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E Jatto & AO Okhamafe Trop J Pharm Res, December 2002; 1 (2)
115
Tropical Journal of Pharmaceutical Research, December 2002; 1 (2): 115-122
 
 © Pharmacotherapy Group,Faculty of Pharmacy, University of Benin,Benin City, Nigeria.All rights reserved
.
Available online at http://www.tjpr.freehosting.net
 
Review Article
 
An Overview of Pharmaceutical Validation andProcess Controls in Drug Development
Elsie Jatto
1
and Augustine O. Okhamafe
2
Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmacy, University of Benin, PMB 1154,Benin City, 300001, Nigeria
 
Abstract
It has always been known that facilities and processes involved in pharmaceutical production impact significantly on the quality of the products. The processes include raw material and equipment inspections as well as in-process controls. Process controls are mandatory in good manufacturing practice (GMP). The purpose is to monitor the on-line and off-line performance of the manufacturing process, and hence, validate it. Thus validation is an integral part of quality assurance.This overview examines the need for pharmaceutical validation, the various approaches and steps involved, and other pertinent considerations.
 
Keywords: 
Drug production, pharmaceutical validation, pharmaceutical process control.
1
Present address: 
Pharmacy Department, National Hospital, Abuja, Nigeria
 2
To whom correspondence should be addressed:
E-mail: 
okhamafe@uniben.edu
 
E Jatto & AO Okhamafe Trop J Pharm Res, December 2002; 1 (2)
116
Introduction
The development of a drug product is alengthy process involving drug discovery,laboratory testing, animal studies, clinicaltrials and regulatory registration. To furtherenhance the effectiveness and safety of thedrug product after approval, many regulatoryagencies such as the United States Foodand Drug Administration (FDA) also requirethat the drug product be tested for itsidentity, strength, quality, purity and stabilitybefore it can be released for use. For thisreason, pharmaceutical validation andprocess controls are important in spite of theproblems that may be encountered
1
.Process controls include raw materialsinspection, in-process controls and targetsfor final product. The purpose is to monitorthe on-line and off-line performance of themanufacturing process and then validate it.Even after the manufacturing process isvalidated, current good manufacturingpractice also requires that a well-writtenprocedure for process controls is establishedto monitor its performance
2
.This paper provides an overview ofpharmaceutical validation and processcontrols in drug development. The validationconcept can be applied to new drugs, newdosage forms and generic drugdevelopment.
Essentials of Pharmaceutical Validation
Validation is an integral part of qualityassurance; it involves the systematic studyof systems, facilities and processes aimed atdetermining whether they perform theirintended functions adequately andconsistently as specified. A validatedprocess is one which has beendemonstrated to provide a high degree ofassurance that uniform batches will beproduced that meet the requiredspecifications and has therefore beenformally approved. Validation in itself doesnot improve processes but confirms that theprocesses have been properly developedand are under control
3
. Adequate validationis beneficial to the manufacturer in manyways
3
:
•
It deepens the understanding ofprocesses; decreases the risk ofpreventing problems and thus assuresthe smooth running of the process.
•
It decreases the risk of defect costs.
•
It decreases the risk of regulatory non-compliance.
•
A fully validated process may requireless in-process controls and end-product testing.Validation should thus be considered in thefollowing situations:
•
Totally new process;
•
New equipment;
•
Process and equipment which havebeen altered to suit changing priorities;and
•
Process where the end-product test ispoor and an unreliable indicator ofproduct quality.When any new manufacturing formula ormethod of preparation is adopted, stepsshould be taken to demonstrate its suitabilityfor routine processing. The defined processshould be shown to yield a productconsistent with the required quality. In thisphase, the extent to which deviations fromchosen parameters can influence productquality should also be evaluated. Whencertain processes or products have beenvalidated during the development stage, it isnot always necessary to revalidate the wholeprocess or product if similar equipment isused or similar products have beenproduced, provided that the final productconforms to the in-process controls and finalproduct specification. There should be aclear distinction between in-process controland validation. In production, tests areperformed each time on a batch to batchbasis using specifications and methodsdevised during the development phase. Theobjective is to monitor the processcontinuously
4.
 
 
E Jatto & AO Okhamafe Trop J Pharm Res, December 2002; 1 (2)
117
Major Phases in Validation
The activities relating to validation studiesmay be classified into three:
Phase 1
: 
This is the Pre-validationQualification Phase which covers allactivities relating to product research anddevelopment, formulation pilot batch studies,scale-up studies, transfer of technology tocommercial scale batches, establishingstability conditions and storage, and handlingof in-process and finished dosage forms,equipment qualification, installationqualification, master production document,operational qualification and processcapacity.
Phase 2 
: 
This is the Process ValidationPhase. It is designed to verify that allestablished limits of the critical processparameter are valid and that satisfactoryproducts can be produced even under theworst conditions.
Phase 3 
: 
Known as the ValidationMaintenance Phase, it requires frequentreview of all process related documents,including validation of audit reports, toassure that there have been no changes,deviations, failures and modifications to theproduction process and that all standardoperating procedures (SOPs), includingchange control procedures, have beenfollowed. At this stage, the validation teamcomprising of individuals representing allmajor departments also assures that therehave been no changes/deviations thatshould have resulted in requalification andrevalidation
5
. A careful design and validationof systems and process controls canestablish a high degree of confidence that alllots or batches produced will meet theirintended specifications. It is assumed thatthroughout manufacturing and control,operations are conducted in accordance withthe principle of good manufacturing practice(GMP) both in general and in specificreference to sterile product manufacture.The validation steps recommended in GMPguidelines can be summarized as follows
5
:
•
As a pre-requisite, all studies shouldbe conducted in accordance with adetailed, pre-established
protocol
orseries of protocols, which in turn issubject to formal – change controlprocedures;
•
Both the personnel conducting thestudies and those running the processbeing studied should be appropriately
trained
and
qualified
and be suitableand competent to perform the taskassigned to them;
•
All data generated during the course ofstudies should be formally
reviewed
 and
certified
as evaluated againstpre-determined criteria;
•
Suitable
testing facilities,equipment, instruments
and
methodology
should be available;
•
Suitable clean room facilities shouldbe available in both the ‘local’ andbackground environment. Thereshould be assurance that the cleanroom environment as specified issecured through initial commissioning(qualification) and subsequentlythrough the implementation of aprogramme of re-testing – in-processequipment should be properly
installed, qualified
and
maintained
;
•
When appropriate attention has beenpaid to the above, the process, ifaseptic, may be validated by means of“
process simulation”
studies;
•
The process should be revalidated atintervals; and
•
Comprehensive
documentation
 should be available to define supportand record the overall validationprocess.Protocols should specify the following indetail
6
:
•
The objective and scope of study.There should already be a definition ofpurpose;
•
A clear and precise definition ofprocess equipment system or sub-system, which is to be the subject of
of 00

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