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Guidance Documents on Process Validationfor Biotechnology-derived MedicinalProducts – A Regulatory UpdateBrigitte Brake, Federal Institute for Drugsand Medical Devices, BfArM, GermanFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
DisclaimerThe perspectives and opinions presented in thistalk are those of the presenterFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)2
Which documents are available in the EU? Draft Guideline on Process Validation for the Manufacture ofBiotechnology-Derived Active Substances and Data to beProvided in the Regulatory Submission(EMA/CHMP/BWP/74521/2014) Guideline on Process Validation for Finished Products Information and Data to be Provided in 2012)Information on data to be provided in regulatorysubmissionsFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)3
ICH Q7 EudraLex - Volume 4 GMP Guidelines.Part II - Basic Requirements for Active Substances usedas Starting Materials (2000) Chemicals & BioChapter 12 Validation 12.4 Approaches to Process Validation12.5 Process Validation Programm 3 approaches to validation :prospective / concurrent / retrospective includes CQA/CPP Not mentioned:continuous process verification – ongoing process verificationFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)4
EudraLex Volume 4 GMP GuidelinesAnnex 15: Qualification and Validation for Drug Productunder Revision, Feb.2014 Chemicals & BioIncludes new concepts (ICH Q8, 9, 10, and CHMP Guideline)Lifecycle approachTraditional approach and/or a continuous verificationapproachFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)5
GMP Annex 15: Qualification and Validation for Drug Productunder Revision, Feb.2014 Process validation should establish whether all qualityattributes and process parameters which are consideredimportant for ensuring the validated state and acceptableproduct quality can be consistently met by the process Prospective Validation recommended;Concurrent Validation only exceptional circumstances;Retrospective Validation not included “Continuous process verification” in context of QbDdevelopmentContinuous process verification on-going processverification Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)6
GMP - Annex 15: Qualification and Validation4. PROCESS VALIDATIONTraditional approach to validation A number of batches manufactured under routine conditions to confirmreproducibility. The number of batches and the number of samples taken should bebased on quality risk management principles, allow the normal range ofvariation and trends to be established A process validation protocol should define the critical processparameters (CPP), critical quality attributes (CQA) and acceptancecriteria. Justification for being critical or non-criticalFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)7
GMP - Annex 15: Qualification and Validation4. PROCESS VALIDATIONContinuous process verification For products developed by a QbD approach, where it has beenscientifically established that routine process control provides ahigh degree of assurance of product quality, The process verification system should be defined and thereshould be a science based control strategy for the requiredattributes for incoming materials, critical quality attributes andcritical process parameters to confirm product realisation Number of batches necessary to demonstrate a high level ofassurance that the process is capable of consistently deliveringquality product to be justified. hybrid approach: traditional approach and continuous processverification can be usedFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)8
GMP - Annex 15: Qualification and Validation4. PROCESS VALIDATIONOngoing Process Verification during Lifecycle To monitor product quality to ensure that a state ofcontrol is maintained throughout the product lifecyclewith the relevant process trends evaluated. The extent and frequency of ongoing process verificationshould be reviewed periodically and modified ifappropriate, considering the level of processunderstanding and process performance at any point intime in the product lifecycle.Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)9
GMP -Annex 15: Qualification and Validation4. PROCESS VALIDATIONConcurrent validation Only in exceptional circumstances where there is a strongrisk – benefit to the patient, it may be acceptable not tocomplete a validation program before routine productionstarts and concurrent validation could be used. Sufficient data to support a conclusion that any givenbatch of product is uniform and meets the definedacceptance criteriaFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)10
FDA Guidance for Industry, Process Validation: GeneralPrinciples and Practices, January 2011Process validation activities in three stagesContinued process verificationFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)11
Update of the Note for Guidance(NfG) on Process Validation in thelight of ICH Q8-10 Introduces possibility to usecontinuous process verification Introduces design spaceverification concept Biological products are broughtinto the scope Slight update of traditionalapproach section No new requirements forauthorised productsFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)12
Guideline on Process Validation for Finished Products- PV is a lifecycle approach Process validation incorporates a lifecycle approachlinking product and process development, validation ofthe commercial manufacturing process and maintenanceof the process in a state of control during routinecommercial production.Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)13
Guideline on Process Validation for Finished Products- Scope Document provides guidance on the validation of themanufacturing process, which can be considered as thesecond stage in the product lifecycle. The first stage (process design) is covered in the note forguidance on pharmaceutical development (ICH Q8R2) andthe third stage (ongoing process verification) is coveredunder GMP (Annex 15).Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)14
Guideline on Process Validation for Finished Products General Considerations The manufacturing process should be validated beforethe product is placed on the market.In exceptional circumstances concurrent validation maybe accepted (e.g. urgent medical need)Approaches:traditional, continuous process verification, hybridFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)15
Guideline on Process Validation for Finished Products- Continuous Process Verification an alternative approach to process validation based on a continuousmonitoring of manufacturing performance, based on the knowledgefrom product and process development studies and / or previousmanufacturing experience It is a science and risk-based real-time approach to verify anddemonstrate that a process that operates within the predefinedspecified parameters consistently produces material which meets allits Critical Quality Attributes (CQAs) and control strategyrequirements. It may use extensive in-line, on-line or at-line monitoring and / orcontrols to evaluate process performance.Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)16
Guideline on Process Validation for Finished Products Continuous Process Verification Extensive in-line, on-line or at-line controls and monitor processperformance and product quality on each batch. PAT tools such as NIR spectroscopy with or without feedback loop andmultivariate statistical process control (MSPC) Justification of the continuous process verification strategy, supportedwith data from at least laboratory or pilot scale batches. (S2.6) A description of the continuous process verification strategy includingthe process parameters and material attributes that will be monitoredas well as the analytical methods that will be employed The stage at which the process is considered to be under control andthe validation exercise completed prior to release of the product to themarket to be defined Continuous process verification can be introduced at any time of thetheDevicesproductFederallifecycleInstitute for Drugsofand Medical The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)17
Guideline on Process Validation for Finished ProductsDesign Space Verification A design space will normally be developed at laboratory orpilot scale.During scale up the commercial process is generally conductedand validated in a specific area of the design space, defined asthe target interval or Normal Operating Range (NOR). During the product lifecycle, moving from one area to anotherwithin the design space (i.e. change in the NOR) it will benecessary to confirm the suitability of the design space andverify that all product quality attributes are still being met inthe new area of operation within the design space. This istermed ‘design space verification’. It is not necessary to verify entire areas of the Design Space orthe edge of failureFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)18
Design Space Verification (2) If the parameters investigated during development of thedesign space have not been shown to be scale independentand the process has been validated using traditional processvalidation a verification protocol should be provided in thedossier.If continuous process verification has been utilised a designspace verification strategy should be included as part of thecontinuous process verification strategy.Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)19
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Guideline on Process Validation for the Manufactureof Biotechnology-derived Active Substances and Datato be Provided in the Regulatory Submission Scope: Recombinant proteins and polypeptides(Principles apply to all type of biological products) Process validation studies should normally be completed andincluded in the Marketing Authorisation Application (MAA) Process validation activities do not end at the time of themarketing authorisation, but continue through the lifecycle ofthe product and its processFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)21
Guideline on Process Validation for the Manufactureof Biotechnology-derived Active Substances and Datato be Provided in the Regulatory SubmissionProcess Development not considered as part of process validation, processdevelopment comprises an essential role in defining the criteriaand conditions to be addressed in process validation studiesProcess Validation – Evaluation and Verification Prospective process validation is expected for biotechnologyderived active substances Process validation activities would normally includei) evaluation that process steps and the complete processare capable to perform as intended andii) verification on commercial scale batches that theprocess does perform as intendedFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)22
Guideline on Process Validation for the Manufactureof Biotechnology-derived Active Substances and Datato be Provided in the Regulatory Submission Process evaluation studies, performed at small and/or full scale,should provide evidence that the complete manufacturing processand each step/operating unit have been appropriately designed andare controlled to obtain a product of the intended quality Process verification studies should confirm that the finalmanufacturing process performs effectively and is able to produce anactive substance or intermediate meeting its predeterminedacceptance criteria, on an appropriate number of consecutive batchesproduced with the commercial process and scale The set of controls used in process validation activities (e.g. qualityattribute, process indicator, process parameter, controls implicit in thedesign of the process) are expected to go beyond the routine controlsystemFederal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)23
Guideline
Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. Guideline on Process Validation for Finished Products - PV is a lifecycle approach 13
