Home >  Comparability for Biotech Products: An industry perspective on past & future aspects Mary B. Sliwkowski, Ph.D. VP, Regulatory CMC &

Comparability for Biotech Products: An industry perspective on past & future aspects Mary B. Sliwkowski, Ph.D. VP, Regulatory CMC &


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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Disclaimer 

    The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.

 

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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

  • Insulin
  • Growth  hormone
 
 

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

  • 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


  • 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
 
 

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 

  • Rodent PK
  • Primate PK/PD
 

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 


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