guidance documents on process validation for...

Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)

Guidance Documents on Process Validation for Biotechnology-derived Medicinal

Products – A Regulatory Update

Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM, German


The perspectives and opinions presented in this talk are those of the presenter

Disclaimer

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Which documents are available in the EU?

• Draft Guideline on Process Validation for the Manufacture of Biotechnology-Derived Active Substances and Data to be Provided in the Regulatory Submission (EMA/CHMP/BWP/74521/2014)

• Guideline on Process Validation for Finished Products - Information and Data to be Provided in Regulatory Submissions (EMA/CHMP/CVMP/QWP/BWP/70278/2012)

Information on data to be provided in regulatory submissions

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ICH Q7 = EudraLex - Volume 4 GMP Guidelines. Part II - Basic Requirements for Active Substances used as Starting Materials (2000)

• Chemicals & Bio

Chapter 12 Validation • 12.4 Approaches to Process Validation

• 12.5 Process Validation Programm

• 3 approaches to validation : prospective / concurrent / retrospective

• includes CQA/CPP

• Not mentioned: continuous process verification – ongoing process verification

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EudraLex Volume 4 GMP Guidelines Annex 15: Qualification and Validation for Drug Product under Revision, Feb.2014

• Chemicals & Bio

• Includes new concepts (ICH Q8, 9, 10, and CHMP Guideline)

• Lifecycle approach

• Traditional approach and/or a continuous verification approach

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• Process validation should establish whether all quality attributes and process parameters which are considered important for ensuring the validated state and acceptable product 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 QbD development

• Continuous process verification = on-going process verification

GMP Annex 15: Qualification and Validation for Drug Product under Revision, Feb.2014

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GMP - Annex 15: Qualification and Validation 4. PROCESS VALIDATION

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Traditional approach to validation

• A number of batches manufactured under routine conditions to confirm reproducibility.

• The number of batches and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established

• A process validation protocol should define the critical process parameters (CPP), critical quality attributes (CQA) and acceptance criteria. Justification for being critical or non-critical



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Continuous process verification

• For products developed by a QbD approach, where it has been scientifically established that routine process control provides a high degree of assurance of product quality,

• The process verification system should be defined and there should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation

• Number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product to be justified.

• hybrid approach: traditional approach and continuous process verification can be used



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Ongoing Process Verification during Lifecycle

• To monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated.

• The extent and frequency of ongoing process verification should be reviewed periodically and modified if appropriate, considering the level of process understanding and process performance at any point in time in the product lifecycle.


GMP -Annex 15: Qualification and Validation 4. PROCESS VALIDATION

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Concurrent validation

• Only in exceptional circumstances where there is a strong risk – benefit to the patient, it may be acceptable not to complete a validation program before routine production starts and concurrent validation could be used.

• Sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria


FDA Guidance for Industry, Process Validation: General Principles and Practices, January 2011

Process validation activities in three stages

Continued process verification

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Update of the Note for Guidance (NfG) on Process Validation in the light of ICH Q8-10 • Introduces possibility to use

continuous process verification

• Introduces design space verification concept

• Biological products are brought into the scope

• Slight update of traditional approach section

• No new requirements for authorised products


• 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

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• Document provides guidance on the validation of the

manufacturing process, which can be considered as the

second stage in the product lifecycle.

• The first stage (process design) is covered in the note for

guidance on pharmaceutical development (ICH Q8R2) and

the third stage (ongoing process verification) is covered

under GMP (Annex 15).

Guideline on Process Validation for Finished Products - Scope

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• The manufacturing process should be validated before the product is placed on the market. In exceptional circumstances concurrent validation may be accepted (e.g. urgent medical need)

Approaches:

traditional, continuous process verification, hybrid

Guideline on Process Validation for Finished Products - General Considerations

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• an alternative approach to process validation based on a continuous monitoring of manufacturing performance, based on the knowledge from product and process development studies and / or previous manufacturing experience

• It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its Critical Quality Attributes (CQAs) and control strategy requirements.

• It may use extensive in-line, on-line or at-line monitoring and / or controls to evaluate process performance.

Guideline on Process Validation for Finished Products - Continuous Process Verification

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• Extensive in-line, on-line or at-line controls and monitor process performance and product quality on each batch.

• PAT tools such as NIR spectroscopy with or without feedback loop and multivariate statistical process control (MSPC)

• Justification of the continuous process verification strategy, supported with data from at least laboratory or pilot scale batches. (S2.6)

• A description of the continuous process verification strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed

• The stage at which the process is considered to be under control and the validation exercise completed prior to release of the product to the market to be defined

• Continuous process verification can be introduced at any time of the lifecycle of the product

Guideline on Process Validation for Finished Products - Continuous Process Verification

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• A design space will normally be developed at laboratory or pilot scale. During scale up the commercial process is generally conducted and validated in a specific area of the design space, defined as the target interval or Normal Operating Range (NOR).

• During the product lifecycle, moving from one area to another within the design space (i.e. change in the NOR) it will be necessary to confirm the suitability of the design space and verify that all product quality attributes are still being met in the new area of operation within the design space. This is termed ‘design space verification’.

• It is not necessary to verify entire areas of the Design Space or the edge of failure

Guideline on Process Validation for Finished Products Design Space Verification

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• If the parameters investigated during development of the design space have not been shown to be scale independent and the process has been validated using traditional process validation a verification protocol should be provided in the dossier. If continuous process verification has been utilised a design space verification strategy should be included as part of the continuous process verification strategy.

Design Space Verification (2)

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Guideline on Process Validation for the Manufacture of Biotechnology-derived Active Substances and Data to 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 and

included in the Marketing Authorisation Application (MAA)

• Process validation activities do not end at the time of the

marketing authorisation, but continue through the lifecycle of

the product and its process

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Guideline on Process Validation for the Manufacture of Biotechnology-derived Active Substances and Data to be Provided in the Regulatory Submission Process Development

• not considered as part of process validation, process development comprises an essential role in defining the criteria and conditions to be addressed in process validation studies

Process Validation – Evaluation and Verification • Prospective process validation is expected for biotechnology-

derived active substances • Process validation activities would normally include i) evaluation that process steps and the complete process are capable to perform as intended and ii) verification on commercial scale batches that the process does perform as intended

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• Process evaluation studies, performed at small and/or full scale, should provide evidence that the complete manufacturing process and each step/operating unit have been appropriately designed and are controlled to obtain a product of the intended quality

• Process verification studies should confirm that the final manufacturing process performs effectively and is able to produce an active substance or intermediate meeting its predetermined acceptance criteria, on an appropriate number of consecutive batches produced with the commercial process and scale

• The set of controls used in process validation activities (e.g. quality attribute, process indicator, process parameter, controls implicit in the design of the process) are expected to go beyond the routine control system

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Process Evaluation

• demonstrate that the design of the manufacturing process and its

control are appropriate for commercial manufacturing

• Studies should include process evaluation of all steps in the

manufacture. All in-puts and out-puts should be described

• The applicant should base the inputs and outputs studied on their

potential criticality and justify their selection

• For those which are not studied further it may be needed to explain

how it is ascertained that these are kept within the range that has

been shown to be non-critical

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Process Evaluation cont.

• Contribution of data from small scale studies to the overall validation

package is expected and acceptable

• To be demonstrated that the small scale model is an appropriate

representation of the proposed commercial scale

• Successful demonstration of the suitability of the small scale model

could reduce data requirements for process verification (e.g. reduced

number of batches) and/or impact on control strategy

• Where prior knowledge or platform manufacturing experience is

utilised, the contribution of these data to the overall validation

package will depend upon justification that the data is

representative of the proposed commercial process

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Process Verification

• Process verification studies should confirm that the final

manufacturing process (i.e. full scale commercial process) performs

effectively and is able to produce an active substance or intermediate

meeting its predetermined controls and acceptance criteria

• Such studies are generally performed in accordance to the expected

Normal Operating Ranges (NOR)

• Process verification data (including process step results, batch

analyses) should normally be completed and presented in the

regulatory submission on an appropriate number of consecutive

batches produced with the commercial process and scale

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Continous Process Verification

could be used and may facilitate acceptance of fewer batches in the verification studies. Requires understanding of the process and product, and the use of process analytical technologies

Ongoing Process Verification

Subsequent to successful process validation activities for regulatory

submission, companies should monitor product quality and process

performance to ensure that a state of control is maintained throughout

the commercial part of the product lifecycle. These activities have to be

performed in compliance with EU GMP

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Upstream Process Validation

• Evaluation and verification of the cell culture steps to the collection of the last harvest obtained at/or beyond production level are capable to perform as intended

• Potential impact of raw materials (e.g. quality of media, supplements, treatment such as gamma irradiation of animal sera) should be evaluated, in the light of the variability of these materials (e.g. intrinsic to the material, related to change in supplier) and of their influence on the quality of the product

Multiple Harvests • Where multiple harvests from one cell culture run are collected, it

should be demonstrated that the increasing cell age during the culture run does not have an impact on quality

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Downstream Process Evaluation

• The capacity of the proposed purification procedures to

deliver the desired product and to remove product and

process-related impurities to acceptable levels to be

evaluated

• Process conditions and performance

parameters/indicators to be evaluated

• Columns to be evaluated throughout the expected lifetime

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Downstream Process Verification

• Confirm the clearance capability of the entire downstream process, - in accordance to normal acceptable ranges - are able to consistently generate the targeted quality of process intermediates and active substance.

• Reprocessing, as defined in ICH Q7, could be considered in exceptional circumstances and should be appropriately described and validated in the regulatory submission (usually restricted to some refiltration or re-concentration steps upon technical failure of equipment )

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Hold time, storage and transportation

• impact of the hold times and conditions on the product

quality

• conducted as real-time, real-conditions studies, usually on

commercial scale material lab-scale studies if

appropriately justified

• shipping and transportation of intermediates and active

substance A short summary of the study should be

provided

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Differences between EU and FDA guidances

• There are differences reflecting regional regulations

• EMA guidelines are aimed at industry and assessors

and provide guidance on the information to be included in submissions

for MAA

• FDA guidance is mainly aimed at industry and inspectors,

includes considerations for premises and equipment qualifications

(in EU covered in Annex 15 to EU GMP Guide)

• Similar approaches to Continuoued Process Verification

• Continued verification/ ongoing verification (verification during product

lifecycle ) not part of MAA and assessment, but considered part of EU

GMP.

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ICH Q8-11/ EU Guidelines/ FDA Guidance/

ICH Q8 / Q11

Traditional approach or

Enhanced approach with CPP, CQA,

PARs or Design Space

FDA guidance Process design

First stage

EU Guideline

3 validation batches or

Continuous Verification

FDA guidance Process qualification

Second stage

EU GMP

Process Verification during lifecycle

Maintenance of the state of control

FDA Guidance Continued Verification

Third stage

ICH Q10 Tech transfer, Scale-up

ICH Q10 Process performance, state of control

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• Are principles and practices for Process Validation and the information to be included in the regulatory submission are the same across the EU and in the US ?

• Terminology for the concept of « process verification »

« Continuous process verification » : ICH and EU

« Continued process verification » : FDA

« Ongoing process verification » : EU

• Use of common language will facilitate acceptability of the PV data package in different regions of the world

Terminology matters?

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Thank you for your attention!


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