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Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 373


Thakur Anjana*
, RanaAC
, Singh Gurpreet
, Saini Seema

Department of Pharmaceutics, Rayat Institute of Pharmacy, RailMajra S.B.S Nagar,Punjab, India
Department of Pharmacology, Rayat Institute of Pharmacy, Rail Majra S.B.S Nagar, Punjab, India
The main purpose of this work is to present the role of process validation in
pharmaceutical industry. In pharmaceutical industry validation is one of the important
step in achieving and maintaining the quality of final product. Process validation is done
in order to know whether the process is producing the final product with its
predetermined specifications and acceptance criteria. Quality is the most important
requirement in the manufacturing process. All the drugs must be manufactured to the
highest quality level. Quality cannot be guaranteed just by the end product testing but we
have to control carefully each critical step during the manufacturing process. Thus
process validation plays an important role in pharmaceutical industry.
Keywords: Process validation, Qualification, Good manufacturing practices.
The main objective of any pharmaceutical unit is to manufacture products of requisite
attributes and quality consistently, at the lowest possible cost. The concept of validation
was first proposed by two Food and drug administration (FDA) officials, Ted Byers and
Bud Loftus, in the mid 1970s in order to improve the quality of pharmaceuticals. In a
guideline, validation is act of demonstrating and documenting that any procedure,
process, and activity will consistently lead to the expected result. The goal of the
validation is to ensure that quality is built into the system at every step. In general, an
entire process is validated and a particular object within that process is verified.
Validation mainly based on, FDA regulations describing current good manufacturing
practices (CGMP) for finished pharmaceutics are provided in 21 CFR parts 210 and
211.The regulation also set out an expectation that the different parts of the production
process are well defined and controlled, such that the result of that production will not
substantially change over time. The main purpose of setting validation is to monitor the
on line and off-line performance of the manufacturing process thus, validation is an
integral part of quality assurance.
Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 374

USFDA defined Process Validation as establishing documented evidence which provide
a high degree of assurance that a specific process will consistently produce a product
meeting its predetermined specification and quality characteristics

EUROPEAN COMMISSION defined Process Validation as Validation is the act of
demonstrating and documenting evidences that a procedure operates effectively. Process
validation is the means of ensuring and providing documentary evidences that processes
are capable of consistently producing a finished product of the required quality
The most compelling reason for process validation is to guarantee, as far as possible, that
all processes and machinery in the pharmaceutical manufacturing process are being used
in a way, which will ensure safety, integrity, quality and strength of dosage form. Process
validation is very important if there is significant change to the premises, the facilities,
the equipment or the process, which may affect the quality of the product, directly or
indirectly, should be validated

Assurance of quality
Process optimisation
Reduce testing in process and in finished goods
Increased output
Time bound
Easier maintenance of equipment


It would not be feasible to use the equipments without knowing whether it will
produce the product we wanted or not.
Detailed study of the manufacturing process-validation is necessary if failure to
be reduced and productivity improved.
The pharmaceutical industry uses expensive materials, sophisticated facilities and
equipments and highly qualified personnel.
Validation should thus be considered in the following situations:
Totally new process;
Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 375

New equipment;
Process and equipment which have been altered to suit changing priorities;
Process where the end product test is poor and unreliable indicator of product
PROCESS VALIDATION: A documented evidence with a high degree of assurance
that a specific process will consistently produce a product meeting its predetermined
specifications and quality characteristics. Process validation may take the form of
prospective, concurrent or retrospective validation and process qualification or re-
The guidelines on general principles of process validation mention four types of
1, 9
1. Prospective validation:
Establishing documented evidence prior to process implementation that a system does
what it proposed to do based on pre-planned protocols. This approach to validation is
normally undertaken whenever the process for a new formula must be validated before
routine pharmaceutical production commences.
2. Concurrent validation: Concurrent validation is used for establishing documented
evidence that a facility and processes do what they purport to do, based on information
generated during actual imputation of the process. In process monitoring of critical
processing step and end product testing of current production can provide documented
evidence to show that the manufacturing process is in a state of control.
3. Retrospective validation: The retrospective validation option is chosen for established
products whose manufacturing processes are considered stable and when on the basis of
economic consideration alone and resource limitations, prospective validation programs
cannot be justified. Prior to undertaking retrospective validation, wherein the numerical
in process and/or end product test data of historic production batches are subjected to
statistical analysis ,the equipment, facilities and subsystems used in connection with the
manufacturing process must be qualified in conformance with CGMP requirements.
4. Revalidation:
Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 376

Revalidation provides the evidence that changes in a process and/or the process
environment that are introduced do not adversely affect process characteristics and
product quality. Almost all GMP texts recommend that whenever there are significant
changes in the facility, equipment or process, re-validation should be carried out. The
FDA process validation guidelines refer to quality assurance system in place that requires
revalidation whenever there are changes in packaging,(assumed to be the primary
container-closure systems), formulation, equipment or processes which could impact on
product effectiveness.
Process Validation involves a series of activities taking place over the life cycle of the
product and process. The FDA Guideline describes process validation activities in three
Stage1-Process Design: The commercial process is defined during this stage based on
knowledge gained through development and scale up activities
Stage2-Process Qualification: During this stage the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing
Stage3-Continued Process Verification: On going assurance is gained during routine
production that the process remains in a state of control
A successful validation program depends upon the information and knowledge from the
product and process development. This knowledge and understanding is the basis for
establishing and approach to control the manufacturing process that results in product of
desired quality attributes.
Before any batch from the process is commercially distributed for use by consumers, a
manufacturer should have gained a high degree of assurance in the performance of the
manufacturing process such that it will meet consistently produce API and Drug Products
meeting those attributes relating to identity, strength, quality, purity and potency. The
assurance should be obtained from laboratory-, pilot-, and or commercial scale studies.
Information and data should demonstrate that the commercial manufacturing process is
capable of consistently producing acceptable quality products within commercial
manufacturing conditions.

Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 377

A manufacturer should:
Understand the source of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and ultimately on the
product attributes
Control the variation in a manner commensurate with the risk it represent to
the process and product.

Written procedures should be in place to describe the actions to be taken if a change is
proposed to a product component, process environment, processing site or any other
change that may affect product quality. The change control system should ensure that all
notified or requested changes are satisfactorily investigated, documented and authorized.
Products made by processes subjected to changes should not be released for sale without
full awareness and consideration of the change by the validation team
6, 7.

A Written plan stating how validation will be conducted, production and packaging
equipment, and decision point on what constitutes acceptable test result. The validation
protocol provides a synopsis of what is hoped to be accomplished. The protocol should
list the selected process and control parameters, state the number of the batches to be
included in the study, and specify how the data once assembled will be treated for
The validation protocol should be numbered, signed and dated and should contain
minimum the following information:
1. Title
2. Scope and objective
3. Responsibility
4. Protocol Approval
5. Validation Team
6. Product composition
7. Process flow chart
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8. Manufacturing Process
9. Review of equipments/utilities
10. Review of process parameters
11. Validation procedures

12. Sampling locations
13. Documentation
14. Acceptance criteria
15. Summary &conclusion

A validation master plan is a document that summarizes the company overall philosophy,
approaches to be used for establishing performance adequacy. The validation master plan
should provide an overview of the entire validation operation, its content and planning. It
should therefore be brief, concise and clear and comprise all prospective, concurrent and
retrospective as well as re-validation. The validation master plan should not repeat
information documented elsewhere but should refer to existing documents such as policy
documents, validation protocols and reports
5, 7

The strategy selected for process validation should be simple and straightforward.
1. The use of different lots of raw materials should be included (active drug substance
and excipient )
2. Batches should be manufactured in the equipment and facilities designed for eventual
commercial production.
3. Batches should be run in succession and on different days and shifts
4. Critical process variables should be set within their operating ranges and should not
exceed their upper and lower control limits during process operation
14, 15
5. Failure to meet the requirements of the validation protocol with respect to process
input and output control should be subjected to process requalification and subsequent
revalidation following a thorough of analysis of process data and formal discussion by
the validation team

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1, 6
Process parameters
Dry mixing
Impeller speed
Mixing time
Kneading during Binder addition
Kneading at slow Speed after Binder addition
Kneading at slow speed
Wet milling
Screen Size
Screen Integrity before and after use
Inlet Temperature
Outlet temperature
Product bed temperature
Screen Integrity before and after use
Dry Milling
Screen Size
Screen integrity before and after use
Lubrication Time
RPM of cage blender
Yield of lubricated granules
Granules flow from granules container to Feeder
Machine Overload pressure
Weight of 20 tablets
Individual weight variation
Tablet thickness
Disintegration Time
Baffle type
Spray Nozzle Aperture
Pan Load
Temperature of Inlet air
Temperature of Exhaust air
Coating Pan RPM
Atomizing Pressure
Spray Rate
Distance Between gun & tablet bed
Average Weight gain
Sealing Roller Temperature
Leak Test

Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Thakur et al IC Value 4.01 380

CRITICAL FACTORS: Critical factors which affect effective process validation
1. All the critical point of the process should be clearly identified.
2. The process should run using the extremes of the system at the critical points.
3. The quality system should support the validation effort by way of document control,
preventive maintenance, calibration, etc.
4. Adequate data are required to provide statistical support to demonstrate product

1. Head of quality assurance: For protocol authorisation & preparation of summary
2. Head of engineering: Providing utilities and engineering support
3. Validation manager: Manufacturing of validation batches & preparation of protocol
4. Production manager: Manufacturing of batches &review of protocol & report
5. Specialist validation discipline: all areas
From the above studies, it is concluded that process validation is a key element in the
quality assurance of pharmaceutical product. Pharmaceutical validation and process
control are necessary to ensure that drug product will meet pharmaceutical standards for
quality, purity, stability and efficacy. A process validation strategy which is developed at
early stage of product development is necessary for a successful validation program.
Thus, Validation is the documented act of demonstrating that a procedure , process and
activity will consistently lead to the expected result.
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For Correspondence:
Thakur Anjana