Les enjeux

réglementaires:
Comment intégrer la spécificité des
biotechnologies

Kowid HO
Department for evaluation of biological product
1)
Complexité des produits
issues des biotechnologies
 Typical biotech manufacturing process
Wild vector Gene of interest

Host cell Expression vector Genetic

development Q5A
Expression system (1 clone) Q5B
Q5D
Master Cell Bank Q5E
Cell banks

Working Cell Bank Q9

Q5A Q7A Q10
Culture / Fermentation
Q5C
Purification Production Q5E
Q6B
DRUG SUBSTANCE Q11
Sterile filtration / Aseptic filling
Q5E
Sterilisation Q6B
Aseptic filling
DRUG PRODUCT Q8
3 Biotech challenges
Q8R
 Biological medicinal product
Spectrum of complexity

Spectrum of complexity

Aspirin IFN alfa

IgG FVIII …
~1300AA, ~2330AA, Virus like particle
MW: 0.2 kDa 165AA, MW: 19 kDa MW: ~150 kDa MW: ~330 kDa MW: ~20 000 kDa

Chemicals Recombinant DNA Blood- Immunologicals Advanced

4 derived Biotech challenges
therapy
technology
PHYSICOCHEMICAL CHARACTERISTICS BIOLOGICAL CHARACTERISTICS

VARIABLE REGION
- Deamidation BINDING
- Oxidation - Affinity
- N-term Pyro-Glu - Avidity
- Glycosylation - Immunoreactivity /
- Glycation crossreactivity
- Conformation - Unintentional reactivity
… …

CONSTANT REGION
EFFECTOR FUNCTION
- Deamidation
- Complement interaction
- Oxidation
- FcRn, FcγR interaction
- Acetylation
- Mannan binding ligand interaction
- Glycation
- Mannose receptor interaction
- Glycosylation (fucosylation,
…
sialylation, galactosylation,
mannosylation…)
- C-term Lys
- Di-sulfide bond shuffling/ cleavage
- Fragmentation/clipping
OTHER BIOLOGICAL PROPERTIES
- Conformation
- PK properties
…
- Epitope / Immunogenicity
- Modulatory region (Tregitope …)
…

5 Biotech challenges
 Biological medicinal product
Modes of action of Mab

6 Source: GB Kress, EMEA workshop on biosimilar MAB, 2009 Biotech challenges

 Biological medicinal product
Example: Impact of glycosylation of Mab

7 Source: GB Kress, EMEA workshop on biosimilar MAB, 2009 Biotech challenges

 Biological medicinal product
Purity / Impurity profile

PURITY PROFILE

desired Product related

product substances

Peptide 3D- Post-translational

??? PROFILE structure
variants variants
Product related degradation Process related
impurities impurities

IMPURITY PROFILE
8 Biotech challenges
 Biological medicinal product
Immunogenicity

• The immune system can detect alterations in proteins missed by

analytical methods
• Immunogenicity of biopharmaceuticals may have serious clinical
consequences (e.g. loss of efficacy, cross reaction with endogeneous
counterpart, hypersensitivity, anaphylaxis…)
• Antibodies may be:
• Non-neutralizing
no impact on clinical efficacy

• Neutralizing antibodies
inhibition (up to complete loss) of the

therapeutic effect

9 Biotech challenges
 Biological medicinal product
Immunogenicity

Molecular structure
Foreign
protein

« Close to Human protein »

Natural Human
protein
Less likely to be Breaking tolerance ? More likely to be
New epitopes ?
immunogenic immunogenic

10 Biotech challenges
 Biological medicinal product
Immunogenicity example – Host Cell Protein (HCP)

PROCESS A1 PRODUCT A1 High immunogenicity

Investigation

High level of HCP detected with new method

(process specific)

Revision of manufacturing process

PROCESS A2 PRODUCT A2 Reduced immunogenicity

11 Biotech challenges
 Biological medicinal product
Immunogenicity example – Formulation change

PROCESS B1 PRODUCT B1 Low immunogenicity

Formulation change (HSA removal)

Increased
PROCESS B2 PRODUCT B2 immunogenicity

Investigation

Rubber stopper Cold chain

leachates
Improved Process
control strategy improvement?
Improved
Coated stopper supply chain

PROCESS B2' PRODUCT B2' Reduced immunogenicity

12 Biotech challenges
 Biological medicinal product
“Biotech paradigm”

• Analytical challenge:
• Complex purity/impurity profile
• Many unknowns

• Manufacturing challenge:
• One change… a cascade of changes…
• Necessity to reconsider downstream steps
… and upstream steps, as appropriate
• No a priori classification: any change may impact on
the quality, safety and efficacy profile

• Biotechnology derived products are defined by

the product and… its process

13 Biotech challenges
 Biological medicinal product
Quality assessment
Control of raw and
starting materials

Good Control of cell substrate

manufacturing & cell bank
Practice
QUALITY
CONTROL
Control of drug substance
Process and drug product
validation

In Process
Control
14 Biotech challenges
 Biological medicinal product
Quality assessment

Safety & Efficacy profiles

Clinical trial

Control of raw and

starting materials

Good Control of cell

manufacturing substrate & cell bank
Practice
QUALITY
CONTROL Control of drug
substance and drug
Process
validation product

In Process
Control

15 Biotech challenges
2
Repère sur les acteurs et outils
réglementaires
 Regulatory environment
Afssaps

Afssaps
Siège Social et Laboratoires
PARIS 143/147, boulevard Anatole France
93285 SAINT-DENIS CEDEX
01.55.87.30.00
www.afssaps.fr

LYON
Afssaps Laboratoires
321, avenue Jean Jaurès
MONTPELLIER 69007 LYON

Afssaps Laboratoires
635, rue de la Garenne
37740 Vendargues
Directeur général, Jean Marimbert
950 personnels environ
Budget 2009 : 109.6 millions €

17 Biotech challenges
 Regulatory environment
Afssaps

Jean MARIMBERT
Directeur Général
Michel POT Fabienne BARTOLI
Secrétaire général Adjointe au directeur général

Evaluation Evaluation Evaluation de

des des la publicité
Laboratoires
médicaments Dispositifs des produits Inspection
et
et des médicaux cosmétiques
contrôles
produits et biocides
biologiques J.C. M. STOLTZ
A. NICOLAS
GHISLAIN C.
Ph. LECHAT DESMARES

18 Biotech challenges
 Regulatory environment
Afssaps

Evaluation des médicaments et des produits biologiques

Ph. LECHAT

Evaluation des Affaire

Evaluation et de Evaluation
essais cliniques réglementaires et
la surveillance thérapeutique Evaluation de la Evaluation des
et des gestion des
du risque et de des demandes qualité produits
médicaments à procédures
l'information d'AMM pharmaceutique biologiques
statut particulier d'AMM
A. CASTOT S. FORNAIRON A. SAWAYA P. ZORZI
C. BELORGEY F. ROUSSELLE

19 Biotech challenges
 Accompagnement de l'innovation

20 Biotech challenges
 Council of Europe
European Directorate for the European Pharmacopoeia
Strasbourg
Quality of Medicines
& health care (EDQM)
STRASBOURG
47 member states
European Union
http://www.ich.org/cache/compo/276-254-1.html
Commission
(DG enterprise & industry)
European Medicines Agency (EMEA)
London
BRUSSELS
27 member states

21 Biotech challenges
 Regulatory environment
European Medicines Agency (EMEA)

• 1995: European Agency for the

Evaluation of Medicinal Products
(EMEA)

• 2004 (EC No 726/2004): European

Medicines Agency (EMEA)
• Coordinates scientific resources for
the evaluation, supervision and
pharmacovigilance of medicinal
products
• Scientific resources: 27 member
states

http://www.emea.europa.eu
22 Biotech challenges
 Regulatory environment
European Medicines Agency (EMEA)

EMEA
Inspection
sector
CHMP CVMP
Committee for Medicinal Committee for Medicinal
Product for Human use Product for Veterinary use
Eric Abadie Gérard Moulin

EMEA
Scientific
CAT Committees PDCO
Committee for
Paediatric Committee
Advance Therapy
Daniel Brasseur
Christian Schneider

COMP HCMP
Committee of Orphan Committee for Herbal
Medicinal Product Medicinal Product
Konstantin Keller
23 Kerstin Westermark Biotech challenges
 Regulatory environment
European Medicines Agency (EMEA)
Similar Biological (Biosimilar)
Medicinal Products Working Party (BMWP)
Christian Schneider
Vaccine Working Party (VWP)
Biologics Working Party (BWP)
Michael Pfleiderer
Jean-Hugues Trouvin

Quality Working Party (QWP) Blood Product

Joint CHMP/CVMP Working Party (BPWP)
Jean-Louis Robert Rainer Seitz

Patients' and Consumers' Cell-based Products

Working Party (PCWP) Working Party (CPWP)
CHMP Paula Salmikangas
Nikos Dedes & Isabelle Moulon
Eric Abadie

Efficacy Gene Therapy

Working Party (EWP) Working Party (GTWP)
Barbara van Zwieten-Boot Klaus Cichutek

Pharmacovigilance Scientific Advice (SAWP)

Working Party (PhWP) Bruno Flamion
June Munro Raine
Safety Working Party (SWP) Pharmacogenomics Working Party (PgWP)
Beatriz Silva Lima Eric Abadie

24+ Specific ad-hoc working groups or subgroup meetings when needed Biotech challenges
25 Biotech challenges
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/eudralex_en.htm
26 Biotech challenges
http://www.emea.europa.eu/htms/human/humanguidelines/biologicals.htm
http://www.ich.org/cache/compo/276-254-1.html

http://www.ich.org/cache/compo/276-254-1.html
27 Biotech challenges
 Regulatory environment
Quality & multidisciplinary guidelines

• EMEA Guideline effective in 2009:

• Development, production, characterization and specifications for monoclonal antibodies
and related product

• Allergen products: production and quality issues

• Quality of biological active substances produced by stable transgene expression in

higher plants

• The replacement of rabbit pyrogen testing by an alternative test for plasma derived
medicinal products

• Virus Safety Evaluation of Biotechnological Investigational Medicinal Products

• Similar biological medicinal products containing low-molecular-weight-heparins

• Non-clinical and clinical development of similar medicinal products containing recombinant

interferon alpha

• ICH Considerations General Principles to Address Virus and Vector Shedding

• Quality, non-clinical and clinical issues relating specifically to recombiant adeno-associated

viral vectors

28 … Biotech challenges
 Regulatory environment
Quality & multidisciplinary guidelines

• Ongoing guidelines in 2009:

• Guideline on products from transgenic animal

• Chemical and Pharmaceutical Quality documentation concerning Biological Investigational

Medicinal Products in Clinical Trials

• Revision of the guidance on Similar medicinal products containing recombinant

Erythropoietins

• Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use

• Revision of the guideline on pharmaceutical aspects of the product information for human
vaccines

• Position statement on CJD and Plasma-Derived and Urine-Derived Medicinal Products

• Revision of the guideline on Parametric Release

• ICH Q11 - Development and Manufacture of Drug Substances (chemical entities and
biotechnological/biological entities)

…
29 Biotech challenges