International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Points To Consider – Biotherapeutics vs
S...
Agenda
• Background and value of biological medicines
• Special characteristics of biological medicines
Size / Structural ...
Biologics have revolutionized modernBiologics have revolutionized modern
medicine – and will continue to do so
3
International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Special characteristics of biological
med...
Biologics are more complex than small
MammalianBacteria, Yeast
molecules…
protein proteinProtein
( )
Glycoprotein
(with su...
Biotherapeutics differ from chemically-
synthesized molecules in both complexitysynthesized molecules in both complexity
&...
Biotherapeutics have special features
By intrinsic nature Generally very specific action; rare side effects
mimic body pro...
International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Development & Manufacturing
ChallengesCha...
Biological products:Biological products:
Complex manufacturing process
9
Good Manufacturing Practice requirementsGood Manufacturing Practice requirements
for biotherapeutics and small molecules
10
Characterization Considerations
Biologics are mainly proteins with complexBiologics are mainly proteins with complex 
stru...
Uses of analytical tools in theUses of analytical tools in the
characterization of biopharmaceuticals
12
Types of Impuritiesyp p
that need to be tested
Product‐related
sequence variants
Process‐related
media supplements sequenc...
Stability considerations
• Biologics generally less stable and more temperature sensitive 
than small molecules
S f bi l i...
I i i Eff d f
• A vast majority of biopharmaceuticals can cause an immune response such as T
Immunogenicity: Effects and f...
Establishing the immunogenicity profile
• Immunogenic safety can only be assessed through clinical and post‐
marketing pro...
International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Regulatory AspectsRegulatory Aspects
Manufacturing ChangesManufacturing Changes
• Biotech development is the continuous implementation of 
changes that increas...
Changes may have a negative impact
Example – Impact on patient safety:
• Change: from HSA formulation to a polysorbate
U h...
Comparability: Throughoutp y g
the Product Lifecycle
• To avoid possible impact on patient safety and/or efficacy, 
post‐a...
Possible Outcomes of Comparability
21
Adapted from: M Melainie & Y Bobinnec/ Comparability Protocols for Biotechnological ...
Biological products and theirg p
processes - Summary
• In contrast to uniform small molecule products, biological 
product...
Conclusion
Due to the special nature of biotherapeutics there is a need for:
Especially dedicated legislation or guidance ...
International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
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Ifpma - Points to consider - biotherapeutics vs small molecule medicines - Wong KC

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Ifpma - Points to consider - biotherapeutics vs small molecule medicines - Wong KC

  1. 1. International Federation f Ph ti lof Pharmaceutical Manufacturers & Associations Points To Consider – Biotherapeutics vs Small Molecule Medicines Kum Cheun Wongg Head Asia Pacific Policy & Liaison Novartis Asia Pacific 2013 APEC Harmonization Centre Biotherapeutic Workshop Seoul, Korea  25 26 S t b 201325‐26 September 2013
  2. 2. Agenda • Background and value of biological medicines • Special characteristics of biological medicines Size / Structural complexity Development, Manufacturing & Distribution challenges Immunogenicity • Regulatory Aspects Key considerations for evaluating changes throughout  lifecycle 2
  3. 3. Biologics have revolutionized modernBiologics have revolutionized modern medicine – and will continue to do so 3
  4. 4. International Federation f Ph ti lof Pharmaceutical Manufacturers & Associations Special characteristics of biological medicinesmedicines
  5. 5. 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 2013 25 Sep 2013 Monoclonal antibody ~150 kDa calcitonin ~3.5 kDa epoetin ~30 kDa somatropin ~22 kDa filgrastim ~19 kDa aspirin 0.18kDa5
  6. 6. 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;11:341-346 3. Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56. 6
  7. 7. Biotherapeutics have special features By intrinsic nature Generally very specific action; rare side effects mimic body proteins, low off‐target toxicity Might provoke unwanted immune responseg p p „immunogenicity“ Need special transport and storage conditions fridge; to be handled with carefridge; to be handled with care Often have a long duration of action less frequent dosing Administration Generally need devices delivery by injections; would be digested when taken up orallyorally Usually prescribed by specialists often severe and chronic nature of treated diseases 7
  8. 8. International Federation f Ph ti lof Pharmaceutical Manufacturers & Associations Development & Manufacturing ChallengesChallenges
  9. 9. Biological products:Biological products: Complex manufacturing process 9
  10. 10. Good Manufacturing Practice requirementsGood Manufacturing Practice requirements for biotherapeutics and small molecules 10
  11. 11. Characterization Considerations Biologics 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 11 Purity, impurities and contaminants
  12. 12. Uses of analytical tools in theUses of analytical tools in the characterization of biopharmaceuticals 12
  13. 13. Types of Impuritiesyp p that need to be tested Product‐related sequence variants Process‐related media 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. 13
  14. 14. Stability considerations • Biologics generally less stable and more temperature sensitive  than small molecules S f bi l i i ll• Storage temperatures for biologics are typically: Frozen: ‐ 40ºC Refrigerated: 2 – 8ºC With limited excursions to room temperature  • Drug products also require frozen &/or refrigerated storage Some time out of refrigeration (TOR) may be validated Extensive shipping validation studies 14
  15. 15. I i i Eff d f • A vast majority of biopharmaceuticals can cause an immune response such as T Immunogenicity: Effects and factors A 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 structure Contaminants and process‐related impurities lFormulation Handling and storage Route of administration: SC > IM > IV • Patient factors Genetic factors Dose and treatment duration Concomitant 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;1:457-62 15
  16. 16. 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 bioassays the limitations of current analytical methods the 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 16
  17. 17. International Federation f Ph ti lof Pharmaceutical Manufacturers & Associations Regulatory AspectsRegulatory Aspects
  18. 18. 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 IV LO Pre- clinical Ph I Ph II Ph IIILI Market Also after obtaining marketing approval biotherapeuticals are modified 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 18
  19. 19. Changes may have a negative impact Example – Impact on patient safety: • Change: from HSA formulation to a polysorbate U 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 quality safety: serious adverse event (Pure Red Cell Aplasia) • Hypothesis: leachables acted as adjuvants triggering  immunogenicity 19 Adapted from: I Markovic;, US FDA / Working with FDA: Biological Products and Clinical Development
  20. 20. Comparability: Throughoutp y g the Product Lifecycle • To avoid possible impact on patient safety and/or efficacy,  post‐approval changes have to be evaluated C 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 f quality, safety and efficacy” 20
  21. 21. Possible Outcomes of Comparability 21 Adapted from: M Melainie & Y Bobinnec/ Comparability Protocols for Biotechnological Products ; BioProcess International 11(6) June 2013
  22. 22. Biological products and theirg p processes - 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   22
  23. 23. Conclusion Due 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 23
  24. 24. International Federation f Ph ti lof Pharmaceutical Manufacturers & Associations Thank you!Thank you!
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