Dr. Steffen Gross Section Mono-/Polyclonal Antibodies Paul-Ehrlich-Institut Germany pei.de

1. Dr. Steffen Gross Section Mono-/Polyclonal Antibodies Paul-Ehrlich-Institut Germany http://www.pei.de ‘New challenges for regulatory agencies when evaluating QbD approaches within licensing documentation’

2. Disclaimer The view expressed in the following is the ones of the presenter and does not necessary express the view of either the CHMP, BWP, EDQM or the Paul-Ehrlich-Institut

3. Outline • Flexibility in the manufacturing process, concerns of the industry • Process changes, impact on product quality (case studies) • Quality by design and GMP • EMA/PAT (Process Analytical Technology) Team • Non-clinical program for charcterisation

4. Quality Risk Management The Regulatory Quality System (Q9) Quality Risk Management Quality by Design Quality (Pharmaceutical Development) by Design Quality (Q8) Systems Quality Existing Existing GMP GMP ’ ’ s s Systems (Q10) Quality by design

5. Variation Regulation (EG) Nr. 1234/2008 Annex II Classification of Variations 2. Major variations of type II shall comprise the following: (a) Variations related to the addition of a new therapeutic indication or to the modification of an existing one (b) Variations related to substantial modifications of the summary of product characteristics due to new clinical or pre-clinical findings; (c) Variations related to changes outside the range of approved specifications, limits or acceptance criteria; (d) Variations related to modifications in the manufacturing process of the active substance for a biological medicinal product; (e) Variations related to the introduction of a new design space or the extension of an approved one, where the design space has been developed in accordance with the relevant European and international scientific guidelines. (g-k) veterinary medical product or vaccine human influenza

6. Classification Changes not requiring any prior approval Changes requiringprior approval Design Space Type IA Minor var. minimal or no impact on Q/S/E Type IB Minor var. Type II Major var. Significant impact on Q/S/E Extension as listed in Annex I to Reg. (strength, Pharm. form..) Do and tell Variations Evaluation Procedure adapted to the level of risk

7. Variation? Design space: • proposed by the applicant • subject to regulatory assessment and approval. • it is the multidimensional combination and interaction of input variables and process parameters. Working within a design space • not considered as a change • movement out of the design space = change, which generates a Type II Variation

8. Main concerns from Industry • No “improvements” for biologicals/immunologicals • Flexibility with regard to implementation of ICH Q8, Q9, Q10 • Advise to inform RMS/EMEA of upcoming post-authorisation submissions for the following 6-12 months • Typ IA – rejection by NCA – how to mitigate • Typ IB by default – re-classification to Type II • Grouping issues • Worksharing issues

9. “The process is the product. “ • fluctuations in the manufacturing • process • (e.g., pH, temperature, culture media): Batch inconsistency(glycosylation spectra, aggregates) - changes in the manufacturing process (e.g., expression system): New product (cell bank) • „One process – one product“ paradigm

10. Production of monoclonal antibodiesPlatform manufacturing As for any medicinal product, the manufacturing process of a product that has been developed using a platform manufacturing approach should be appropriately validated at the time of marketing authorisation application. Validation studies should include data derived from the final manufacturing process and site(s) used to produce the product to be commercialised. Nevertheless, when appropriately justified and documented, data derived from other relevant experience may be used to support or reduce the data derived from the final commercial process to be submitted.

11. Subtle changes to the structure can result in profound effects on the activity • complexity in specified biological molecules. • The structure of specified biologicals is related to the function (biological activity) • e.g. genetic Instability of Cell Banks • Issues within Fermentation and Purification • resulting in changes in …… • Post Translational Modifications • Product Degradation or Modification • resulting in differences in …… • Purity • Biological activities • (Immunogenicity)

12. Change in manufacturing process active substanceExampel 1 • New process to increase yield and consistency; • Operational process flow and process controls identical Change: cell culture: working volumes, culture duration, culture media and feed purification: increase column loading, resins but same ligand , number of cycles Documentation: Testing of the EPC confirmed genetic stability of the cell line as well as the viral safety serum-free culture medium. No TSE-risk components Process validation: clearance of process related impurities, Consistency, Column Life time Validation, viral clearance Demonstration of comparability according to Q5E

13. Comprehensive set of analytical methods increasing sensitivity • Physicochemical characterisation, e.g. • Mass spectrometry techniques (e.g., MALDI-TOF) • Nuclear magnetic resonance • Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) • Primary structure • peptide map • Secondary structure detection, e.g. • Circular dichroism in near- and far-UV spectra • Product related variants and impurities • SEC, CE-SDS, CZE, CEX, etc. • Antigen-antibody interaction, e.g. • Surface plasmon resonance • FACS • Combination of methodologies, e.g. • liquid chromatography combined with mass spectrometry

14. Physico-chemical charactersation

15. Impact on activity by posttranslational modifications

16. Complex mode of actions • Activation of effector mechanisms, Immunmodulation • - ADCC • - CDC • - activation of T-cells • Targeting • Inhibition • - blocking of ligand binding • - inhibition of dimerisation, internalisation, shedding • Induction of apoptosis

17. Global manufacturing process harmonization, adaption of the manufacturing process

18. Process harmonisation – Example 2afucosylated structures and ADCC

19. Conclusion/Action • The applicant commits to • continue to better understand the observed phenomenon regarding ADCC clustering by the investigation of afucosylation and relative ADCC activity and the impact of depth filtration on glycopattern and provide more information as soon as it is available • use depth filtration in the media preparation process at both sites in order to improve site to site-consistency of the glycopattern 2. The following information should be submitted as FUM • a) The afucosylation and ADCC data from the next ten batches produced with depth filtration should be provided. • b) The applicant is asked to screen their pharmacovigilance data and discuss whether there might be a correlation if the number of registered adverse events might be correlated to the source of the used batch and therefore possibly linked to a different ADCC.

20. Achievement Process harmonizationExampel 3 • several submissions in order to harmonize the manufacturing process across different sites • data in the dossier seem to prove the harmonisation process • release data did not show differences • extented characteristion revealed (minor) differences between sites • detection of AE • root cause investigation

21. Guideline on similar biological medicinal products (CHMP/437/04) • Scope: Any biological medicinal product • Biotechnology derived protein • Immunogicals (e.g. vaccines and allergens): • Blood products or recombinant alternatives: • Others (e.g. gene, cell therapy) • "Generic approach": not appropriate to biologics due to complexity of molecular structure and/or production • Biosimilarity to be established at all levels: Q / S / E • Reference medicinal product: must be authorised in the Community on the basis of a complete dossier

22. Development of a biosimilar following a QbDapproach. targetdefinition characterisation Refinement Development of a biosimilar Product QbD process development comparability exercise

23. Quality guideline (CHMP/BWP/49348/2005) Comparability exercise versus reference product Comparison against official data is not sufficient Quality attributes: -not expected to be identical. -Limits: not wider than the range of variability of the reference product -Differences: to be justified in relation to safety and efficacy.

24. Biosimilar Product Development Intial originator quality range Comparability exercise for claiming biosimilarity Complete quality range for justification of limits and claiming biosimilarity New originator quality range ADCC Exampel 4 basic variants

25. „Design Space“ Concept for biosimilars •ICH Q8, Q9 and Q10 are applicable for biosimilars manufacturers for their own developments in the same way as for the originators. •A „design space“depends on a particular manufacturing process

26. “The process is the product. “ characterisation of the manufacturing process characterisation of the drug substance/drug product

27. Quality by DesignQbD • A harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science • New ICH guidelines (High level guidelines, more visionary, less prescriptive, flexible regulatory approaches) • Pharmaceutical Development (Q8) • Quality Risk Management (Q9) • Pharmaceutical Quality Systems (Q10)

28. Quality Risk Management The Regulatory Quality System (Q9) Quality Risk Management Quality by Design Quality (Pharmaceutical Development) by Design Quality (Q8) Systems Quality Existing Existing GMP GMP ’ ’ s s Systems (Q10) Interaction assessors-inspectors Requirement for close interaction assessors-inspectors Assessment: stronger focus on IPC

29. Reflection Paper

30. Involvment of experts (assessors) today • Covers Module 3 of CTD (common technical document) • Eudralex Volume 2 • In connection with Good Manufacturing Practice guidelines • Eudralex Volume 4, Part I and II plus Annexes (Annex 1)

31. Areas of special interest for experts Master Cell Bank and Working Cell Bank • Storage Conditions and Maintenance • Verify that the written procedures reflect accurately what is submitted in the application • Determine that batch records follow written procedures • Determine the identity and traceability of the MCB/WCB • Check the conditions of storage at each location • Check the accessability to MCB and WCB • Document any samples of the MCB/WCB that failed to meet all specifications

32. Cell culture and fermentation • Inoculation and Aseptic Transfer • Handling of cells, equipment in the inoculation area • Monitoring of Growth Parameters and Control • Review cell growth records (e.g. IPC) • Contamination Control • Review written procedures to determine what investigations and corrective actions

33. Extraction, Isolation and Purification • Adequate descriptions and specifications for all equipment, columns, reagents, buffers and expected yields. • In-process controls • Process validation • Column life time and labelling • Re-processing steps • Holding times • Sampling, delivery of samples to QC • Cleaning procedures to avoid cross contamination

34. Laboratory controls (1) • Training • Laboratory personnel should be adequately trained for the jobs they are performing • Training records; e-learn systems • Equipment Maintenance/Calibration/Monitoring • documentation and schedules for maintenance, calibration, and monitoring of laboratory equipment. • Method Validation • Firms should have raw data to support validation parameters in submitted applications.

35. Laboratory controls (2) • Standard/Reference Material • Reference standards should be well characterized and documented, properly stored, secured, and utilized during testing • Storage of reserve/retain samples • Qualification of standards • Critical reagents • Laboratory cultures and reagents, such as enzymes, antibodies, test reagents, etc. • Laboratory SOPs • Procedures should be written, applicable and followed and present.

36. Advantage ofassessors • Experts know different facilities of the same MAH • Ususally competent Land authorities inspect the same facilities • Experts are familiar with the dossier • cell banks • manufacturing process • including validation • in-process controls • control of drug substance/drug product • analytical methods • Reference material • Stability/shelf life

37. Quality Risk The Regulatory (Q9) Quality System Management Quality Risk Management Quality by Design Quality (Pharmaceutical Development) Quality (Q8) Systems Existing Quality GMP s ’ ’ Systems (Q10) Adventageforassessors • Experiences taken into consideration for assessments • Insight into the manufacturing processes • New developments • On side discussion with the company

38. Process improvements under the “QbD” paradigm: • Process transfers under an expanded change protocol in the US • EU perspective on Expanded change protocols

39. EMA PAT Team • has started its activities in January 2004 • Composition • quality assessors for chemical products (appointed by QWP) • GMP inspectors (appointed by the GMDP IWG) • an observer appointed by BWP • Activities: • guidance documents currently published on the EMA website • co-organised with industry training and workshops on QbD, • Discussion/advice to several pharmaceutical companies on QbD/PAT elements and strategies • December 2006: mandate • quality assessors for biological products (appointed by BWP) were added to the team.

40. Problem statement • No formal system in place for involvement of the PAT Team with assessment of applications and SA procedures • team involved if there is a request from the applicant or upon information received from one of the EMA staff team members. • Discussion with companies: informal • Unclear role of the team in both assessments of applications and SA procedures. • Some overlap of activities with ICH Quality Implementation Working Group (IWG) e.g.Q/As

41. Discussion • Until this specific competence is more wide spread among regulators, any pre-submission advice on QbD coming from EMA is handled through the PAT Team. • Advice on QbD/PAT: possibility to obtain a more formal outcome. • should be handled through the existing Scientific Advice procedure, • but a draft report by the team and subsequently adopted by BWP, GMDP IWG and/or QWP as relevant and CHMP/CVMP • Broader scientific advice that includes QbD aspects: • normal scientific advice procedure should be used • but the procedure should be modified so that: • the preparation of the initial recommendation on QbD matters is done by the team, and • successively adopted by the relevant working party/group together with the other parts of the scientific advice request.

42. Discussion • Annual joint meetings with BWP, GMDP IWG and QWP should be organised. • Mandate should be reconsidered periodically (e.g. every 5 years), in order to evaluate if the general knowledge on QbD reached by assessors and inspectors still justifies the role of the team in the provision of scientific advice for QbD related matters.

43. Proposal from the secretariatMandate of the group • Organise/participate in training of assessors and inspectors as well as pharmaceutical industry on QbD • Routinely participate to the assessment report peer review of centralised applications including QbD/PAT elements • Discuss, upon request from companies, QbD/PAT overall strategies during early pharmaceutical development phases of products • Provide recommendation to the relevant working parties/groups/committees in order to facilitate the provision of formal scientific advice to applicants seeking advice in the context of QbD/PAT • Provide, upon request from National Competent Authorities and/or applicants, support for the assessment of applications in decentralised, mutual recognition and national procedures on matters related to Quality by Design and PAT • Provide, upon request from Supervisory Authorities and/or companies, advice on inspections/GMP matters involving QbD/PAT elements, including the possibility of participation of PAT members to GMP inspections • Develop guidance to facilitate the implementation of the new approaches to quality through an integrated application of ICHQ8, Q9 and Q10 within the EU regulatory system, also through input to the work of the ICH Quality Implementation Working Group

44. Proposal from the secretariatComposition • core group with 23 members appointed by CHMP on proposal from the QWP, BWP, GMDP IWG and EMA as applicable and additional experts, individuated by QWP, BWP or GMDP IWG on an ad hoc basis to participate to specific meetings for specific products under discussion • Composition of the core group: • 5 experts from QWP • 5 experts from BWP • 4 GMP inspectors • Chairs of the BWP, QWP and GMDP IWG • 1 EDQM staff appointed by EDQM • 4 EMA staff + 1 EMA staff responsible for the scientific secretariat. • Expertise in the core group to cover, in addition to general expertise in the field of QbD, the main specialist areas for assessment of applications with QbD/PAT elements and related inspections, including for example, but not limited to: • Chemiometrics • Mathematical models • Statistics • Near Infra Red spectroscopy • Sensors used in PAT • Application of PAT to biologicals

45. Biologics are threesome Quality Non-Clinical • impurities • batch inconsistency • contaminants • microheterogeneity • fragments • tissue cross-reactivity? • toxicity? • immunotoxicity? B R I D G I N G Clinical • additional safety measures required? • immunogenicity

46. Conclusion Quality Current methodology sensitive to detect differences in primary structure, identity and amount of related variants including aggregates, glycosylation profile etc. Major question is not the ability to detect differences but the determination of their clinical relevance to be answered by combining physicochemical results with functional assays and the qualification in preclinical and clinical studies

47. Understanding of signaling pathways Source: MA W.W., Adjei A.A.; CA Cancer J Clin. 2009 Mar-Apr;59(2):111-37.

48. Dossier requirements CTD Module Originator QbD Dossier comparability data Quality Quality Non clinical Non clinical cross reference clinical clinical cross reference (extrapolation?)

49. The End Comparable?