Comparability for Biotech Products:
An industry perspective on past &
future aspects
Mary B. Sliwkowski, Ph.D.
VP, Regulatory CMC & Info Systems
Company
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Agenda
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Comparability: what, why, when, how
Experience so far
Challenges & lessons learned
The future
Why do we need ‘comparability’?
• Small molecule drugs
– Fully defined by physico-chemical methods
• Biotech products
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Complex mixtures of 100s - 1000s of forms
Post-translational modifications
Higher order structure
Defined by characterization & process
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Physico-chemical
Biologic (in vitro)
Animal (pharmacokinetics, toxicology, immunogenicity)
Human (safety, efficacy)
Process qualification & validation
– Well-characterized but not fully defined
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: Global Guidance
• 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 preand 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: History of U.S. Biotech Regulation
*PTC
for Biotech
1986
PDUFA I
PDUFA II
REGO
PDUFA III
CBER/CDER
Integration
FDAMA
ICH
‘92
1980
First Biotech
Drugs
• Insulin
• Growth
hormone
‘97
‘98
‘02 ‘03
‘04
‘05 ‘06 ‘07
2000
1990
First Biotech
Biologics
‘94
PDUFA IV
CBER/CDER
Inter-center
Agreement
• Comparability
Guidance
• Comparability
Protocols
• First WCBP Symposium
• Specified Products
• BLA replaced PLA & ELA
• Eliminated FDA Lot Release
• Created Team Biologics
• Quality by Design
• Design Space
• Process
Analytical
Technology (PAT)
• Expanded Change
Protocols
Regulatory Mechanisms
• 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
Comparability: Throughout the Product Lifecycle
Clinical Development
• some product variability (lot-to-lot, inter-campaign) is desirable
• process changes expected
• 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
What triggers comparability efforts?
• Manufacturing facility changes
– Site, scale, equipment
• Process changes
– Cell culture, fermentation
• Cell line changes
– Recovery
– Formulation
– Delivery mechanism or system
• Supplier changes
– Raw materials
– Primary components
• Regulatory expectation changes
Hierarchy of Comparability Testing
Category
Testing
Determined on case by case basis
A - Basic Package
• CoA
• Extended characterization of variants & impurities
• Accelerated degradation
B - Biological
Characterization
C - Animal PK/PD
• In vitro functional bioassays & binding studies
• Real time & accelerated stability
D - Human
Bioequivalence
E - Human Clinical
Trials
• Direct comparison of pre- and post-change
• Adequately powered
• Rodent PK
• Primate PK/PD
• To confirm efficacy, safety, and/or immunogenicity
Chronology of Key Biotech Product Approvals
1982 - 2007
Follistim
Forteo
Humulin R
(1982)
Humatrope
Glucagon
Thyrogen
Ceredase
Protropin
85
86
87
88
89
90
91
92
Nutropin
Cerezyme
93
94
95
Mylotarg
Ovidrel
96
97
98
Increlex
Natrecor
99
00
01
02
03
04
05
NovoSeven
Ontak
Activase
Intron A
Epogen
/Procrit
Avonex
Retavase
Proleukin
Neupogen Pulmozyme
Leukine
Betaseron
Actimmune
ReoPro
CDER (N=14)
CBER (N=48)
> $1 Billion Annual International Sales
Simulect
Synagis
Remicade Refacto
Herceptin
Benefix
Campath
Enbrel
Infergen
Kineret
Neumega
Xigris
Rituxan
Aranesp
Zenapax
Regranex
Fabrazyme
Amevive
Xolair
Bexxar
Raptiva
Zevalin
Elitek
Humira
Rebif
06
07
Lucentis
Myozyme
Elaprase
Vectibix
Abatacept
Galsulfase
Avastin
Erbitux
Tysabri
What is the GNE experience
• 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 have we learned
• Don’t make process changes between Phase III and
approval
• Platforms have limitations
– Each Mab has unique challenges
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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
Challenges
• Evolution of analytical methods
– Increased sensitivity
– New forms
• Higher order structure
• Linkage to safety & efficacy
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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
Acknowledgements
Wassim Nashabeh
Kathy Francissen
Reed Harris
Amita Joshi
Ron Taticek
Ray Arnold
Loel McPhee