World Journal of Pharmaceutical Research

Waghmare et al. World Journal of Pharmaceutical Research

SJIF Impact Factor 8.084

Volume 11, Issue 17, 276-287. Review Article ISSN 2277– 7105

A BRIEF REVIEW ON PHARMACEUTICAL VALIDATION AND

PHARMACEUTICAL PROCESS VALIDATION

Sumesh B. Waghmare*, Sidheshwar S. Patil, Raviraj R. More, Rahul S. Solunke,

Sharad V. Usnale and Vidya S. Jadhav

MSS Maharashtra College of Pharmacy, Nilanga, Latur, Maharashtra,India.

ABSTRACT
Article Received on
25 October 2022, Validation is one of the crucial processes in establishing and
Revised on 15 Nov. 2022, maintaining the final product's quality. We can ensure that the final
Accepted on 05 Dec. 2022
DOI: 10.20959/wjpr202217-26466 product is of the highest quality if every stage of the production
process is checked. The art of validation involves planning and
carrying out the planned actions while also documenting them.
*Corresponding Author
Validation and quality control work together to guarantee the items'
Sumesh B. Waghmare
MSS Maharashtra College full quality. Process validation emphasises process design components
of Pharmacy, Nilanga, and maintaining process control during commercialization. It also
Latur, Maharashtra,India. makes clear that it is an ongoing programme and synchronizes
process validation operations with the lifecycle of the product. This
article provides a general introduction to pharmaceutical validation in the pharmaceutical
manufacturing process as well as an outline of its significance.

KEYWORDS: Pharmaceutical Validation, Process Validation, Prospective Validation,

Retrospective Validation, Concurrent Validation, Re-Validation.

INTRODUCTION
Since its initial formal introduction in the United States in 1978, the notion of validation has
undergone ongoing development. Over time, the definition of validation has broadened to
include a variety of activities, from computerized systems used in clinical trials to analytical
methods used to check the integrity of therapeutic ingredients and medical products.[1,2]

Because each process is unique, there is no one way to validation, although regulatory
agencies like the FDA and EC have created basic non-mandatory guidelines. Validation is
therefore one component of quality assurance connected with a particular process. The term

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Waghmare et al. World Journal of Pharmaceutical Research

"validation" then simply refers to a "evaluation of validity" or a "activity of showing

efficacy." According to the European Community for Medicinal Products, validation is the
"action of showing," in line with GMP principles, that any methods, processes, requirements,
materials, activities, or systems trulyproduce the desired results. [1,2,9]

Why Validation is done[2]

 Using the equipment without knowing whether it will result in the desired product is not
practical.
 The pharmaceutical sector employs highly skilled workers, facilities and equipment, and
expensive materials.
 The effective utilisation of these resources is essential to the industry's survival.
 Costs associated with product failures, rejections, reworks, recalls, and complaints
account for a sizeable portion of the overall manufacturing costs.
 A thorough analysis and control of the manufacturing process is required to lower failure
costs and increase productivity.

Types of validation
1) Analytical validation[2]
Analytical validation is the examination of a product's quality characteristics by testing to
show that the precision, accuracy, strength, purity, and specification have not been
compromised and that dependability has been maintained throughout the product life cycle.

2) Equipment validation[2]
Equipment qualification is often referred to as validation. Installation Qualification (IQ),
Operational Qualification (OQ), and Performance Qualification are the three categories used
to categories equipment validation (PQ). To demonstrate that the installation of the unit has
been appropriately carried out and that the installation standards of the manufacturer have
been satisfied, an IQ documents particular static features of a facility or item. After
installation, the equipment's ability to deliver the operating ranges outlined in the purchase
order must be confirmed. This is known as OQ. The PQs aim to demonstrate that the process
under investigation performs as intended.

3) Process validation[6]
Process validation is a key element of the quality assurance system employed by
pharmaceutical producers since it is essential to the safety and quality of medicinal products.

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Waghmare et al. World Journal of Pharmaceutical Research

In order to assure that high-quality goods can be produced again, process validation is a
systematic strategy to identifying, measuring, assessing, documenting, and revising the key
phases in the manufacturing process. Process validation is a quality control function that aids
in ensuring the quality of drug products by giving proof that the manufacturing process
regularly accomplishes its intended goals.

Pharmaceutical, biotechnological, medical device and herbal businesses all use process
validation extensively. The businesses that have certified manufacturing procedures for some
completed products are still being sought after by regulatory organizations. Validating a
manufacturing process involves continuously tracking and assessing the method's
effectiveness. Unexpected factors may impact the production process and the quality of the
end product, necessitating adaptation or alteration of current parameters due to the
complexity of modern manufacturing processes. The bioavailability of a medicinal product
may change if an ingredient's physical properties are slightly changed, or if chemicals are
added in a different order. In this scenario, a sample of the final product could match
compendial dissolving requirements yet display a much different dissolution pattern than that
which was generated initially. Revalidation may be required as a result of these impacts
following any modification to the process, the product, or the control methods.

Measures that will enable any substantial process modifications to be noticed and rectified
right away must be done in order to maintain a process' validated status. Equipment, SOPs,
production guidelines, environmental factors, or any other feature of the process system that
has an impact on its state of control and, consequently, on the state of validation, may be
covered by such change control methods.

System and equipment qualification is a part of validation, which is the recorded act of
proving that any technique, process, or action will consistently provide the desired outcomes.
As such validation activities will frequently involve training on production material and
operating procedure, training of people involved, and system monitoring during production,
their common goal is to ensure that quality, safety, and effectiveness must be built into the
product and not just tested at the end.

Advantages[4,7]
1. Validation of produced goods that are sensitive to heat is possible since it is a
straightforwardprocedure and moisture-sensitive.

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2. It is possible to modify processes and increase real-time monitoring.

3. Increased capacity for statistical estimation of product and process factors.
4. Minimize the likelihood of issues developing and ensure the process runs smoothly.
5. Enhance data and evaluation skills, as well as confidence in the product quality and
repeatability of the process.
6. Enhanced the capacity for reporting.
7. Improved ability to create testing thresholds and predicted parameters for repeating
manufacturing in relation to validation results.

Prerequisite of process validation[7]

 The process development designee is responsible for reviewing the product development
report, data from pilot scale and scale up batches, and the proposed master formula
documentof the manufactured product.
 The Process Development Designee is responsible for reviewing and verifying the
availability of the analytical method transfer report to the plant and the readiness of the
plant to undertake validation testing and routine testing; this role should coordinate with
QC/QA.
 The Process Development Designee is responsible for creating commercial/exhibit batch
production and control records that contain operational constraints and a comprehensive
process control plan based on development report.
 The Technique After the facility, utility, equipment, laboratory test techniques, and
process validation activities have been approved and released, validation is carried
out. Only a minimal analytical technique validation must be done when the compendia
approach is utilized.
 All specifications for raw materials and packaging materials must come from authorised
vendors and be approved by quality control.
 Preventive maintenance routines are in place, and all the tools and instruments that will
be used are calibrated.
 Appropriate SOPs are in place, and training in equipment use, manufacturing techniques,
andsample tactics has been completed.
 Important process variables and stages have been identified, and their operating ranges
have been determined.
 Before executing process validation batches, all master formulas, manufacturing
instructions, packaging instructions, testing procedures and specification must be

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authorised.
 The equipment and surrounding area have been thoroughly cleaned before the process
validation is started.
 Process engineers will train the operational team and validation team.

Types of process validation[8]

Normally, it would be anticipated that process validation would be done before distributing a
finished good intended for sale (prospective validation). It can be important to validate
procedures during ordinary manufacturing if this is not achievable (concurrent validation).

Processes that have been in operation for a while without seeing any substantial changes
may also be validated in accordance with a methodology that has been authorised
(retrospective validation).

1) Prospective validation
Prospective Validation, first prior to the procedure being used in a commercial setting,
prospective validation involves carrying out the validation technique. The manufacturing
procedure should be divided up into discrete phases throughout the product development
stage. In order to identify the essential factors that might have an impact on the final product's
quality, each phase should be assessed using experience or theoretical considerations. To
ascertain how crucial these aspects are, a set of tests ought to be planned. Every experiment
needs to be carefully planned out and completely recorded in an authorized protocol.

The usage of all machinery, the working environment, and the analytical testing procedures
should have all undergone thorough validation. Only once the important process parameters
have been defined, along with the machine settings, component specifications, and
environmental factors, can master batch documents be created. A series of batches should be
created using this specified method. The number of process runs that are completed and
observations that are taken should, in principle, be enough to allow for the typical range of
variation and trends to be identified, providing ample information for evaluation. It is
commonly accepted that validating a process requires three successive batches or runs that
produce products of the specified quality while staying within the finalized parameters.

2) Concurrent validation
The Inspectorate discourages the unconditional use of this strategy and does not accept it as

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the "standard." There is always a chance that this method may eventually need changing
process specs or parameters. This circumstance frequently raises concerns about what should
be done with the batches that have already been issued for sale but were later discovered to
have undesirable quality features.

3) Retrospective validation
Processes that are reliable and regularly used at many establishments have not gone through a
fully documented validation procedure. To offer the requisite documentation proof that the
procedures are verified, historical data may be used. The design of a protocol, presenting the
findings of the data review, and coming to a conclusion and suggestion are still necessary
processes in this kind of validation.

Retrospective validation is only suitable for thoroughly developed processes with operational
limitations for each crucial stage in the process. It is improper when there have been recent
modifications to the product's formulation, operating procedures, tools, or facilities.

4) Process Re-Validation
Revalidation offers proof that modifications made to a process or its surroundings do not
significantly alter its characteristics or the quality of its product. The process validation's
originaldocumentation requirements still apply.

At frequent intervals, reviews and trend analyses should be performed. In some

circumstances, revalidation is essential. Here are some instances of planned or unforeseen
modifications that could call for re-validation:
 Modifications to the raw materials' (physical characteristics, including moisture,
viscosity, particle size distribution, and density, which may have an impact on the process
or end product.)
 Changes in the manufacturer's active raw material source
 Modifications to the packaging's (primary container/closure system).
 Alterations to the procedure (e.g., mixing time, drying temperatures and batch size)
 Alterations to the machinery (e.g. addition of automatic detection system).
 Alterations to the facility or plant.

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Phases of validation[5]
Three steps are used to categories validation study activities:
Phase 1
The pre-validation phase, also known as the qualification phase, includes all activities related
to product research and development, formulation, pilot batch studies, scale-up studies,
technology transfer to commercial scale batches, setting up stability conditions, storing and
handling in- process and finished dosage forms, equipment qualification, installation
qualification, master formula record, operational qualification, and process capability.

Phase 2
Process Validation Phase (Process Qualification Phase): This phase is used to ensure that
even under the most extreme circumstances, it is still possible to produce products that are
satisfactory.

Phase 3
The validation maintenance phase requires routinely reviewing all process-related documents,
including validation audit reports, to ensure that there have been no alterations to the
production process and that all SOPs, including the Change Control procedures, have been
adhered to.

The Validation Team ensures that no modifications or deviations that should have called for
requalification and revalidation have occurred at this level.

Elements of validation[1]
Design qualification (DQ)
Design qualification (DQ) is the process of formally assessing a design's compliance with
operational and legal requirements at a suitable point in the project.

DQ check items
 Standards for manufacturing goods and legal obligations.
 Performance standards.
 Air flow, movement flow, and pressure engines in the facility.
 Dependability and effectiveness.
 Commissioning specifications. Construction skills and equipment installation.
 Access to and maintenance of vital instruments and equipment.

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 Impact on environment and safety.

Installation qualification (IQ)

Installation qualification (IQ) is a recorded assurance that all elements of a facility, utility, or
piece of equipment that may have an impact on product quality are installed properly and in
accordance with authorised specifications.

IQ check items
 Install at ion conditions (wiring, utilities and functionality).
 Calibration, preventive maintenance, cleaning schedules.
 Safety features.
 Supplier documentation, prints, drawings and manuals.
 Software documentation. Spare parts list.
 Environmental conditions (such as clean room requirements, temperature and humidity).
 Equipment design features (i.e. materials of construction clean ability).

Operational qualification (OQ)

Operational qualification (OQ) is a documented confirmation that all components of a
facility, utility, or machinery component that may have an impact on product quality function
as intendedover the course of all expected ranges.
 Process control limitations (line speed, temperature, pressure, and setup parameters).
 Software parameters.
 Raw material requirements.
 Operating procedures for processes.
 Needs for material handling.
 Control over process change.
 Training

Performance qualifying (PQ)

Performance qualifying (PQ) is a formalised confirmation that every component of a
building, utility, or piece of equipment operates as intended and satisfies predefined
acceptance standards.

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PQ check items
 Actual product and process specifications and guidelines set out in OQ.
 The product's acceptability.
 Confirmation of process capacity as determined by OQ.
 Repeatability and long-term stability of the method.

Table 1: Responsible authorities for validation.[1]

Department
Responsibility
/Designation
Responsible for manufacturing of batches and review of
Manager Production
protocol and report.
Manager QC Responsible for analysis of samples Collected
Executive QC Responsible for samples collection and submission to QC
Manager Maintenance Providing utilities and engineering Support
Responsible for preparation of protocol and manufacturing of
Executive Production
validation batches
Responsible for protocol authorization and preparation of summary
Manager QA
report.

Types of documentation in validation[4]

The various documentation to be prepared during the validation process are:
1) Standard operating process (SOPs)
2) Validation protocol (VP)
3) Validation master plan (VMP)
4) Validation reports (VR)

1) Standard operating process (SOPs)[6]

Standard Operating Procedures (SOPs) are issued to provide detailed instructions to
employees on their individual areas of responsibility, job instructions, suitable requirements,
and necessary records. To claim conformity with GMP principles or other statutory laws and
regulations, certain general steps must be followed. The preparation and upkeep of the work
space, such as cleaning and sterilising, and the testing area, are the general features addressed
by the SOPs.

2) Validation protocol
Validation protocol consists of:
 Objectives and the scope
 Responsible Staff

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 SOPs' description
 equipment or devices to be utilised
 Measurement requirements
 Norms and criteria as necessary
 Validation stages
 Parameter for critical processes
 sampling, the need for testing, and an extra test
 stress testing when necessary
 established approval standards
 Reviews
 Interpretation of the results obtained
 Deviations\Conclusion

Validation master plan (VMP)[2]

The validation master plan (VMP) is the document that outlines all the specifics needed to
carry out the validation procedure, as well as the deadlines for finishing the task and the roles
involved in the validation plan. It gives a quick overview of the company's validation work
programme. In accordance with WHO recommendations, a validation master plan is a high-
level document that develops the validation strategy for the whole project and evaluates the
manufacturer's technique. Any process, technique, or procedure is genuinely and consistently
capable of achieving the expected output or outcomes, according to the validation master
plan. The validation master planalso summarises the equipment and machinery's qualification
and calibration.

Validation reports (VR)[3]

The confirmed validation methodology, graphical or tabular findings, process monitoring
(forms), and all analytical data of the validated batches should be included in the
authenticated validation report. The validation report should continue with an explanation of
the manufacturing specialist's assertion and recommendation that stability testing be carried
out per protocol on all validation batches in compliance with NDA/ANDA stability plan.

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General view of process validation

Validation life cycle[7]

Validation is an ongoing, dynamic process. The validation process is a thorough examination
of how the system and processes function that ranges from very basic to very broad
theoretical investigation. Its scope includes system and process maintenance, training, and
documentation revision control. Validation evidence has to be visible at the corporate level
and appear in the management structure. A method for establishing and maintaining quality is
validation.

Application of validation[2]
By definition, validation requires the accumulation of documentary evidence relating to a
process, item or equipments or facility. This is achieved by means of a validation protocol,
which details the test to be carried out, the frequency of testing and the result expected (the
acceptance criteria). If the validation programmed is designed, and the protocol issued, before
the equipment or facility comes on stream or before the product manufactured by the process
being validated is distributed, then this constitutes prospective validation, sometimes,
however, systems or processes are in place that that have not previously been validated, but
are functioning well and consistently producing good products, already in distribution.
Validation of such facilities or process is called retrospective validation and is achieved by
the review of historical manufacturing and testing data. Prospective and retrospective
validation may be combined advantageously in sequence to provide a higher level of
assurance that is given by the pre marketing prospective validation alone. Concurrent
validation is applied either to ongoing evaluation of historical data associated with
retrospective validation. Revalidation is an act of repeating all or a portion of the validation
as a result of any modification to the process or facilities that may be lead to changes in the
quality or reproducibility of the product. Revalidation may be triggered by the operation of

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an established.

CONCLUSION
In the fields of drug research, production, and specification of final products, validation is the
term that is most frequently used. A validated process' consistency and dependability in
delivering a high-quality product is crucial for an industry. According to the report,
Pharmaceutical Process Validation is one of the most significant and well-known cGMP
factors.

Quality must be built into the product at every stage and not merely tested for at the end using
quality assurance tools. A number of activities that happen throughout the lifecycle of the
product and process are involved in process validation.

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