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. 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. Biologics have revolutionized modernBiologics have revolutionized modern
medicine – and will continue to do so
3

4. International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Special characteristics of biological
medicinesmedicines

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. 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. 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. International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Development & Manufacturing
ChallengesChallenges

9. Biological products:Biological products:
Complex manufacturing process
9

10. Good Manufacturing Practice requirementsGood Manufacturing Practice requirements
for biotherapeutics and small molecules
10

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. Uses of analytical tools in theUses of analytical tools in the
characterization of biopharmaceuticals
12

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. 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. 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. 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. International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Regulatory AspectsRegulatory Aspects

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. 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. 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. Possible Outcomes of Comparability
21
Adapted from: M Melainie & Y Bobinnec/ Comparability Protocols for Biotechnological Products ; BioProcess International 11(6) June 2013

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. 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. International Federation
f Ph ti lof Pharmaceutical
Manufacturers & Associations
Thank you!Thank you!