quality control - ANSM

incandescentnonBiotechnology

Dec 10, 2012 (4 years and 9 months ago)

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Les enjeux réglementaires:
Comment intégrer la spécificitédes
biotechnologies
KowidHO
Departmentfor evaluationof biologicalproduct
1)
Complexitédes produits
issues des biotechnologies
Biotechchallenges
3
Genetic
development
Wild vector
Gene of interest
Host cell
Expression vector
Expression system (1 clone)
Master Cell Bank
Working Cell Bank
Cell banks
Culture / Fermentation
Purification
DRUG SUBSTANCE
Production
Sterile filtration / Aseptic filling
DRUG PRODUCT
Sterilisation
Aseptic filling
Typicalbiotechmanufacturingprocess
Q5A
Q5B
Q5D
Q5E
Q5A
Q5C
Q5E
Q6B
Q11
Q5E
Q6B
Q8
Q8R
Q7A
Q9
Q10
Biotechchallenges
5
VARIABLE REGION
-Deamidation
-Oxidation
-N-term Pyro-Glu
-Glycosylation
-Glycation
-Conformation …
CONSTANT REGION
-Deamidation
-Oxidation
-Acetylation
-Glycation
-Glycosylation (fucosylation,
sialylation, galactosylation,
mannosylation…)
-C-term Lys
-Di-sulfide bond shuffling/ cleavage
-Fragmentation/clipping
-Conformation …
BINDING
-Affinity
-Avidity
-Immunoreactivity/
crossreactivity
-Unintentional reactivity …
EFFECTOR FUNCTION
-Complement interaction
-FcRn, FcγRinteraction
-Mannanbinding ligandinteraction
-Mannose receptor interaction …
OTHER BIOLOGICAL PROPERTIES
-PK properties
-Epitope/ Immunogenicity
-Modulatoryregion (Tregitope…) …
BIOLOGICAL CHARACTERISTICS
PHYSICOCHEMICAL CHARACTERISTICS
Biotechchallenges
6
Biologicalmedicinalproduct
Modes of action of Mab
Source: GB Kress, EMEA workshop on biosimilarMAB, 2009
Biotechchallenges
7
Biologicalmedicinalproduct
Example: Impact of glycosylation of Mab
Source: GB Kress, EMEA workshop on biosimilarMAB, 2009
Biotechchallenges
9
Biologicalmedicinalproduct
Immunogenicity

The immune system candetectalterationsin proteinsmissedby
analyticalmethods

Immunogenicityof biopharmaceuticalsmayhave seriousclinical
consequences(e.g. lossof efficacy, cross reactionwithendogeneous
counterpart, hypersensitivity, anaphylaxis…)

Antibodiesmaybe:

Non-neutralizing￿no impact on clinicalefficacy

Neutralizingantibodies￿inhibition (up to completeloss) of the
therapeuticeffect
Biotechchallenges
10
Biologicalmedicinalproduct
Immunogenicity
Natural Human
protein
«Close to Human protein»
Foreign protein
New epitopes?
More likelyto be
immunogenic
Breaking tolerance ?
Lesslikelyto be
immunogenic
Molecular structure
Biotechchallenges
11
High immunogenicity
PRODUCT A1
High levelofHCP detectedwithnew method
(processspecific)
Revision of manufacturing process
Reduced immunogenicity
Biologicalmedicinalproduct
Immunogenicityexample–Host CellProtein(HCP)
PROCESS A1
Investigation
PRODUCT A2
PROCESS A2
Biotechchallenges
12
Increased
immunogenicity
PRODUCT B2
Rubberstopper
leachates
Coated stopper
Reduced immunogenicity
Biologicalmedicinalproduct
Immunogenicityexample–Formulation change
PROCESS B2
Investigation
PRODUCT B2'
PROCESS B2'
Low immunogenicity
PRODUCT B1
PROCESS B1
Formulation change (HSA removal)
Cold chain
Improved
supply chain
Improved
control strategy
Process
improvement?
Biotechchallenges
13

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 prioriclassification: any change may impact on
the quality, safety and efficacy profile

Biotechnology derived products are defined by
theproduct
and…
its process
Biologicalmedicinalproduct
“Biotechparadigm”
Biotechchallenges
14
Control of rawand
startingmaterials
Control of cellsubstrate
& cellbank
In Process
Control
Control of drugsubstance
and drugproduct
Process
validation
Good
manufacturing
Practice
QUALITY
QUALITY
CONTROL
CONTROL
Biologicalmedicinalproduct
Qualityassessment
Biotechchallenges
15
Control of rawand
startingmaterials
Control of cell
substrate& cellbank
In Process
Control
Control of drug
substance and drug
product
Process
validation
Good
manufacturing
Practice
QUALITY
QUALITY
CONTROL
CONTROL
Biologicalmedicinalproduct
Qualityassessment
Clinical trial
Safety & Efficacy profiles
2
Repère sur les acteurs et outils
réglementaires
Biotechchallenges
17
Afssaps Laboratoires
321, avenue Jean Jaurès
69007 LYON
Afssaps Laboratoires
635, rue de la Garenne
37740 Vendargues
Directeur général, Jean Marimbert
950 personnels environ
Budget 2009 : 109.6 millions €
Afssaps
Siège Social et Laboratoires
143/147, boulevard Anatole France
93285 SAINT-DENIS CEDEX
01.55.87.30.00
www.afssaps.fr
Regulatory environment
Afssaps
LYON
MONTPELLIER
PARIS
Biotechchallenges
18
Evaluation
des
médicaments
et des
produits
biologiques
Ph. LECHAT
Evaluation
des
Dispositifs
médicaux
J.C.
GHISLAIN
Laboratoires
et
contrôles
A. NICOLAS
Evaluation de
la publicité
des produits
cosmétiques
et biocides
C.
DESMARES
Jean MARIMBERT
Directeur Général
Regulatoryenvironment
Afssaps
Inspection
M. STOLTZ
FabienneBARTOLI
Adjointeau directeurgénéral
Michel POT
Secrétairegénéral
Biotechchallenges
19
Evaluation et de
la surveillance
du risque et de
l'information
A. CASTOT
Affaire
réglementaires et
gestion des
procédures
d'AMM
F. ROUSSELLE
Evaluation des médicaments et des produits biologiques
Ph. LECHAT
Evaluation
thérapeutique
des demandes
d'AMM
S. FORNAIRON
Evaluation des
produits
biologiques
P. ZORZI
Evaluation des
essaiscliniques
et des
médicamentsà
statutparticulier
C. BELORGEY
Regulatoryenvironment
Afssaps
Evaluation de la
qualité
pharmaceutique
A. SAWAYA
Biotechchallenges
20
Accompagnement de l'innovation
Biotechchallenges
21
http://www.ich.org/cache/compo/276-254-1.html
European Medicines Agency (EMEA)
London
Council of Europe
European Directorate for the
Quality of Medicines
& health care (EDQM)
STRASBOURG
47 member states
European Union
Commission
(DG enterprise & industry)
BRUSSELS
27 member states
European Pharmacopoeia
Strasbourg
Biotechchallenges
22
Regulatoryenvironment
EuropeanMedicinesAgency(EMEA)

1995: EuropeanAgencyfor the
Evaluation of MedicinalProducts
(EMEA)

2004 (EC No 726/2004): European
MedicinesAgency(EMEA)

Coordinatesscientificresourcesfor
the evaluation, supervision and
pharmacovigilance of medicinal
products

Scientificresources: 27 member
states
http://www.emea.europa.eu
Biotechchallenges
23
Regulatoryenvironment
EuropeanMedicinesAgency(EMEA)
EMEA
Scientific
Committees
CHMP
Committee for Medicinal
Product for Human use
Eric Abadie
CVMP
Committee for Medicinal
Product for Veterinary use
GérardMoulin
COMP
Committee of Orphan
Medicinal Product
Kerstin Westermark
HCMP
Committee for Herbal
Medicinal Product
Konstantin Keller
PDCO
Paediatric Committee
Daniel Brasseur
CAT
Committee for
Advance Therapy
Christian Schneider
EMEA
Inspection
sector
Biotechchallenges
24
Regulatoryenvironment
EuropeanMedicinesAgency(EMEA)
CHMP
Eric Abadie
Biologics Working Party (BWP)
Jean-HuguesTrouvin
Safety Working Party (SWP)
Beatriz Silva Lima
Pharmacovigilance
Working Party (PhWP)
June Munro Raine
Quality Working Party (QWP)
Joint CHMP/CVMP
Jean-Louis Robert
Blood Product
Working Party (BPWP)
Rainer Seitz
Efficacy
Working Party (EWP) Barbara van Zwieten-Boot
Scientific Advice (SAWP)
Bruno Flamion
Gene Therapy
Working Party (GTWP)
Klaus Cichutek
+ Specific ad-hoc working groups or subgroup meetings when needed
Cell-based Products
Working Party (CPWP)
Paula Salmikangas
Patients' and Consumers'
Working Party (PCWP)
Nikos Dedes& Isabelle Moulon
PharmacogenomicsWorking Party (PgWP)
Eric Abadie
Vaccine Working Party (VWP)
Michael Pfleiderer
Similar Biological (Biosimilar)
Medicinal Products Working Party (BMWP)
Christian Schneider
Biotechchallenges
25
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/eudralex_en.htm
Biotechchallenges
26
http://www.emea.europa.eu/htms/human/humanguidelines/biologicals.htm
Biotechchallenges
27
http://www.ich.org/cache/compo/276-254-1.html
http://www.ich.org/cache/compo/276-254-1.html
Biotechchallenges
28
Regulatoryenvironment
Quality& multidisciplinaryguidelines

EMEA Guideline effective in 2009:

Development, production, characterizationand specificationsfor monoclonal antibodies
and relatedproduct

Allergenproducts: production and qualityissues

Qualityof biologicalactive substances producedby stable transgeneexpression in
higherplants

The replacement of rabbitpyrogentestingby an alternative test for plasma derived
medicinalproducts

Virus SafetyEvaluation of BiotechnologicalInvestigationalMedicinalProducts

Similarbiologicalmedicinalproductscontaininglow-molecular-weight-heparins

Non-clinicaland clinicaldevelopmentof similarmedicinalproductscontainingrecombinant
interferonalpha

ICH ConsiderationsGeneral Principlesto AddressVirus and VectorShedding

Quality, non-clinicaland clinicalissues relatingspecificallyto recombiantadeno-associated
viral vectors

Biotechchallenges
29
Regulatoryenvironment
Quality& multidisciplinaryguidelines

Ongoingguidelines in 2009:

Guideline on productsfromtransgenicanimal

Chemicaland Pharmaceutical Qualitydocumentation concerningBiologicalInvestigational
MedicinalProductsin ClinicalTrials

Revisionof the guidance on Similarmedicinalproductscontainingrecombinant
Erythropoietins

Immunogenicityassessmentof monoclonal antibodiesintendedfor in vivo clinicaluse

Revisionof the guideline on pharmaceuticalaspects of the productinformation for human
vaccines

Position statementon CJD and Plasma-Derivedand Urine-DerivedMedicinalProducts

Revisionof the guideline on ParametricRelease

ICH Q11 -Developmentand Manufacture of Drug Substances (chemicalentitiesand
biotechnological/biologicalentities)