A REVIEW ON PHARMACEUTICAL VALIDATION & PROCESS …

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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


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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,


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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


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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]


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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


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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]


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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]


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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]


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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]


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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]


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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


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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


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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.


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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.


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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]

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http://www.labcompliance.com/


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Technology, 2000; 6: 505-506.

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Guidelines for Pharmaceutical Dosage Forms.

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