Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Sharma et al

PHARMA SCIENCE MONITOR

AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

PROCESS VALIDATION IN PHARMACEUTICAL INDUSTRY: A REVIEW

Ajay Sharma* and Seema Saini
Department of Pharmaceutics, Rayat Institute of Pharmacy, Rayat and Bahra Campus, Railmajra, Distt.
Nawanshahar, Near Ropar, Punjab, India.

ABSTRACT
Validation is a tool of quality assurance which provides confirmation of the quality in
equipment system, manufacturing processes, software and testing methods. Validation
assures the products with predetermined quality characteristics and attributes can be
reproduced consistently/reproducibly with in the established limits of the manufacturing
process operation at the manufacturing site. Validation is required in order to move a
product from development to commercial production. Different dosage form have
different validation protocol. This paper presents an introduction, basic concepts involved
in process validation, approaches for process validation and general overview on process
validation in pharmaceutical industry.
Keywords: Process validation, Pharmaceutical industry, Quality assurance, Approaches.
INTRODUCTION
The concept of validation has expanded through the years to encompass a wide range of
activities from analytical methods used for the quality control of the drug substances and
drug products to computerized systems for clinical trials. In pharmaceutical
organizations, validation is a fundamental segment that supports a company commitment
to quality assurance. Validation is a tool of quality assurance which provides
confirmation of the quality in equipment system, manufacturing processes, software and
testing methods. Validation assures the products with predetermined quality
characteristics and attributes can be reproduced consistently/reproducibly with in the
established limits of the manufacturing process operation at the manufacturing site.
Validation is required in order to move a product from development to commercial
production. Validation is also effective in minimizing the cost of the financial
expenditure of an organization, as a validated process is more efficient and produces less
reworks, rejects and wastage 1, 2.
Process validation is defined as the collection and evaluation of data, from the process
design stage through commercial production, which establishes scientific evidence that a
process is capable of consistently delivering quality product. Process validation involves

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a series of activities taking place over the lifecycle of the product and process. Process
validation is a term used in the medical device industry to indicate that a process has been
subject to such scrutiny that the result of the process (a product, a service or other
outcome) can be practically guaranteed. This is vitally important if the predetermined
requirements of the product can only be assured by destructive testing.
Process validation establishes the flexibility and strict control in the manufacturing
process control in the attainment of desirable attributes in the drug products while
preventing undesirable properties 3.
As per the ICH guidelines defines as Process validation: ‘Process validation is the
means of ensuring and providing documentary evidence that processes within their
specified design parameters are capable of repeatedly and reliably producing a finished
product of required quality’4.
Validation of a process entails demonstrating that, when a process is operated within
specified limits, it will consistently produce product complying with predetermined
(design and development) requirements. In general, the validation of a process is the
mechanism or system used by the manufacturer to plan, obtain data, record data, and
interpret data. These activities may be considered to fall into three phases: 1) an initial
qualification of the equipment used and provision of necessary services – also know as
installation qualification (IQ); 2) a demonstration that the process will produce acceptable
results and establishment of limits (worst case) of the process parameters – also known as
operational qualification (OQ); and 3) and establishment of long term process stability –
also known as performance qualification (PQ).
Effective process validation contributes significantly to assuring drug quality. The basic
principle of quality assurance is that a drug should be produced that is fit for its intended
use. This principle incorporates the understanding that the following conditions exist:
• Quality, safety, and efficacy are designed or built into the product.
• Quality cannot be adequately assured merely by in-process and finished-product
inspection or testing.
• Each step of a manufacturing process is controlled to assure that the finished
product meets all quality attributes including specifications.

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According to Indian GMP (Good Manufacturing Practice), validation study is an essential

part of GMP required to be done as per predetermined protocols 5.
The FDA defines process validation as follows: Process validation is establishing
documented evidence which provides a high degree of assurance that a specific process
will consistently produce a product meeting its pre-determined specifications and quality
characteristics 6.
OBJECTIVES OF PROCESS VALIDATION
1) The manufacturing process, in addition to the individual equipment, must be validated.
2) The goal is to create a robust manufacturing process that consistently produces a drug
product with minimal variation that adheres to quality criteria of purity, identity, and
potency.
3) A validation plan for the manufacturing process should be drafted and executed by
engineers in order to satisfy guidelines. The validation plan usually involves just a PQ
section.
4) Just as equipment validation, major changes after the initial validation will result in the
need for subsequent revalidation.
5) In the end, process validation will ensure a robust product that is highly reproducible
over time.
BASIC CONCEPT OF PROCESS VALIDATION
• Calibration, verification and maintenance of process equipment.
• Prequalification or revalidation.
• Establishing specifications and performance characteristics.
• Selection of methods, process and equipment to ensure the product meets
specifications.
• Qualification or validation of process and equipment.
• Testing the final product, using validated analytical methods, in order to meet
specifications.
• Challenging, auditing, monitoring or sampling the recognised critical key steps of the
process 3.
NEED OF VALIDATION

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1. It would not be feasible to use the equipments without knowing whether it will
produce the product we wanted or not.
2. The pharmaceutical industry uses expensive materials, sophisticated facilities &
equipments and highly qualified personnel.
3. The efficient use of these resources is necessary for the continued success of the
industry. The cost of product failures, rejects, reworks, and recalls, complaints are the
significant parts of the total production cost.
4. Detailed study and control of the manufacturing process- validation is necessary if
failure to be reduced and productivity improved.
5. The pharmaceutical industries are concerned about validation because of the
following reasons.
6. Assurance of quality.
7. Cost reduction.
8. Government regulation 7,8.
STAGES OF PROCESS VALIDATION
The three stages of process validation are;
Stage 1 – Process Design: The commercial manufacturing process is defined during this
stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine
production that the process remains in a state of control.
Stage 1 includes performing process understanding studies to establish all process
parameters, determining which parameters are critical, and executing supporting
validation studies. Process design is the activity of defining the commercial
manufacturing process that will be reflected in planned master production and control
records. The goal of this stage is to design a process suitable for routine commercial
manufacturing that can consistently deliver a product that meets its quality attributes.
Stage 2 includes the performance of three consecutive runs at the intended commercial
scale. During the process qualification (PQ) stage of process validation, the process
design is evaluated to determine if it is capable of reproducible commercial manufacture.

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This stage has two elements: (1) design of the facility and qualification of the equipment
and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-
compliant procedures must be followed. Successful completion of Stage 2 is necessary
before commercial distribution. Products manufactured during this stage, if acceptable,
can be released for distribution.
STAGE 1: STAGE 2: STAGE 3:
PROCESS PRE – PROCESS LIFECYCLE
QUALIFICATION QUALIFICATION QUALIFICATION

Parameter risk Statistical process control

assessment
↓ Change control
Range studies At least 3 consecutive
↓ runs at scale Re-validation
Critical parameter
determination

Stage 3 is the ongoing assessment of process performance through life cycle qualification
and management of process changes. The goal of the third validation stage is continual
assurance that the process remains in a state of control (the validated state) during
commercial manufacture. A system or systems for detecting unplanned departures from
the process as designed is essential to accomplish this goal. Adherence to the CGMP
requirements, specifically, the collection and evaluation of information and data about the
performance of the process, will allow detection of undesired process variability 9, 10.
PLANING FOR VALIDATION
All validation activities should be planned. The key elements of a validation programme
should be clearly defined and documented in a validation master plan (VMP) or
equivalent documents.
• The VMP should be a summary document, which is brief, concise and clear.
• The VMP should contain data on at least the following:
1. Validation policy.
2. Organisational structure of validation activities.
3. Summary of facilities, systems, equipment and processes to be validated.

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4. Documentation format: The format to be used for protocols and reports.

5. Planning and scheduling.
6. Change control.
7. Reference to existing document.
8. Incase of large projects, it may be necessary to create separate validation master plans
11
. TYPES OF VALIDATION
Validation can be prospective, concurrent, retrospective or revalidation (repeated
validation).
• Prospective validation: Prospective validation is defined as the establishment of
documented evidence that a system does what it purports to do based on a pre
planned protocol. This validation is usually carried out prior to the introduction of
new drugs and their manufacturing process. This approach to validation is
normally under taken when ever new formula, process or facility must be
validated before routine pharmaceutical formulation commences. In fact
validation of process by this approach often leads to transfer of the manufacturing
process from the development function to product. The objective of prospective
validation is to prove or demonstrate that the process will work in accordance
with a validation master plan or protocol prepared for pilot product trails.
• Retrospective validation: Retrospective validation is defined as the
establishment of documented evidence that a system does what it purports to do
on review and analysis of historical information. The sources of such data are
production, QA and QC records. The issues to be addressed here are changes to
equipment, process, specification and other relevant changes in the past.
• Concurrent validation: It is similar to the prospective, except the operating firm
will sell the product during the qualification runs, to the public as its market price.
This validation involves in process monitoring of critical processing steps and
product testing. This helps to generate and documented evidence to show that the
production process is in a state of control.
• Revalidation: It is the repetition of a validation process or a part of it. This is
carried out when there is any change or replacement in formulation, equipment

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plan or site location, batch size and in the case of sequential batches that do not
meet product specifications and is also carried out at specific time intervals in
case of no changes 2, 12, 13.
STRATEGY FOR VALIDATION OF METHODS
The validity of a specific method should be demonstrated in laboratory experiments using
samples or standards that are similar to the unknown samples analyzed in the routine. The
preparation and execution should follow a validation protocol preferably written in a step
by step instruction format as follows:
• Develop a validation protocol or operating procedure for the validation.
• Define the application purpose and scope of method.
• Define the performance parameters and acceptance criteria.
• Define validation experiments.
• Verify relevant performance characteristics of the equipment.
• Select quality materials, e.g. standards and reagents;
• Perform pre-validation experiments;
• Adjust method parameters and/or acceptance criteria, if necessary;
• Perform full internal and external validation experiments;
• Develop SOPs, for executing the method routinely;
• Define criteria for revalidation.
• Define type and frequency of system suitability tests and/ or analytical quality
control (AQC) checks for the routine; and
• Document validation experiments and results in the validation report 14.
VALIDATION PROTOCOLS
Protocol should specify the following in details;
• General information.
• Objective.
• Background/revalidation.
• Summary of development and technical transfer (form R & D or another site activity
to justify in process testing and controls: any previous validations.
• List of equipments and their qualification status.

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• Facilities qualification.
• Process flow chart.
• Manufacturing procedure narrative.
• List of critical processing parameters and critical excipients.
• Sampling, test and specification.
• Acceptance criteria.
Validation protocol is a written plan stating how validation will be conducted. The
document should give details of critical steps of manufacturing process that should be
measured, the allowable range of variability and the manner in which the system will be
tested 2.
According to Indian GMP (Good Manufacturing Practice), validation study is an essential
part of GMP required to be done as per predetermined protocols. Prospective process
validation is carried out during the development stage by means of risk analysis of the
production process which is broken down into individual steps. These are then evaluated
on the basis of past experience to determine whether they might lead to critical situation
The risk is evaluated, the potential causes are investigated and assessed for probability &
extent, the teal plan are drawn up, & priorities are set. The trial are then performed and
evaluated & overall assessment is made. If the end results are acceptable the process is
considered to be satisfactory. Unsatisfactory processes must be modified & improved
until a validation exercise proves them to be satisfactory. This form of validation is
essential in order to limit the risk of error occurring on the production scale. The present
work deals with identification of critical stage and their consequent evaluation by
challenging its upper and lower specifications 15.
IMPORTANCE OF PROCESS VALIDATION
The main advantages to be obtained from validation are assurance of quality and process
optimization, both resulting in a reduction of total costs.
Assurance of Quality
Validation is an extension of the concepts of quality assurance since close control of the
process is necessary to assure product quality and it is not possible to control a process
properly without thorough knowledge of the capabilities of that process without validated

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and controlled processes, it is impossible to produce quality products consistently. End

product testing, in the absence of validation, gives little assurance of quality for variety
reasons, among which are
1. Very limited sample size.
2. The limited number of tests performed on a sample. For example, it is impractical to
test for all potential impurities or contaminants.
3. The limited sensitivity of the test.
Process Optimization
The optimization of a process for maximum efficiency, while maintaining quality
standards, is a
consequence of validation. Literal meaning of word to optimize is “To make as effective,
perfect or useful as possible”. The optimization of the facility, equipment, systems, and
processes results in a product that meets quality requirements at the lowest cost.
Reduction of quality costs
Quality costs are divided in to four categories. They are:
a) Preventive costs.
b) Appraisal costs.
c) Internal failure costs.
d) External failure costs.
e.g. of internal failure costs: Any validated and controlled process will result in fewer
internal failures like
Fewer rejects
Reworks
Re-tests
Re-inspection
Process validation makes it possible to do the job right the first time. Also, a scientifically
studied and controlled process makes it unlikely that defective products will be
dispatched to market thus no recalls or market complaints 15.
APPROACHES TO PROCESS VALIDATION
There are two basic approaches to the validation of the process itself (apart from the
qualification of equipment used in production, the calibration of control and measurement

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instruments, the evaluation of environmental factors, etc). These are the experimental
approach and the approach based on the analysis of historical data. The experimental
approach, which is applicable to both prospective and concurrent validation, may
involve:
1. extensive product testing,
2. simulation process trials,
3. challenge/worst case trials, and
4. Control of process parameters (mostly physical) 16.
One of the most practical forms of process validation, mainly for non-sterile products, is
the final testing of the product to the extent greater than that required inroutine quality
control. It may involve extensive sampling, far beyond that called for in routine quality
control and specifications, and often for certain parameters only. Thus, for instance,
several hundred tablets per batch may be weighed to determine unit dose uniformity. The
results are then treated statistically to verify the normality of the distribution and to
determine the standard deviation from the average weight. Confidence limits for
individual results and for batch homogeneity are also estimated. Strong assurance is
provided that samples taken at random will meet regulatory requirements if the
confidence limits are within compendia specifications 17.
VALIDATION TEAM
A multidisciplinary team is primarily responsible for conducting and supervising
validation studies. Personnel qualified by training and experience in a relevant discipline
may conduct such studies. The working party would usually include the following staff
members such as;
Head of quality assurance.
Head of engineering.
Validation manager.
Production manager.
Specialist validation discipline: all areas 18.
VALIDATION REPORT

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A written report should be available after completion of the validation. If found

acceptable, it should be approved and authorized (signed and dated). The report should
include at least the following:
• Title and objective of study.
• Reference to protocol.
• Details of material.
• Equipment.
• Programmes and cycles used.
• Details of procedures and test methods.
• Results (compared with acceptance criteria).
• Recommendations on the limit and criteria to be applied on future basis 19.
CONCLUSION
Validation is the commonest word in the area of drug development, manufacturing and
specification of finished products. Pharmaceutical validation which includes assay
validation, cleaning validation, equipment validation as well as the overall process
validation is crucial in stability analysis, animal studies and early phases of clinical
development such as bioavailability/bioequivalence studies. So it is necessary, before
approval of a new drug, that an accurate and reliable assessment for its effectiveness and
safety for the intended indication and target patient population is demonstrated.
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[Link]

For Correspondence:
Ajay Sharma
Email: sharmaajay177@[Link]

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