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
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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)
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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.
(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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4. ICH Q5 Series - for biotherapeuticQ p
products
Additional WHO and Regional Guidances
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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
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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
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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.)
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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
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9. Complex Biological Manufacturingp g g
Process
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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!
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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
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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
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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
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14. Immunogenicityg y
Influencing factors
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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
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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
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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.
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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
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19. Comparabilityp y
… the bridge to safety & efficacy
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20. W ki ith H lth A th iti fWorking with Health Authorities from
Regulatory/Compliance Perspective
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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.
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22. Centralised Approval - Decision Making
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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
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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!
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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
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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.
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27. Th k !Thank you!
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