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Ifpma - Current development reg strategies for biotherapeutic products - Jane Bai

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Ifpma - Current development reg strategies for biotherapeutic products - Jane Bai

  1. 1. International Federation of Pharmaceutical Manufacturers & Associations Current Development / Regulatory Strategies for Biotherapeutic Productsg p Jane Bai Regulatory CMC Advisor Bayer Healthcare 2013 APEC Harmonization Centre Biotherapeutic Workshop Seoul, Korea 25‐26 September 201325 26 September 2013 1
  2. 2. Agenda • Defining Biotherapeutic Products h ll i h i l• Key Challenges to Biotherapeutic Development  • Manufacturing in living systems C l M f t i P• Complex Manufacturing Processes • Complex Characterization  • Getting it Right • Close Communication with Health Authorities• Close Communication with Health Authorities  • Scientific Advice/Protocol Assistance (EU) 2 © IFPMA 2013
  3. 3. D fi i Bi th tiDefining Biotherapeutics Biologics (US): BLA (Biologics License Application)Biologics (US): BLA (Biologics License Application) Biologics, in contrast to drugs that are chemically synthesized, are derived from  living sources (such as humans, animals, and microorganisms). Most biologics are  complex mixtures that are not easily identified or characterized, and many  biologics are manufactured using biotechnology. Biological and related products  include blood, vaccines, tissue, allergenics and biological therapeutics.  ( Biotechnological Medicinal Products (EU):  Medicinal product developed by means of one of the following biotechnological  processes: • Recombinant DNA (rDNA) technology, • Controlled expression of genes coding for biologically active proteins in  prokaryotes and eukaryotes including transformed mammalian cells, • Hybridoma and monoclonal antibody methods ( l h l d d )• (NTA Volume 2A, Chapter 4: Centralized Procedure) 3 © IFPMA 2013
  4. 4. ICH Q5 Series - for biotherapeuticQ p products Additional WHO and Regional Guidances 4 © IFPMA 2013
  5. 5. Development Challengesp g for Biotherapeutics • Manufacture in living systems (organisms / cell lines)• Manufacture in living systems (organisms / cell lines) no two cell lines are the same (each biological medicinal product uses a unique cell line as starting material) post translational modifications • Complex Manufacturing Systems p g y susceptible to contamination (e.g. viral, bacterial, mycoplasmal,  prion, etc) i i j d hminor process variants can cause major product changes product related immunogenic risk factors include e.g. protein structure, posttranslational modifications, aggregates, impurities, ..structure, posttranslational modifications, aggregates, impurities, .. • Complex Characterization need to establish comparability after process changes 5 © IFPMA 2013
  6. 6. Selection Strategy for Biotechnological host cell options: • Genetically altered microorganisms, such as E.coli or yeasty g , y Postranslational modifications not needed • Genetically altered mammalian cells, such as Chinese Hamster Ovary  (CHO) cells Baby Hamster Kidney cells (BHK)(CHO) cells, Baby Hamster Kidney cells (BHK) Well characterized cell substrates for biotech products • Transgenic animals or transgenic plants, such as Bt corn, tobacco Avoids complex fermentation and media components, can pose purification challenges • Other sources such as Insect Cell Lines 6 © IFPMA 2013
  7. 7. Cell Banking Strategyg gy • Cell banks are a characterized starting source for eachCell banks are a characterized starting source for each  production batch • Master Cell Bank (MCB) and Working Cell Banks (WCBs) are  prepared from the selected cell clone • MCB is supposed to be sufficient for the lifetime of the product  ( d )(new MCB = new product) • Characterization of host cells and cell banks (safety): H ll i i d hi f h ll liHost cells: origin, source and history of the cell lines,  exposure to adventitious agents Cell banks: analysis of the expression construct geneticCell banks: analysis of the expression construct, genetic stability, identity (DNA sequencing), purity (DNA  contaminants, viruses etc.) 7 © IFPMA 2013
  8. 8. Viral Safety Strategy ofy gy Biopharmaceutical Products 2 f i h f i h h b d dIn over 25+ years of rDNA Biotech Manufacturing there has been no reported product  association with transmission of virus agent. S f t d tt ib t d t th th ill f i l f t GMPSafety record attributed to the three pillars of viral safety GMPs: • Careful selection/testing of raw materials and reduction of any animal/human  based materials, where feasible; • Routine in process monitoring of manufacturing processes for infectious agents;• Routine in‐process monitoring of manufacturing processes for infectious agents;  and • Designing and demonstration of manufacturing processes to  remove/inactivate(clear) wide variety theoretical viruses Incorporation of Nanoremove/inactivate(clear) wide variety theoretical viruses. Incorporation of Nano  filtration technology provided additional assurance of viral clearance and safety of  Biotech Products. Cell Bank Qualification Testing is an essential part of viral safety selection and  screening strategy and establishing that Biopharmaceutical manufacturing starting  raw material is free of detectible infectious agents.g 8 © IFPMA 2013
  9. 9. Complex Biological Manufacturingp g g Process 9 © IFPMA 2013
  10. 10. Regulatory Challenges • Demonstration of production of consistent quality,  appropriate validation I t l h ld b bl f it i l t• In‐process controls should be capable of monitoring relevant  quality attributes (product‐ and process‐related impurities as well as relevant critical process parameters)well as relevant critical process parameters) The process is the product! 10 © IFPMA 2013
  11. 11. Characterization of theCharacterization of the Active Substance Early in Development l h• Structural characterization amino acid sequence, amino acid composition, terminal amino acid  sequence, peptide mapping, disulfide bridges, carbohydrate structure • Physico‐chemical characterization Molecular weight/size, isoelectric point, molar absorption coefficient,  electrophoretic pattern chromatographic pattern spectroscopic profileselectrophoretic pattern, chromatographic pattern, spectroscopic profiles • Immunological Properties Binding assay, determine binding affinity to target, avidity and  i i i (i l i i d i i ) d fi i i f bi diimmunoreactivity (incl. cross‐reactivity and toxicity), definition of binding  part • Biological activityg y Assessed by in‐vitro and/or in‐vivo assays, discussion of mechanism of  action 11 © IFPMA 2013
  12. 12. Heterogeneity Strategyg y gy • Need different orthogonal methods to characterize• Need different orthogonal methods to characterize • Establish consistency between preclinical, clinical, and  commercial lotscommercial lots • Need to identify, control, and characterize variants early in  developmentp 12 © IFPMA 2013
  13. 13. Identify and Control Impurities P d t l t d• Product related: • Aggregates, misfolded or truncated forms M difi ti d id t d idi d i• Modifications: deamidated or oxidized species,  disulfide bridge errors, degradants • Understand functionality• Understand functionality • Process related: • Host cell proteins• Host cell proteins • Residual host cell DNA • Fermentation or purification components• Fermentation or purification components • Can potentially validate clearance through process 13 © IFPMA 2013
  14. 14. Immunogenicityg y Influencing factors 14 © IFPMA 2013
  15. 15. Immunogenicity - Relevance No effect Cross‐react with  native protein and  induce adverseinduce adverse  symptoms, e.g. Epo (PRCA) Alter pharmacokinetics Neutralize therapeutic effects, e.g. factor VIII 15 © IFPMA 2013
  16. 16. Systematic process and product design: Linking unit operations to the delivery of quality,Linking unit operations to the delivery of quality, safety and efficacy Safety & Efficacy Identity Purity Strength Quality Identify Impact Potency IsoformsBi t Impurities Identity Purity Strength QualityPotency Aggregates D d t Peptide MapBiopotency Clarity/Color OxidationHost Cell Protein SterilityProtein Content pHContaminants Degradants Endotoxins Clarity/ColorHost Cell Protein DeamidationOsmolality DNA Potential Critical Quality Attributes Process Parameters Identify Process Parameters Unit Operation16 © IFPMA 2013
  17. 17. ICH Q5E: Comparability of Biotech/Biological Products Subject to Changes in TheirProducts Subject to Changes in Their Manufacturing Processes (2003) • During product development, it is expected that multiple  changes in the manufacturing process will occur that could  impact drug product quality safety and efficacyimpact drug product quality, safety, and efficacy. • Comparability exercises are generally performed to bridge  nonclinical and clinical data generated with pre‐change tononclinical and clinical data generated with pre change to  post‐change product in order to facilitate further  development and, ultimately, to support the marketing  authorization. • Establish no clinically meaningful differences in safety, purity  and potency between products. 17 © IFPMA 2013
  18. 18. Regulatory considerations:g y comparability A ti h t i ti ( ti l t d d) f lit• A comparative characterization (partial or extended) of quality  parameters is the basis for the comparability assessment,  additional pre‐clinical or clinical studies may become necessary Always case‐by‐case decision! • Comparability studies are required to bridge: pre‐clinical and clinical data generated with pre‐change andpre‐clinical and clinical data generated with pre‐change and  post‐change product Phase I / Phase II / Phase III material • Extent of comparability studies depends on the stage of  development – do changes early in development and avoid  changes during Phase III • Discussion of the comparability plan with Health Authorities is  advisable 18 © IFPMA 2013
  19. 19. Comparabilityp y … the bridge to safety & efficacy 19 © IFPMA 2013
  20. 20. W ki ith H lth A th iti fWorking with Health Authorities from Regulatory/Compliance Perspective 20 © IFPMA 2013
  21. 21. Frequent Communication and MeetingsFrequent Communication and Meetings with Health Authorities • Review Strategies and obtain agreement on data  requirements and end points • Provides opportunities for communications about  evolving regulatory environment • Avoids surprises when applications are submitted  and potential license and launch delays if additional a d po e a ce se a d au c de ays add o a or different data is required • Make use of Scientific Advise requests for questionsMake use of Scientific Advise requests for questions  not directly addressed by current global Guidance. 21 © IFPMA 2013
  22. 22. Centralised Approval - Decision Making 22 © IFPMA 2013
  23. 23. Scientific Advice / Protocol Assistance (SAWP) • All scientific advice requests are handled through the Scientific  Advice Working Party (SAWP) • Written exchange (i e no meeting) unless SAWP requests an oral• Written exchange (i.e. no meeting) unless SAWP requests an oral  hearing • Advice is signed off by CHMPg y • Contributions to the advice come from CHMP, CAT, COMP and  PDCO, as appropriate to the questions asked • 40‐day (no meeting) or 70‐day (with meeting) procedure… but allow  time for preparation F di t d i t• Fees vary according to scope and circumstances • Statistics show that taking (and following) scientific advice increases  the probability of MA approvalthe probability of MA approval 23 © IFPMA 2013
  24. 24. Scientific Advice – objectives Primary: • To understand the data requirements for obtaining a  k ti th i ti (CAT / CHMP)marketing authorisation (CAT / CHMP) Other possible objectives: T d d h d i f i i i• To understand the data requirements for maintaining  orphan dug status when the MA is granted (COMP) • To obtain formal advice regarding paediatric• To obtain formal advice regarding paediatric development (PDCO) • To augment a data package for out‐licensing purposes• To augment a data package for out‐licensing purposes • ..or even to help facilitate a decision to discontinue  development!development! 24 © IFPMA 2013
  25. 25. Scientific Advice – documentation • Cover letter C l d d i f• Completed advice request form • Letter of Authorisation (if working through a third party) • Background information (following EMA template): Concise summary of key information Proposals for future work (e.g. CMC strategy, nonclinical and clinical protocol  outlines)outlines) Questions Company position statements for each question (sufficiently detailed to stand  alone)alone) Supporting data (i.e. the background detail) • Supporting documents Product profile Investigator brochure References (but not too many!)References (but not too many!) Previous scientific advice 25 © IFPMA 2013
  26. 26. In Summary Bi th ti d t b i d i d f li i• Biotherapeutic products, being derived from living systems and having complex product attributes, are vulnerable to manufacturing changes impacting productg g p g p safety and efficacy. • Changes during development and post marketing th i ti b l t d d i l t d th hauthorisation can be evaluated and implemented through use of comparability exercises demonstrating pre- and post changes having no predictive impact to productpos c a ges a g o p ed c e pac o p oduc safety and efficacy. • Strategies supporting product development, h t i ti d lif l t b tcharacterization, and life-cycle management are best previewed and aligned with Health Authorities to support optimal development and availability to patients.optimal development and availability to patients. 26 © IFPMA 2013
  27. 27. Th k !Thank you! 27 © IFPMA 2013