International Federationof Pharmaceutical Manufacturers & Associations

Current Development / Regulatory Strategies for Biotherapeutic Products g p

Jane BaiRegulatory CMC AdvisorBayer Healthcare

2013 APEC Harmonization Centre Biotherapeutic WorkshopSeoul, Korea25‐26 September 201325 26 September 2013

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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)

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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. (http://www.fda.gov/AboutFDA)

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)

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ICH Q5 Series - for biotherapeutic Q pproducts

Additional WHO and Regional Guidances

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Development Challenges p gfor 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 productuses a unique cell line as starting material)post translational modifications

• Complex Manufacturing Systems p g ysusceptible 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. proteinstructure, posttranslational modifications, aggregates, impurities, ..structure, posttranslational modifications, aggregates, impurities, ..

• Complex Characterizationneed to establish comparability after process changes

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Selection Strategy forBiotechnological 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, tobaccoAvoids complex fermentation and media components, can pose purification challenges

• Other sources such as Insect Cell Lines

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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 agentsCell banks: analysis of the expression construct geneticCell banks: analysis of the expression construct, geneticstability, identity (DNA sequencing), purity (DNA contaminants, viruses etc.)

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Viral Safety Strategy of y gyBiopharmaceutical 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

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Complex Biological Manufacturing p g gProcess

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Regulatory Challenges• Demonstration of production of consistent quality, 

appropriate validationI 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 aswell as relevant critical process parameters)well as relevant critical process parameters)

The process is the product!

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Characterization of theCharacterization of the Active Substance Early in Development

l h• Structural characterizationamino acid sequence, amino acid composition, terminal amino acid sequence, peptide mapping, disulfide bridges, carbohydrate structure

• Physico‐chemical characterizationMolecular weight/size, isoelectric point, molar absorption coefficient, electrophoretic pattern chromatographic pattern spectroscopic profileselectrophoretic pattern, chromatographic pattern, spectroscopic profiles

• Immunological PropertiesBinding 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 yAssessed by in‐vitro and/or in‐vivo assays, discussion of mechanism of action

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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

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Identify and Control ImpuritiesP d t l t d• Product related:• Aggregates, misfolded or truncated formsM 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

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Immunogenicityg yInfluencing factors

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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

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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 ParametersIdentify Process Parameters

Unit Operation16

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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.

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Regulatory considerations: g ycomparability

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 productPhase 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

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Comparabilityp y… the bridge to safety & efficacy

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W ki ith H lth A th iti fWorking with Health Authorities from Regulatory/Compliance Perspective

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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 aor 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.

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Centralised Approval - Decision Making

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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 preparationF 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

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Scientific Advice – objectivesPrimary:

• 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 paediatricdevelopment (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!

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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 informationProposals for future work (e.g. CMC strategy, nonclinical and clinical protocol outlines)outlines)QuestionsCompany position statements for each question (sufficiently detailed to stand alone)alone)Supporting data (i.e. the background detail)

• Supporting documentsProduct profileInvestigator brochureReferences (but not too many!)References (but not too many!)Previous scientific advice

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In SummaryBi 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 product g g p g psafety 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 product pos c a ges a g o p ed c e pac o p oducsafety 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.

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Th k !Thank you!

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