (IRS).
• *Certain Risk 2 observations may be upgraded to a Risk 1. They are indicated with an arrow
(↑) Health Canada Guide 0023
 HEALTH CANADA INSPECTIONS

The HPFBI classifies GMP observations into 3

categories:
• Risk 1 (Critical ) Observations
• No air filtration system to eliminate airborne contaminants that are likely to be
generated during fabrication or packaging.
• Risk 2 (Major) Observations
• Damages (holes, cracks or peeling paint) to walls/ceilings immediately adjacent
or above manufacturing areas or equipment where the product is exposed.
• Risk 3 (Other) Observations
• Damages to surfaces not directly adjacent or above exposed products.
 HEALTH CANADA INSPECTIONS

HPFBI Classification:
• Critical observations are those which are likely to result in a
non-compliant product or a situation that may result in an
immediate or latent health risk
• It also includes observations of fraud, misrepresentation or
falsification of data or products
• This is documented as Risk 1 Observation (Critical)
 HEALTH CANADA INSPECTIONS

HPFBI Classification:
• Major observations are observations that may result in a drug
not consistently meeting its market authorization (specs and
quality specified in the NDS/ANDS).
• This is documented as Risk 2 Observation (Major)
HEALTH CANADA INSPECTIONS

HPFBI Classification:
• Other Observations are those that are not critical or
major but are a departure from GMPs
• This is documented as Risk 3 Observation (Other)
 HEALTH CANADA INSPECTIONS

• The HPFBI will issue one of two possible ratings for an

establishment after an inspection:
• A rating of Compliance means that the HPFBI
recommends that the company will continue, or be
issued, an Establishment License (i.e. company is
granted the right to produce drugs, test drugs,
warehouse drugs, import drugs, etc.).
• A rating of Non-Compliance means that the company
will not continue, or be issued, an Establishment
License. It may be temporarily suspended until
corrective actions are taken, or it may be terminated.
 HEALTH CANADA INSPECTIONS

RESPONSIBILITY FOR SENIOR MANAGEMENT

• Senior Management is expected to ensure that effective Procedures and

Controls are implemented
• To ensure that a global approach to investigations would be taken and
where required, impact to all affected batches are considered
• To ensure that timely and thorough Investigations are completed
• To ensure that Root Causes are determined and Corrective and Preventive
Action Plans are implemented
• To make decisions with supportable documentation and to ensure that
these are available for review in a timely manner
FDA REGULATORY INSPECTIONS
 FDA INSPECTIONS
• The FDA targets an inspection once every 2 years (unless
there is cause for an inspection to be scheduled earlier than
this, due to an investigation, a major recall or complaint)
• This inspection may be triggered by a New Drug Application
(NDA) or an Abbreviated New Drug Application (ANDA)
• The FDA will then inform the Canadian company that they
wish to perform a Pre-Approval Inspection (PAI) for that
product
• The FDA also performs routine surveillance
domestic/foreign inspections under its Compliance Program
 FDA INSPECTIONS

• There are several reasons for FDA inspections:

• Routine periodic inspection= Drug Process
Compliance FDA program number 7356.002
• Due to a follow up on a prior inspection
• Or Incident, recall or complaint related
• Pre-approval inspection (PAI)= FDA Compliance
program number 7346.832
• Post-approval inspections= FDA Compliance
program number 7346.843
• Note: The programs are Guidance Documents not Regulations
 FDA INSPECTIONS

• The FDA also uses a System Based Approach to their

inspections. The FDA has published a guideline on
this approach, as well as guidelines for inspections
of various types of systems or products (e.g. Guide
to Inspection of Topical Drug Products). These
guidelines are available at www.fda.gov (follow the
industry link)
 FDA FOCUS ON QUALITY SYSTEMS & RISK
The FDA’s Quality Systems Inspection Program Assess Firm's State of
Control.
At least 2 systems are covered with mandatory coverage of the Quality System: During the
inspection of these systems, the FDA will ensure compliance with cGMPs ., with the SOPs that
the company has written for each of these functions and additional required documentation.

FULL INSPECTION- this includes an inspection of the QUALITY SYSTEM PLUS AT LEAST 3 OTHERS
SYSTEMS
This is the approach taken during an Initial inspection; when there is a history of non-
compliance; when there are significant changes; due to new technologies, equipment, facilities
etc.

ABBREVIATED INSPECTION- this includes an inspection of the QUALITY SYSTEM PLUS 1 OTHER
SYSTEM
This approach is taken during Surveillance inspections; systems are rotated with the Abbreviated
Option (FDA District Office will monitor and decide)
This inspection type is used when the firm has a satisfactory cGMP Compliance history
When there is no significant recall or complaint history, product defects or field alert incidents
When there are no major changes in the manufacturing profile of the firm in the previous two
years
 FDA 6 SYSTEM APPROACH
ACTIVITIES IN DRUG FIRMS ARE ORGANIZED INTO SYSTEMS. THE IDEA IS THAT DEFICIENCIES
IN ONE SYSTEM WILL AFFECT OTHER SYSTEMS AS WELL.

FDA Systems Approach (6 systems)

SYSTEMS 21 CFR 211

QUALITY SUBPART B-ORGANIZATION AND PERSONNEL

FACILITIES AND SUBPART C-BUILDINGS AND FACILITIES

EQUIPMENT SUBPART D-EQUIPMENT

MATERIALS SUBPART E-COMPONENTS AND

CONTAINER/CLOSURES
PRODUCTION SUBPART F-PRODUCTION AND PROCESS
CONTROLS
PACKAGING AND LABELING SUBPART G-PACKAGING AND LABELING

Quality System Controls SUBPART I-LABORATORY

IF ALL SYSTEMS ARE CONTROLLED-HELPS IN ENSURING THE PRODUCTION OF DRUGS THAT

MEET THE INTENDED SAFETY, IDENTITY, STRENGHT, QUALITY AND PURITY CHARACTERISTICS
 FDA INSPECTIONS

• The FDA’s System Based Approach to inspections of

Drug Manufacturers is described in the FDA
guideline 7356.002.
• FDA has broken down each pharmaceutical
company into 6 systems.
 FDA INSPECTIONS

• There are regular FDA inspection schedules based on general and

more specific cGMP’s requirements.
• There are four types of FDA cGMP Inspections

1. Pre-approval
2. Post-approval
3. Surveillance (routine)*
4. For-cause or directed**
*1-3 have compliance programs and FDA’s procedures are available
**The for cause or directed inspections are the most unscripted…are
harder to prepare for and the Investigator may have a specific
assignment that is not publicly available.
 FDA INSPECTIONS
FDA INSPECTION TYPES:
1. Pre-approval inspection Program ( Program #7346.832). This inspection
type is to review the details for the
• Submission of an NDA and ANDA
• Submission of a variation (e.g. different strength, color, different
container sizes and configurations)
• New products and/or manufacturing changes
• Site changes

2. Post-Approval Inspection Program (Program # 7346.843). This inspection

type is to review the details for the :
 Products marketed under a recently approved application
 Changes in production and control practices that occur after approval are
monitored (6-24 months)
 The Inspection plan is based on the reason for inspection (pre-approval
inspection, past history etc.)
 Inspection assignments are issued by CDER (Center for Drug Evaluation
and Research) based on the risk level of the facility
 FDA INSPECTIONS
FDA INSPECTION TYPES:
 3. Surveillance Inspections; Drug Manufacturing Inspections (Program #
7356.002) This inspection includes both domestic and international
inspections

 4. FOR CAUSE INSPECTIONS . This inspection type is to review the details

for :
 Investigation due to recalls or significant complaints
• Past inspection history
 FDA INSPECTIONS

• When the FDA performs an inspection,

they record all of the details on an
Establishment Inspection Report (EIR).
• If they find cGMP violations, they are
recorded on a Form FDA-483 (commonly
referred to as a ‘483’).
• If the cGMP violation is critical, the FDA
may issue a Warning Letter
 FDA INSPECTIONS
At the Exit meeting, understand the outcome of the inspection
You need to obtain satisfactory closure to this inspection
For the exit discussion
• Ensure that Senior Management is present and other required
employees (Subject Matter Experts)
• Agree on the discussion strategy
• Manage the meeting
• Be proactive
• Do not make commitments you cannot keep; keep time lines
reasonable
• Present any disagreement professionally, calmly, logically, back this
up with facts and evidence
• Remember to focus on the root causes of items on the 483
• Don’t be afraid to ask the investigator to support their position with
objective evidence