International Federationf Ph ti lof Pharmaceutical

Manufacturers & Associations

Points To Consider – Biotherapeutics vsSmall Molecule Medicines

Kum Cheun WonggHead Asia Pacific Policy & LiaisonNovartis Asia Pacific

2013 APEC Harmonization Centre Biotherapeutic WorkshopSeoul, Korea 25 26 S t b 201325‐26 September 2013

Agenda• Background and value of biological medicines• Special characteristics of biological medicines

Size / Structural complexityDevelopment, Manufacturing & Distribution challengesImmunogenicity

• Regulatory AspectsKey considerations for evaluating changes throughout lifecycle

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Biologics have revolutionized modernBiologics have revolutionized modernmedicine – and will continue to do so

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International Federationf Ph ti lof Pharmaceutical

Manufacturers & Associations

Special characteristics of biological medicinesmedicines

Biologics are more complex than small

MammalianBacteria, Yeast

molecules…

protein proteinProtein

( )

Glycoprotein

(with sugars)Peptide

(no sugars) (with sugars)

1x 19x 105x 122x 170x 833x

© IFPMA 201325 Sep 2013

Monoclonal antibody

~150 kDa

calcitonin

~3.5 kDa

epoetin~30 kDa

somatropin

~22 kDa

filgrastim~19 kDa

aspirin

0.18kDa5

Biotherapeutics differ from chemically-synthesized molecules in both complexitysynthesized molecules in both complexity& sensitivity

Biotherapeutics Small Molecules

Small Molecule

Image Source: Tim Osslund photographer (Amgen staff); Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time. Images not to scale. 1. Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework Br J Clin Pharmaco l.

2007;65:619-620; 2. Roger SD. Nephrology. 2006;11:341-3463. Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56.

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Biotherapeutics have special features

By intrinsic nature Generally very specific action; rare side effectsmimic body proteins, low off‐target toxicity

Might provoke unwanted immune responseg p p„immunogenicity“

Need special transport and storage conditionsfridge; to be handled with carefridge; to be handled with care

Often have a long duration of actionless frequent dosing

Administration Generally need devicesdelivery by injections; would be digested when taken up

orallyorally

Usually prescribed by specialistsoften severe and chronic nature of treated diseases

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International Federationf Ph ti lof Pharmaceutical

Manufacturers & Associations

Development & Manufacturing ChallengesChallenges

Biological products:Biological products: Complex manufacturing process

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Good Manufacturing Practice requirementsGood Manufacturing Practice requirementsfor biotherapeutics and small molecules

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Characterization ConsiderationsBiologics are mainly proteins with complexBiologics are mainly proteins with complex structures:

Primary Structure (linear sequence of amino acids)S d St t (2D f ldi )Secondary Structure (2D folding)Tertiary Structure (3D folding of a single chain)Quaternary Structure (connection of several chains)chains)

How do we begin the characterization of suchHow do we begin the characterization of such products? Determination of ...

Physico‐chemical properties

Biological activity

Immunochemical properties

Purity impurities and contaminants

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Purity, impurities and contaminants

Uses of analytical tools in theUses of analytical tools in thecharacterization of biopharmaceuticals

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Types of Impurities yp pthat need to be tested

Product‐relatedsequence variants

Process‐relatedmedia supplements sequence variants 

amino acid modifications

misfolded protein

media supplements 

residual host‐cell protein / DNA misfolded protein

free PEG (unreacted), etc.

DNA 

chromatography leachables

adventitious agents, etc.adventitious agents, etc.

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Stability considerations

• Biologics generally less stable and more temperature sensitive than small moleculesS f bi l i i ll• Storage temperatures for biologics are typically:

Frozen: ‐ 40ºCRefrigerated: 2 – 8ºCWith limited excursions to room temperature 

• Drug products also require frozen &/or refrigerated storageSome time out of refrigeration (TOR) may be validatedExtensive shipping validation studies

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I i i Eff d f• A vast majority of biopharmaceuticals can cause an immune response such as T

Immunogenicity: Effects and factorsA vast majority of biopharmaceuticals can cause an immune response, such as T cell activation, anti‐GH antibodies

• In some cases, e.g. vaccines, immunogenicity is desired• Product related factors• Product‐related factors

Protein structureContaminants and process‐related impurities

lFormulationHandling and storageRoute of administration: SC > IM > IV

• Patient factorsGenetic factorsDose and treatment durationConcomitant diseases and/or medication Congenital deficiencies 

Source: EMEA/CHMP/BMWP/14327/2006 : Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins

Source: Schellekens, H. Bioequivalence and The Immunogenicity of Biopharmaceuticals. Nat Rev Drug Discovery 2002;1:457-6215

Establishing the immunogenicity profile

• Immunogenic safety can only be assessed through clinical and post‐marketing program due to:

the human immune system being more sensitive than the availablethe human immune system being more sensitive than the available physical tests or bioassaysthe limitations of current analytical methodsthe lack of standardized assaysthe lack of standardized assays

• Rare immune‐mediated reactions (e.g. 1 in 10,000 patient‐years) will only become apparent through robust post‐marketing surveillanceonly become apparent through robust post marketing surveillance

• Immunogenicity should be addressed in the Risk Management Plan taking into account risks identified during product development andtaking into account risks identified during product development and potential risks and consequences of unwanted immune response to patients

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International Federationf Ph ti lof Pharmaceutical

Manufacturers & Associations

Regulatory AspectsRegulatory Aspects

Manufacturing ChangesManufacturing Changes• Biotech development is the continuous implementation of 

changes that increase product and process experience

• Also after obtaining marketing approval biotherapeuticals are

Ph IVLO Pre-

clinical Ph I Ph II Ph IIILIMarket

Also after obtaining marketing approval biotherapeuticals aremodified on an ongoing basis

Market

20-50 20-300 300-3000 patients

Up to 25 000L

Pilot scale production Small scale production

Upscale of production Commercialised large scale production

200L 1000L ~10‘000L Up to 25,000L

Physical design Process optimization Process improvements

Process characteriza-

tion and validation

Potential major changes supported by appropriate comparability and/or bridging data Dual sourcing

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Changes may have a negative impactExample – Impact on patient safety:

• Change: from HSA formulation to a polysorbateU h d t i l t ( fill d i ith• Unchanged container closure system (pre‐filled syringes with uncoated rubber stoppers)

• Source: vulcanizing agents leached from rubber stopper overSource: vulcanizing agents leached from rubber stopper over time

• Outcome: no detectable changes in product qualitysafety: serious adverse event (Pure Red Cell Aplasia)

• Hypothesis: leachables acted as adjuvants triggering immunogenicity

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Adapted from: I Markovic;, US FDA / Working with FDA: Biological Products and Clinical Development

Comparability: Throughout p y gthe Product Lifecycle• To avoid possible impact on patient safety and/or efficacy, 

post‐approval changes have to be evaluatedC bili i ll bli h d l b l l• Comparability is a well established global regulatory mechanism based on ICH Q5E “Comparability of Biotechnological / Biological Products Subject to Changes inBiotechnological / Biological Products Subject to Changes in Their Manufacturing Process”

• Per ICH Q5E:Per ICH Q5E: • “The goal of a comparability exercise is to ascertain that pre‐ and post‐change product is comparable in terms of p p g p p fquality, safety and efficacy”

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Possible Outcomes of Comparability

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Adapted from: M Melainie & Y Bobinnec/ Comparability Protocols for Biotechnological Products ; BioProcess International 11(6) June 2013

Biological products and their g pprocesses - Summary

• In contrast to uniform small molecule products, biological products are complex, sensitive and heterogeneous mixtures of protein molecules

• Each stage of the complex manufacturing process confers i i h l i bi l i l d iunique properties to the resulting biological product mixture

• Process understanding, extensive process validation and a unique control strategy ensure the consistency of a biologicalunique control strategy ensure the consistency of a biological product produced by an established process

• Changes in the composition of the product mixture could affect• Changes in the composition of the product mixture could affect its safety and efficacy  

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ConclusionDue to the special nature of biotherapeutics there is a need for:

Especially dedicated legislation or guidance on biotherapeutics that regulate the:biotherapeutics that regulate the:

• Development, registration and post‐marketing surveillance; as well assurveillance; as well as

• Pharmacovigilance

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International Federationf Ph ti lof Pharmaceutical

Manufacturers & Associations

Thank you!Thank you!