Comparability for
Biotech Products:
An industry perspective
on past & future aspects
Mary B. Sliwkowski, Ph.D.
VP, Regulatory CMC &
Info Systems
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Agenda
- Comparability:
what, why, when, how
- Experience
so far
- Challenges
& lessons learned
- The future
- Small molecule
drugs
- Fully defined by physico-chemical
methods
- Biotech products
- Complex mixtures of 100s -
1000s of forms
- Post-translational modifications
- Higher order structure
- Defined by characterization
& process
- Physico-chemical
- Biologic (in
vitro)
- Animal (pharmacokinetics,
toxicology, immunogenicity)
- Human (safety,
efficacy)
- Process qualification
& validation
- Well-characterized but not
fully defined
Why
do we need ‘comparability’?
Comparability:
What is it?
- “Comparability
is the demonstration of a high degree of similarity between products
produced by different manufacturing processes, equipment and/or sites,
such that no adverse impact on quality, safety or efficacy occurs”
- Comparability
is NOT identity
- Comparability
is a well established global regulatory mechanism based on ICH Q5E
“Comparability of Biotechnological / Biological Products Subject to
Changes in Their Manufacturing Process”
- Per ICH Q
5E:
- “The goal of a comparability
exercise is to ascertain that pre- and post-change product is comparable
in terms of quality, safety and efficacy”
- “The demonstration of
comparability does not necessarily mean that the quality attributes
of the pre-change and post-change are identical, but that they are highly
similar…”
Comparability:
Global Guidance
Comparability:
History of U.S. Biotech Regulation
ICH
*PTC
for
Biotech
1986
First Biotech Drugs
First Biotech Biologics
PDUFA
I
1980
1990
2000
‘02
‘03
‘92
‘97
‘98
PDUFA
II
PDUFA
III
‘04
CBER/CDER
Inter-center
Agreement
CBER/CDER
Integration
‘05
‘06
FDAMA
- Quality
by Design
- Design
Space
- Process
Analytical Technology (PAT)
- Expanded
Change Protocols
REGO
- First WCBP
Symposium
- Specified
Products
- BLA replaced
PLA & ELA
- Eliminated
FDA Lot Release
- Created
Team Biologics
‘94
‘07
- Comparability
Guidance
- Comparability
Protocols
PDUFA
IV
- Post-Approval
Submission (PAS)
- Conduct qualification of change
and submit data for approval prior to implementation
- Comparability
Protocol
- Pre-specify testing, validation
studies and acceptance criteria for change to be made
- Pre-change approval may allow
reduced reporting category when implement change
- Initially only for specific,
pre-defined change to single product
- Expanding to broader applications
- multi-change, multi-product
- Expanded
Change Protocol (TBD)
- Linked to Quality by Design
approach (ICH Q8)
- Provide evidence of sufficient
product knowledge (Critical Quality Attributes - CQAs) and process understanding
(Critical Process Parameters - CPPs) to define a Design Space in which
can operate more freely
- EU Variation
regulations being revised
Regulatory
Mechanisms
Comparability:
Throughout the Product Lifecycle
Clinical
Development
• some product variability (lot-to-lot,
inter-campaign) is desirable
• collecting clinical and non-clinical
data
Phase
III – Registration
• process, control system, formulation
locked
• collecting pivotal clinical data
• qualification, validation lot production
- process changes will require
BE and/or efficacy data
Post-Approval
• apply comparability guidance (ICH
Q5E)
• match historical data sets
- Manufacturing
facility changes
- Process changes
- Cell culture, fermentation
- Recovery
- Formulation
- Delivery mechanism or system
- Supplier
changes
- Raw materials
- Primary components
- Regulatory
expectation changes
What
triggers comparability efforts?
Hierarchy
of Comparability Testing
- To confirm
efficacy, safety, and/or immunogenicity
E - Human Clinical Trials
- Direct comparison
of pre- and post-change
- Adequately
powered
D - Human Bioequivalence
C - Animal PK/PD
- In vitro
functional bioassays & binding studies
- Real time
& accelerated stability
B - Biological Characterization
- CoA
- Extended
characterization of variants & impurities
- Accelerated
degradation
A - Basic Package
Testing
Determined on case by
case basis
Category
Fabrazyme Amevive Xolair
Bexxar Raptiva
Chronology
of Key Biotech Product Approvals
1982 - 2007
03
87
98
97
95
96
88
89
90
91
92
93
94
99
01
00
CBER (N=48)
CDER (N=14)
Activase
86
85
Nutropin
Glucagon
Thyrogen
Mylotarg
Ovidrel
Natrecor
Protropin
Cerezyme
Ceredase
Follistim
Forteo
Epogen/Procrit
Neupogen
Leukine
Actimmune
Proleukin
Pulmozyme
Betaseron
ReoPro
Intron A
Abatacept
Galsulfase
Avonex
Retavase
Benefix
Infergen
Neumega
Rituxan
Zenapax Regranex
Simulect
Synagis
Remicade
Herceptin
Enbrel
NovoSeven
Ontak
Refacto
Zevalin
Elitek Humira Rebif
Humulin R (1982)
> $1 Billion Annual
International Sales
02
Campath
Kineret
Xigris Aranesp
04
05
06
Avastin
Erbitux
Tysabri
Lucentis
Myozyme
Elaprase
Vectibix
Humatrope
Increlex
07
- 23 years
of commercial manufacture
- 14 products
with 8 process version changes
- Drug substance
transfers/sites completed
- Within GNE network: 14 across
4 sites
- Out to partners/CMOs: 8 across
6 sites
- In to GNE: 1 at 1 site
- Drug Product
transfers/sites completed
- Within GNE network: 10 across
3 sites
- Out to partners/CMOs: 11 across
8 sites
- Submitted
13 PAS & 12 CP
- Many transfers
planned as rebalance mfg network
- GNE internal
documents: Quality & Regulatory Standards
What
is the GNE experience
- Don’t make
process changes between Phase III and approval
- Platforms
have limitations
- Each Mab has unique challenges
- Trastuzumab:
Met oxidation, Asn deamidation
- Omalizumab:
unpaired Cys, Asp isomerization
- Bevacizumab:
dissociable aggregates
- Ranizumab:
Trp oxidation
- Sequence
variants can/do occur
- Minor carbohydrate
variation is sometimes important
- Relevance
of differences is situational
- Maintain
frequent dialog with Agency
- Successful
comparability efforts require due diligence
- Our ultimate
responsibility is to our patients
What
have we learned
- Evolution
of analytical methods
- Increased sensitivity
- New forms
- Higher order
structure
- Linkage to
safety & efficacy
- When is a difference significant?
- Mechanism of action
- Patient population
- Route of administration
- Comparability
is still case by case
- Global regulatory
differences
- Change regulations mechanisms
- Stability requirements
- Timing of transition
Challenges
Acknowledgements
Wassim
Nashabeh
Kathy
Francissen
Reed
Harris
Amita
Joshi
Ron
Taticek
Ray
Arnold
Loel
McPhee