Pat Changing the Validation Paradigm

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Process Analytical Technology - Changing

the Validation Paradigm

Randall Schadt, Ph.D.Pfizer Global Manufacturing, Pfizer Inc.

Introduction

Implementation of Process Analytical Technology (PAT) forpharmaceutical manufacturing has continued to advanceand enable operations that monitor, control, and analyzecritical quality attributes of processes and products whilemanufacturing is in progress, i.e. continuous qualityverification. Pharmaceutical industry and regulatory

agencies such as the FDA have emphasized the benefits ofusing PAT in support of a risk-based approach to cGMPsthat recognizes the extent of scientific knowledgesupporting process validation and process control [1].Implementation of PAT challenges the current validationparadigm to change towards supporting quality by designso that a balance is maintained between compliance andinnovation. Therefore, it is necessary to define PATvalidation that is appropriate, commensurate with intendeduse of data, and practical for a risk-based approach tocGMPs. In this article, a validation approach is describedfor PAT systems and methods intended for use withexisting processes and products.

Practical Validation Approach

A practical validation approach for PAT applications beginswith a required Validation Project Plan stating the intendeduse of PAT data classified as one of three levels:Development, Information Only, or Regulatory-FiledRelease. Also required is a cGMP risk assessment thatstates the potential impact (direct, indirect, none) onproduct quality for the intended use of the PAT systemand/or method. Intended use defined as Developmentinvolves PAT systems and methods under experimental

development or associated with demonstration of PATfeasibility for a specific use. Advancing beyonddevelopment into routine use, it must be emphasized thatthe majority of PAT implementation should be first classifiedas Information Only rather than classified forRegulatory-Filed Release. Specifically, Information Onlyuse involves PAT systems and methods implemented togain process knowledge by measurement of process orproduct quality attributes. There is no intent to use the PATinformation for product release when implemented as anInformation Only application. Only after knowledge has

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sufficiently matured with substantial experience in anInformation Only mode of operation is it appropriate toconsider the use of PAT for product release or in-processrelease with relevant specifications and acceptance criteria.Advancing beyond Information Only use, PATimplementation classified as Regulatory-Filed Releaserequires prior approval of the PAT application (system,method, specifications) being used. This may be

accomplished as outlined by the FDA using the followingsteps [1].

First, a comparability protocol [2] can be submitted tothe FDA outlining PAT research, validation, andimplementation strategies. Following FDA approval ofthis comparability protocol, one or a combination ofthe following regulatory pathways can be adopted forimplementation.PAT can be implemented under the facility's qualitysystem; cGMP inspections by the FDA follow.PAT can be implemented following cGMP inspectionwhereby the FDA's PAT Team conducts a

pre-operational review of the PAT-based facility orapplication.A supplement (CBE, CBE-30 or PAS) can besubmitted to the FDA prior to implementation, and, ifnecessary, the FDA's PAT Team can perform aninspection before implementation.

When PAT is used either to support material, productrelease or for real-time, process control rather thanInformation Only, use of PAT methods should not initiallyresult in deletion of a test or relaxation of acceptancecriteria that are described in the approved productapplication [2]. Specifically, use of PAT is considered anexample of alternative analytical procedures for final

product release [1]. Subsequently, after sufficientexperience has been gained with use of PAT, deletion ofend-product quality tests may then be considered with PATmethods in place for continuous quality verification.

Validation Requirements Based on Intended Use of

PAT Data

All levels of PAT implementation require a ValidationProject Plan with a GMP Risk Assessment for intended useof the specific PAT application and its associated data.Each PAT project (system and its associated methods)should be risk-assessed to determine the potential impact(direct, indirect, none) on product quality. The review is alsorequired to assure compliance with requirements applicableto the defined use of the PAT system and its associatedmethod(s). Accordingly, associated manufacturing andquality documentation may need to be revised to reflect theprocedural and practice changes that need to be adopted toimplement the PAT system and its associated methods. Forexample, use of PAT will result in the generation of anextensive amount of data regarding the manufacturing


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process. Because substantially more product and samplesare being tested with PAT methods than with traditionalmethods, i.e. continuous analysis vs. the traditionalevaluation of a small sample set, results are more likely tobe generated that make it appear that out-of-specificationmaterial or product is being made, when in fact one isseeing normal variability within the process. Specificationsand procedures must be in place that account for such

results, so that repetitive out-of-specification investigationsare not required.

Furthermore, use of ASTM standards or otherinternationally recognized standard practices [1] intendedfor PAT applications, including those contained inpharmacopoeias, may be applied. However, to do so, theiruse must be justified and demonstrated to be directlyapplicable to the intended use of the PAT system and itsassociated methods as defined in the Validation ProjectPlan. With respect to PAT system qualification, the GAMPV-Model for validation can be followed [3]. However, theGAMP V-Model must be interpreted so that PAT system

qualification is appropriate and based on intended use. Theneed for specific system qualification documents should bejustified in the Validation Project Plan. Consideration shouldbe given to the fact that full performance qualification of aPAT system is not necessarily possible prior to conductingPAT method validation and establishing associated methodspecifications, e.g. using on-line PAT systems for processcontrol.

Traditionally, analytical methods must be validatedaccording to pre-defined acceptance criteria specific to theintended use of the method with a qualified system.Analytical test method specifications, for release or not,must be consistent with the validated method. For PAT

method validation, sufficient data must be acquired with aqualified system in routine operation including the processor product interface. Certainly, PAT method specifications,e.g. alert levels, action levels, release limits, should beestablished upon sufficient data acquired using the PATsystem and method in operation. While three lots aretraditionally used for process validation, this may bestatistically insufficient to establish acceptance criteria forthe process or product quality attribute that would bemonitored or controlled by the PAT method in use.Therefore, a statistically relevant and representativesampling plan and rationale suitable for PAT methodvalidation should be implemented, and this should account

for the process or product variability that is intended to betested, monitored, or controlled.

Prior to use of PAT systems and methods for InformationOnly or Regulatory-Filed Release, change control practicesmust be implemented to maintain compliance. Periodicreview of PAT systems and methods in use should identifytrends in results that require preventive or correctiveactions, as well as analyzing the cumulative effect ofchanges relative to original specifications. Periodic reviewshould assess the validity of the PAT method consistent


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with current use of the PAT system, recommend additionalsystem qualification testing or method validation ifnecessary, and determine whether PAT systems andmethods should be retired, replaced, or modified.

In addition to requirements discussed above, based on theintended use of PAT data, i.e. Development, InformationOnly, or Regulatory-Filed Release, the following

requirements for PAT validation should also apply.

Development

Process or Product Quality Attributes acceptancecriteria not required as focus is on feasibility of PATsystem or method prior to its potential use withInformation Only or Regulatory-Filed ReleaseimplementationSystem Qualification User Requirement Specification(URS), and either Factory Acceptance Test (FAT) /Site Acceptance Test (SAT) or Vendor InstallationQualification (IQ) / Operational Qualification (OQ)tests; Vendor Audit recommended to identify vendor'scompliance capabilitiesMethod Validation - not possible due to exploratoryphase of implementation

Information Only

Process or Product Quality Attributes acceptancecriteria under development; attributes monitored andassessed in support of gaining process knowledge or

to identify opportunities to improve process or productqualitySystem Qualification URS, Functional DesignSpecification (FDS), and either FAT/SAT or VendorIQ/OQ tests; applicable pharmacopoeia tests ifscientifically justified; approved IQ/OQ tests only fordata functions that are used (data acquisition, dataprocessing, data management); approvedPerformance Qualification (PQ) tests executed on-lineor at-line (dependent on intended use) with samplematrix and including system to sample or processinterface; Vendor Audit with vendor approvedaccordingly; Traceability Matrix that identifies theconnectivity between URS, FDS, and executed

qualification tests; 21CFRPart 11 assessment withany gaps identified and addressed accordinglyMethod Validation follows scientific strategy based onthe technology and application; based on statisticallyrelevant sampling or measurement plan includingdesign of experiments and multivariate chemometricswhen appropriate; uses qualitative acceptance criteriabased on data trending, e.g. statistical process controlconcepts applied to develop acceptable processsignature with associated quality attributes


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Regulatory-Filed Release

Process or Product Quality Attributes acceptancecriteria established and defined for regulatoryapproval; attributes monitored or controlled with

acceptance criteria to support in-process release ofmaterial or to support product releaseSystem Qualification includes Information Onlyrequirements above; approved IQ, OQ, and PQ maybe more comprehensive in content of verificationbased on intended use of system; use and referenceto integrated system testing by audited vendor maysupport commensurate reduction in approved IQ, OQ,and PQ testingMethod Validation includes Information Onlyrequirements above, however it differs fromInformation Only requirements in that a combinationof qualitative and quantitative acceptance criteria maybe used to support release of material or product;demonstration of equivalency to previousregulatory-filed methods is required only ifscientifically justified and appropriate, i.e. some PATmethods cannot be directly correlated to traditional,lab-based methods.

Conclusions

PAT implementation is facilitated by adopting a practicalvalidation approach as described herein for PAT systemsand methods based on intended use of the PAT data. The

pharmaceutical industry should critically review its validationpractices to enable effective use of PAT. While traditionalvalidation experiences may have served industry's needsprior to the introduction of PAT, validation practices mustnow be interpreted to conform to a science-based approachthat supports quality by design.

References

1. U.S. FDA, Draft Guidance for Industry, PAT AFramework for Innovative Pharmaceutical Manufacturingand Quality Assurance, August 2003.

2. U.S. FDA, Draft Guidance for Industry, ComparabilityProtocols Chemistry, Manufacturing, and ControlsInformation, February 2003.

3. ISPE (GAMP Forum), GAMP Guide for Validation ofAutomated Systems, GAMP4, 2001.

Dr. Schadt is currently the Manager/Team Leader of PfizerInc., Pfizer Global Manufacturing, PAT Validation andDocumentation. His responsibilities include PAT validation


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strategies and associated compliance documentation thatsupports PAT implementation at Pfizer sites worldwide. Histen years of pharmaceutical industry experience in qualityoperations and manufacturing include definition of policies,procedures, analytical methods, standards, and practicalguidance for PAT validation and compliance.

Copyright 2003-2004 rests with the publishers.All rights reserved Copyright Russell Publishing L.L.C.ISSN 1099-8012Website by Banta PubNet

Pat Changing the Validation Paradigm

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