www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1013
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
A REVIEW ON PHARMACEUTICAL VALIDATION & PROCESS
CONTROL AS QUALITY ASSURANCE TOOLS
Vaghela Kuldeepsinh1*, Maisuriya Aakash², Mitali Dalwadi³, Dr. Chainesh Shah
4 and
Dr. Umesh Upadhyay5
Student1,2
, Asst. Professor³, Associated Professor4, Principal
5
Department of Quality Assurance, Sigma Institute of Pharmacy, Bakrol,
Vadodara-390019(Gujarat, India).
ABSTRACT
Process validation is fitting documented proof which supplies a high
degree of affirmation that a specific procedure, method can compactly
deliver a product or result meeting its preset specifications and quality
attributes. Validation is the key method for effective Quality
Assurance. Objectives square measure primarily to assure that the
specific drug product have the identity, strength, quality and purity.
and therefore the next is to determine that a method systematically
performs or not. As per GMP validation protocols square measure
basic items of GMP these square measure needed to be done in step
with predefined conventions, the base that need to be approved
incorporate method, testing and cleansing later such control
methodology, establish to screen the yield and approval of aggregation forms that might be
guilty of fluctuation of medication item. The analysis of validation method gives North
American country the exactness, accuracy, specificity and dependableness of the check
techniques used by the organizations, may well be engineered up and archived. consequently
the validation could be a fundamental piece of the standard affirmation or assurance.[1]
KEYWORDS: GMP, Quality Assurance, Pharmaceutical Validation, Pharmaceutical
method Control.[1]
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 10, 1013-1028 Review Article ISSN 2278 – 4357
*Corresponding Author
Vaghela Kuldeepsinh
Student Department of
Quality Assurance, Sigma
Institute of Pharmacy,
Bakrol, Vadodara-
390019(Gujarat, India).
Article Received on
16 Aug. 2021,
Revised on 05 Sept. 2021,
Accepted on 26 Sept. 2021,
DOI: 10.20959/wjpps202110-20273
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1014
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
INTRODUCTION OF PHARMACEUTICAL VALIDATION
The admirable objective of any pharmaceutical plant is to manufacture products of needful
attribute & quality consistently, at lowest possible cost. Although validation study have been
conducted in pharmaceutical industry for a long time, there is ever increasing interest in
validation owing to their industry’s greater prominence in recent years on quality assurance
program. It is fundamental to useful production operation. Validation is a concept, it has
apposite in US in 1978.Concept of validation has expanded through years to incorporate a
wide range of activities from analytical methods used for the quality control of drug
substances & drug products to computerized systems for clinical trials, labelling or process
control, Validation is founded on, but not prescribed by regulatory requirements and is best
viewed as an important and unbroken part of cGMP. The word validation normally means
assessment of validity & action of proving effectiveness. Validation is a team effort, where
it’s involves people from various disciplines of plant.[2]
Figure 1: Introduction of Validation.
Introduction of pharmaceutical process control
Development of a drug product could be a long method involving drug discovery, laboratory
testing, animal trials & studies, clinical trials & studies. To additional increase effectiveness
& safety of the drug product once approval, several administrative unit like the us Food and
Drug Administration (US-FDA) additionally need that drug product be tested for its identity,
quality, strength, stability & purity before it may be free for used. For this reason,
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1015
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
pharmaceutical validation & method controls area unit vital inspite of the issues that will
been countered. Method controls embrace raw materials examination or audit, in-process
controls & target therefore for final product. the aim is to watch on-line & off-line
performance of them, producing method & then validate it. Even once producing method is
valid, current smart producing observe additionally needs that a literary procedure for method
controls is established to watch it work. QA/QC smart observe steering printed here reflects
utility, acceptableness, cost-effectiveness, existing expertise, potential for application on a
universal basis. A QA/QC program contributes to objectives of excellent observe steering,
specifically to enhance transparency, likeness, consistency, completeness, & confidence in
national inventories of emissions estimates. Outcomes of QA/QC method might end in a
review of inventory or supply class uncertainty estimates.[1]
Scope of Validation
Pharmaceutical Validation is a vast area of work & it practically covers every aspect of
P’ceutical processing activities, hence defining the Scope of Validation becomes a really
difficult task. However, a systematic look at p’ceutical operations, it will point out at least
following areas for p’ceutical validation.[3]
1. Analytical
2. Instrument Calibration
3. Process Utility services
4. Raw materials
5. Packaging materials
6. Equipment
7. Facilities
8. Manufacturing operations
9. Product Design
10. Cleaning
11. Operators
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1016
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Figure 2: Validation Scope Process.
Importance of validation
1. Reduction in rejection.
2. Time bound.
3. Increased output.
4. Avoidance of capital expenditures.
5. Normal mix ups & bottle necks.
6. Process optimization.
7. Assurance of quality.
8. Reduction of quality cost.
9. Minimal batch failures, improving efficiently & productivity.
10. More rapid automation.
11. Fewer complaints about process related failures.
12. Easier maintenance of equipment.
13. Reduced testing in process & in finished goods.
14. More rapid & reliable startup of new equipments.
15. Improved employee awareness of processes.
16. Easier scale up form development work.
17. Government regulation(compliance with validation requirements is necessary for
obtaining approval to manufacture & to introduce new products).[4]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1017
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Planning for Validation
All validation activities ought to be planned. The key parts of a validation programme should
be clearly outlined and documented in a validation program (VMP) or equivalent documents.
The VMP ought to be a outline document, that is temporary, terse and clear.
The VMP ought to contain knowledge on at least the following.
1. Validation policy.
2. Organisational structure of validation activities.
3. outline of facilities, systems, equipment and processes to be validated.
4. Documentation format: The format to be used for protocols and reports.
5. designing and programming.
6. amendment management.
7. relevance existing document.
8. enclose of huge comes, it may be necessary to form separate validation master plans.[5]
Documentation
A written protocol ought to be established that specifies however qualification and validation
can be conducted. The protocol ought to be reviewed and approved. The protocol ought to
specify crucial steps and acceptance criteria. A report that cross-references the qualification
and/or validation protocol ought to be prepared, summarizing the results obtained,
commenting on any deviations ascertained, and drawing the required conclusions, including
recommending changes necessary to correct deficiencies. Any changes to the set up as
defined within the protocol ought to be documented with applicable justification.[1]
After completion of a satisfactory qualification, a format unleash for subsequent step in
qualification and validation ought to be created as a written authorization.[6]
Validation Setup
To establish the specified attributes. These attributes embrace physical additionally as
chemical characteristics. within the case of parenterals, these desirable attributes ought to
embrace stability, absence of pyrogens, and freedom from visible particles.
Acceptance specifications for the merchandise should be established in order to achieve
uniformity and systematically the specified product attributes, and also the specifications
should be derived from testing and challenge of the system on sound applied mathematics
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1018
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
basis throughout the initial development and production phases and continued through
resulting routine production.
The process and instrumentation ought to be hand-picked to achieve the merchandise
specification. For example; style engineers; production and quality assurance individuals
might all be concerned. The process ought to be outlined with a good deal of specificity and
every step of the method should be challenged to work out its adequacy. These aspects are
necessary in order to assure merchandise of uniform quality, purity and performance.[7]
Types of method validation
1. Prospective method Validation
Where associate degree experimental set up referred to as the validation protocol is dead
(following completion of the qualification trials) before the method is place to commercial
use. Most validation efforts need some degree of prospective experimentation so as to
generate validation support information.[7]
2. Concurrent method Validation
Establishing documented proof that process is in a very state of management throughout the
particular implementation of the method. This is often commonly performed by conducting
in-process testing and/or monitoring of vital operations throughout manufacture of every
production batch.[3]
3. Retrospective method Validation
Where historic information taken from the records of the finished production batches area
unit accustomed provide documented proof that the method has been in a very state of
management before the request for such evidence.[8]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1019
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Figure 3: General view of process validation.
BASIC CONCEPT OF PROCESS VALIDATION
Calibration, verification and maintenance of method instrumentation.
• Prequalification or revalidation.
• Establishing specifications and performance characteristics.
• Selection of ways, method and instrumentation to confirm the merchandise meets
specifications.
• Qualification or validation of method and instrumentation.
• Testing the ultimate product, victimisation valid analytical ways, in order to meet
specifications.
• Challenging, auditing, observation or sampling the recognised crucial key steps of the
method.[9]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1020
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Figure 4: Process Validation.
Phases in process validation
1. Phase 1
Pre Validation part or Qualification Phase, that covers all activities regarding product
research & development, formulation pilot batch studies, scale-up studies, transfer of
technology to commercial scale batches, establishing stability conditions & storage, &
handling of in-process & finished dose forms, instrumentation qualification, installation
qualification, master production document, operational qualification & method capacity.[8]
2. Phase 2
Process Validation part (Process Qualification phase), designed to verify that each one
established limits of essential method parameters are valid which satisfactory merchandise
may be produced even beneath “worst case” conditions.[3]
3. Phase 3
Validation Maintenance part, requiring frequent review of all method connected documents,
including validation audit reports to assure that there have been no changes, deviations,
failures, modifications to the assembly method, and that all sops are followed, as well as
amendment Control procedures. At this stage validation team also assures that there are no
changes/ deviations that ought to have resulted in requalification & revalidation.[1]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1021
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
REVALIDATION
Re-validation provides the proof that changes during a method and/or environment that
square measure introduced don't adversely have an effect on method characteristics and
product quality. Documentation needs will be constant as for the initial validation of
process.[10]
Facilities, systems, instrumentality and processes, including improvement, ought to be
sporadically evaluated to verify that they continue to be valid. Where no vital changes are
created to the valid standing, a review with proof that facilities, systems, instrumentality and
processes meet the prescribed needs fullfils the necessity for revalidation. Revalidation
becomes necessary in bound situations. a number of the changes that need validation square
measure as follows.[11]
Changes in raw materials (physical properties like density, viscosity, particle size distribution
and wet etc., that will have an effect on the method or product).[12]
Changes within the supply of active raw material manufacturer.
Changes in packaging material (primary container/closure system)
Changes within the method (e.g., mixing time, drying temperatures and batch size)
Changes within the instrumentality (e.g.,addition of automatic detection system). Changes
of apparatus that involve the replacement of apparatus on a “like for like” basis wouldn't
normally need re-validation except that this new instrumentality should be qualified.
Changes within the plant/facility.
A call to not perform revalidation studies should be totally justified and documented.[1]
Process validation and quality assurance
The relationship of quality assurance and process validation goes well on the far side the
responsibility of any quality assurance (QA) function. all the same, it's a good to mention that
process validation may be a QA tool, because it establishes a top quality normal for the
precise process.[13-14]
Quality assurance in pharmaceutical companies embodies the trouble to assure that products
have the strength, purity, safety and efficacy portrayed within the company’s new drug
application (NDA) filings.[15]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1022
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Although quality assurance is typically designated as a division perform, it must also be
Associate in Nursing integral a part of Associate in Nursing organization activities. once
method validation becomes a general objective of the technical and operational teams among
a company, it becomes the thrust for quality standards in development work, engineering
activities, quality assurance, and production. The quality assurance related to the
pharmaceutical development effort includes the following general functions.[16]
1. to make sure that a legitimate formulation is designated.
2. To qualify the method which will be scaled up to production-size batches.
3. to help the planning of the validation protocol.
4. To manufacture the bio batches for the clinical program, which is able to become the
object of the FDA’s preapproval clearance.
To work with production and engineering to develop and perform the qualification program
for production instrumentality and facilities/process systems.
To develop valid analytical methods to allow.
The steadiness program to be carried out.
The testing of raw materials and finished product
The event of unharness specifications for the raw materials and finished product.
The testing of processed material at certain specific stages.
Quality assurance is that the effort taken to make sure compliance with government rules for
the systems, facilities, and personnel concerned with producing merchandise. QA audits can
be quite varied in scope to realize this assurance. These responsibilities embrace batch record
reviews, critiques of product style, process validation activity, and, possibly, audits of
different departments’ operations.[8]
CHANGE CONTROL
Written procedures need to be in place to explain the actions to be taken if modification is
projected to the start material, product part, technique instrumentality, method atmosphere (or
site), methodology of production or testing or the opposite modification which is able to have
a sway on product quality or responsibility of the method. modification management
procedure need to make sure that enough support information area unit generated to
demonstrate that the revised method will finish during a product of the desired quality, in line
with the approved specifications.[17]
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1023
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
All changes which is able to have a sway on product quality or dependableness of the strategy
need to be formally requested, documented and accepted. The probably impact of the
modification of facilities, systems and instrumentality on the merchandise need to be
evaluated, as well as risk analysis. the necessity for, and therefore the extent of,
requalification and revalidation ought to be determined.[18]
Figure 5: Change Control.
Regulations of Validation
The 3 basic and most significant reasons for validation ar quality assurance, economics and
compliance.
1. Quality assurance
Product quality can't be assumed for a process by routine internal control testing because of
the limitation of applied mathematics sampling and the restricted sensitivity if the finished
product testing. Quality variations among units at intervals a batch, or among completely
different batches, are rarely detected by testing of finished product samples. Validation
challenges the adequacy and dependableness of a system or method to satisfy pre-determined
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1024
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
criteria. A roaring validation, therefore, provides a high degree of confidence that the same
level of quality is systematically engineered into each unit of the finished product, from batch
to batch. The Pharmaceutical makers Association (PMA) and therefore the government
agency have recognized the merchandise quality assurance concept of validation.[7]
2. Economics
The direct social science advantage of validation may be a reduction within the value related
to method monitoring, sampling and testing. The consistency and dependableness of a valid
process to {provide} a top quality product provide indirect value savings ensuing from a
decrease or elimination of product rejections, reworks and retesting. Final unharness of the
merchandise batch would be expedited and freed from delays and complications caused by
drawn-out investigations of method or analytical variances. additionally, product quality
complaints and potential product recollects would be decreased.[8]
3. Compliance
Specific current smart producing Practices (cGMP) references to variation are found in
following sections of 21CFR211.
211.884(d) Variation of suppliers take a look at result for elements once these results are
accepted inlieu of in-house testing after receipt.
211.110(a)- Validation of manufacturing process to ensure batch uniformity and integrity of
drug products.
211.165(e)-Validation of analytical methodologies.
The requirement of validation is also implied in 211.100(a). This section of GMP requires
that written procedures and process controls be established to ensure that the drug products
have to “identify strength, quality and purity are represented to possess”.
The FDA’s draft Mid Atlantic Pharmaceutical Inspection Guidance Program for Prescription
Drug Plants, issued in January 1990,emphasis the importance of validation in the
manufacturing process.[18]
A typical Validation Blueprint of Equipment validation.
Introduction
1. Installation qualification
Facilities
Utilities
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1025
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
instrumentation
2. Operation qualification
Testing Protocols for Utilities and Equipment
3. Validation
Testing protocols for product and Cleaning systems
4. Documentation
5. Validation of the QA testing laboratory
6. SOPs
7. coaching of personnel
8. Organization charts
9. Schedule of events
When a corporation follows the precepts of total quality management (TQM), the thought of
continuous improvement would typically be used.
When method validation is employed as a high quality assurance tool rather than a final, an
organization’s operations can improve or stay at the very best quality level doable. The effort
are going to be properly documented, and the overall attitudes of all the affected personnel
will be positive. Finally, a additional logical approach to pre approval inspections and other
Food and Drug Administration technical interactions are going to be affected.
When the validation activity becomes the focal point of associate degree structure unit’s
effort to hold out its own technical responsibilities, quality standards are going to be
maintained for the merchandise and producing method from the planning and development
stages and throughout the commercial lifetime of the merchandise.
The thought of validation had to be redefined and re-evaluated to accommodate the technical
changes. ancient validation concepts and procedures that were acceptable years past might
not be applicable to today’s operations and instrumentation.
A sensible understanding of the validation concepts and once and the way to use them is of
bigger importance to confirm a pregnant, efficient, effective, and economical validation
program. as a result of usefulness and compliance are each necessary aspects of validation.
Finally, like any project, the validation is not complete while not the required documentation.
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1026
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Special attention ought to be afforded to the physical look of the report, likewise as its
technical contents.[19]
Note for guidance on method validation
Validation is that the act of demonstrating and documenting that a method operates
effectively.
Process validation is that the means that of making certain and providing documentary proof
that processes (within their specified style parameters) area unit capable of systematically
producing a finished product of the desired quality.
In terms of pharmaceutical method validation it is meant that, all the vital parts in an
exceedingly manufacturing method for a pharmaceutical product, from development of the
method through a final validation at the assembly scale ought to be lined.
It is recognised that the term validation is intended to use to the ultimate verification at the
production scale, (typically three production batches).
It is essential that solely valid producing processes area unit used, it's more and more that
information should be submitted within the application for marketing authorisation
demonstrating the validity of the given method.
Thus the progress from pre-formulation formulation pilot manufactures industrial scale
manufacture ought to be shown within the marketing authorisation application written
account to be logical, reasoned and continuous.[20]
Process validation decision tree for change in source of active p’ceutical ingredients.
Figure 6: Process Validation Decision Tree.
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1027
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
CONCLUSION
It is essential, before endorsement of another drug, that a definite and a dependable analysis
of its adequacy and security for the expected sign and target quiet people area unit illustrated.
Pharmaceutical validation, which incorporates assay validation, cleanup validation,
instrumentation validation and to boot the final procedure approval is significant in strength
examination, creature considers and early periods of clinical improvement, as an example,
bioavailability/bioequivalence ponders. when the drug is approved, pharmaceutical validation
and method management area unit vital to ensure that the drug product can meet/set
pharmaceutical standards for identity, quality, purity, strength and stability. By and huge,
pharmaceutical approval and method control provides a specific affirmation of clump
consistency and therefore the trait of the item factory-made synthetic dyestuffs deliver
precarious side-effects, a number of that have cancer-causing intermediates and henceforth a
boycott has been forced by Federal Republic of Germany and a few alternative European
nations on the employment of benzidine dye in material items of vesture sent out into their
nations.[1]
REFERENCE
1. Aida Jacob, Gowrav M P; ”Pharmaceutical Validation and Process Control”;
International Journal of Chem Tech Research, 2018; 11(8): 80-88.
2. L.Nandhakumar, G. Dharmamoorthy, S. Rameshkumar and S. Chandrasekaram., “an
overview of pharmaceutical validation; quality assurance view point., International
journal of research in pharmacy and chemistry, 201; 4(1): ISSN 2231-7881, page no-
1003-1007, 1010.
3. Nash RA and Berry IR. Pharmaceutical Process Validation., second edition, Marcel
Dekker inc, 167-188, 200-202, 205.
4. Validation Master Plan, www.labcompliance.com.
5. Carleton FJ and Agalloco JP. Validation of pharmaceutical processes, sterile products.,
second edition., 1 to 16.
6. Pankaj Verma,N.V. Satheesh Madhav, Vinay kr Gupta,”A Review article on
Pharmaceutical Validation and Process Control”, 2012; 1(7): 51-60.
7. Britain H.G pharmaceutical technology, July 2002; 68 to 70.
8. European Commission Enterprise Directorate General Single market, regulatory
environment, industries under vertical legislation Pharmaceuticals and Cosmetics
www.wjpps.com │ Vol 10, Issue 9, 2021. │ ISO 9001:2015 Certified Journal │
1028
Kuldeepsinh et al. World Journal of Pharmacy and Pharmaceutical Sciences
Brussels, July 2001. EU Guide to Good Manufacturing Practice, Qualification and
validation.
9. British Pharmacopoeia 2002, Department of Health, Scottish Home and Health
department, Volume I, 736.
10. Guide to Inspections of Oral Solid Dosage Forms pre/post Approval Issue for
Development and Validation; issue (1/94); January, 2010.
11. Guideline on General Principles of Process Validation. Washington DC: Centre for Drug
Evaluation and Research, US Food and Drug Administration, 1987.
12. Guidance for Industry process validation: General Principles & Practice, U.S. Department
of Health & Human Services Food & Drug Administration, CDER, CBER, CVM, Nov.
2008.
13. S. Lakshmana Prabu,T.N.K. Suriyaprakas,R. Thirumurugan et al,”Process Validation:
AReview”; Pharma Times, 2014; 46(4): 12-15.
14. Dr. Keyur B. Ahir, Khushboo D. Singh,Sushma P. Yadav,et al,”Overview of Validation
andBasic Concepts of Process Validation”; Scholars Academic Journal of Pharmacy
(SAJP), 2014; 3(2): 178-190.
15. D. Narayana murthy,, Dr. K. Chitra;”Review article on process validation as a quality
assurance tool a Theoritical Approach”; INTERNATIONALE PHARMACEUTICA
SCIENCIA, 2013; 3(2): 6-14.
16. Howard T. Fuller Six Sigma for Validation, Journal of Validation Technology, 2000;
6(4): 749-765, 751.
17. The European agency for evaluation of medical products, London Note for Guidance on
Process Validation, 2001.
18. FDA guidelines on General Principles of Process Validation (May 1987).
19. Chapman KG, Amer G, Brower G, GreenC, Hall WE and Harpaz D.Journal of Validation
Technology, 2000; 6: 505-506.
20. Health Products and Food Branch Inspectorate, Guidance Document Validation,
Guidelines for Pharmaceutical Dosage Forms.