Q11 European Regulatory View on Biotechnological/Biological · PDF fileEuropean Regulatory...

Q11European Regulatory View on Biotechnological/Biological DS

CMC Strategy Forum Europe 2011Barcelona March 21‐23

P.ZORZI

Disclaimer

• I attend this conference as an individual expert and, although being an ex‐member of the ICH Expert Working Group and EU regulator until end of January 2011, the view presented here are based on my own expertise and experience, and do not necessarily reflects the view of EWG, neither EU regulators

• Some of the concepts are currently the subject of active debate

Abbreviations: Bio (Biotechnological/Biological), DS (Drug Substance process/product), DP (drug product process/product)

2PZ/CASSS-March 2011

Q11 ChallengesPrinciples and Scope

• Guidance on S.2.2 to S.2.6. – S.2.6: Process development (same principles as Q8)

But also – S.2.2 Description of Manufacturing /Process Controls – S.2.3 Control of Materials– S.2.4 Controls of Critical Steps and Intermediates – S.2.5 Process Validation and/or Evaluation

• Applicable to « Traditional » and «Enhanced »approach

• Common guidance for NCE and BIO


Q11 ChallengesRegulatory Background

• Q1 Stab (annex Bio Q5C)• Q2 Method validation• Q6A, Q6B Specifications • CTD (specifities for Bio)• Q7 GMP for API

Common ICH guidelines for DS Common ICH guidelines for DS

Common ICH guidelines Common ICH guidelines ««Enhanced approachEnhanced approach»»• Q8 R2 (2009) Pharmaceutical Development• Q9 (2005) Quality Risk Management• Q10 (2010) Pharmaceutical Quality System• Q&A


Q11 ChallengesRegulatory background

NCEBiotech/Bio• Q5A Viral safety

• Q5B Genetic stab

• Q5D Cell substrates (i.e. Starting mat.)

• Q5E Comparability

Specific Biotech ICH guidelines for DS process/productSpecific Biotech ICH guidelines for DS process/product


Key areas

1. Manufacturing process development2. Description of manuf. process /process

controls3. Selection of starting materials /sources

materials4. Control strategy5. Process validation/evaluation6. Lifecycle management


1‐Manufacturing Process Development

• Same principles as those described in Q8 for DP are applicable for DS– CQA definition

• Same Process development tools for identification of CQAs (complex products such as Biotechnological/Biological products) – Risk assessments (Q9) to rank or prioritise quality attributes.

– Prior knowledge (Q10)can be used at the beginning of development and assessments can be iteratively updated with development data (including data from non‐clinical and clinical studies) during the lifecycle



• Reference made to existing ICH Bio guidelines• Impurities are an important class of potential drug substance CQAs because of their potential impact on drug product safety Q6B

• Process‐related or product related • Contaminants (e.g., adventitious viral, bacterial, ormycoplasma contamination)

• An applicant can choose either a traditional approach or an enhanced approach to drug substance development, or a combination of both Q8



Manufacturing process development should include, at a minimum, the following elements:• Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on product quality can be studied and controlled;

• Defining an appropriate manufacturing process;• Defining a control strategy to ensure process performance and drug substance quality.



An enhanced approach to manufacturing process development would additionally include the following elements:• A systematic evaluation, understanding and refining of

the manufacturing process, including;– Identifying, through e.g. prior knowledge, experimentation and

risk assessment, the material attributes and process parameters that can have an effect on drug substance CQAs;

– Determining the functional relationships that link material attributes and process parameters to drug substance CQAs;


1‐Design Space

• Same definition as Q8:– Working within the design space is not considered as a change.

– Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.

• Proven acceptable ranges continue to be acceptable from the regulatory perspective but are not considered a design space


1‐Design SpaceQ&A

• Can a design space be applicable to scale‐up (Yes), to a site change (Yes)

• Can a design space be developed for single and/or multiple unit operations? Yes

• Is it possible to develop a design space for existing products? yes• Is there a regulatory expectation to develop a design space for an

existing product? No• Does a set of proven acceptable ranges alone constitute a design

space? No (However proven acceptable ranges continue to be acceptable from the regulatory perspective but are not considered a design space )


1‐Submission of Manufacturing Process Development Information

in section 3.2.S.2.6 of the CTD• Overall Process Development Summary

– List of drug substance CQAs;– Brief description of the stages in the evolution of the manufacturing process and control strategy;

– Brief description of the material attributes and process parameters that impact drug substance CQAs;

– Brief description of the development of any design spaces


1‐Submission of Manufacturing Process Development Information

in section 3.2.S.2.6 of the CTD• Comprehensive information

– Drug Substance CQAs• list• rationale for designating these properties/characteristics as CQAs• Links with others sections of the CTD (e.g., 3.2.S.3.1, Elucidation of Structure and other Characteristics, 3.2.S.7 Stability, 3.2.P.2.1, Components of the Drug Product).

– Manufacturing Process History– Manufacturing Developmental Studies


2‐Description of Manufacturing Process and Process Controls

• Q11 refers to M4Q S.2.2• Design space description• Details given in CTD/S.2.2 for bio, not repeated in Q11, to be adressed– Batch(es) and scale definition – Cell culture and harvest , – Purification and modification reactions


3‐Selection of Starting Materials and Source Materials

• Detailed section for synthetics drugs• For Biotech, brief statement with appropriate references to ICH existing guidelines– Cell banks are the starting point for manufacture of biotechnological/biologics products: ICH Q5A, Q5B, and Q5D

– Qualification of Source Materials for Bio : ICH Q5A, Q5B and Q5D.


4‐Control Strategy

• Same definition as ICH Q10• Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy.


4‐Control Strategy : Submission of data

• Overall drug substance control strategy – to be addressed in section “justification of the drug substance specification” (3.2.S.4.5)

– Including the relationship of the design space(s) to the overall control strategy

• Individual elements of the control strategy to be provided in the appropriate CTD sections including:– Description of Manufacturing Process and Process Controls (3.2.S.2.2);– Control of Materials (3.2.S.2.3);– Controls of Critical Steps and Intermediates (3.2.S.2.4);– Container Closure System (3.2.S.6);– Control of Drug Substance (3.2.S.4).


5‐Process Validation/Evaluation

• Same definition as ICH Q7• Continuous process verification :

– As an alternative to the traditional process validation, continuous process verification (ICH Q8) can be utilised in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle. (Q&A)



• Additionnal guidance for bio DS– Ability of the process to remove product‐related impurities, process‐related impurities and potential contaminants (ICH Q6B, Q5A)

– Lifetime of chromatography columns : experimental studies at small‐scale models, to be confirmed during commercial‐scale production.

– Limit of in vitro cell age for commercial production should be assessed. (ICH Q5B and Q5D)



• Additionnal guidance for bio DS– When platform manufacturing is used: manufacturing process should be appropriately validated at the time of marketing authorisation application

– Process validation batches should be representative of the commercial process, taking into account the batch definition as detailed in the process description

– Data to be provided at the time of marketing application for Bio DS : both commercial‐scale process validation studies and small‐scale studies.

– Appropriate Sections of the CTD : 3.2.S.2.5 and Appendix 3.2.A.2 viral contaminants (Q5A)


6‐Lifecycle Management

• Continual improvement across the entire product lifecycle (Q10)– Product quality review (Q7)– Knowledge from other products– Knowledge from innovative technologies

• Knowledge management includes (but not limited to)

– Process development activities– Tech transfer to internal sites and contract manufacturers– Process validation over the lifecycle– Changes management activities


6‐Lifecycle Management

• Changes to the manufacturing process:– Should be subject to internal change management processes as part of the overall Quality System

– Biologicals : ICH Q5E– Report to the regulatory authorities : in accordance with regional regulations and guidelines

• Movement within the design space do not require approval by regional regulatory authorities


Conclusion

• Q11 applies to Bio DS the principles already stated in Q7, 8, 9, 10 (do not bring other new concepts)

• Q11 applicable to traditional/enhanced. Same terminology used for both

• Interpretation of concepts common to DS and DP : see Q&A

• Q5 serie and Q6B remains basic grounds for Bio DS manufacturing process and product

• Q11 is not a « variation » guideline (refer to regional regulatory requirement)


Conclusion

• Dossier submission– Traditional approach : fully acceptable– Be clear with the terminology used in your dossier

• Use ICH definitions . Provide your own definition only where necessary

– Be clear with the design space(s) claim – Be clear with the links between concepts/sections,

• Example:– Justification of CQA : in the dev section (from Q11) – Justification of Spec in the section S.4.5 (fromCTD)– Justification of control strategy : in section S.4.5 (from Q11)


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