Development Lifecycle and Specifications

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Development Lifecycle and Specifications
From IND to Licensure
The content reflects the views of the speaker and
do not necessarily reflect those of the FDA
Steven Kozlowski Division of Monoclonal
Antibodies OBP/OPS/CDER
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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Regulatory Basis for IND Specifications
21 CFR 312.23 (a)(7)(iv)

• (a) the acceptable limits and analytical methods
  used to assure the identity, strength, quality,
  and purity of the drug substance
• (b) same for drug product

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Regulatory Basis for IND Specifications
Content and Format of INDsfor Phase 1 Studies
F.2.d Drug Substance

• Proposed acceptable limits supported by simple
  analytical data, of the clinical trials material
  should be provided. (C of A suggested)
• Validation data and established specifications
  ordinarily need not be submitted at the initial
  stage of drug development.

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Regulatory Basis for IND Specifications
Content and Format of INDsfor Phase 1 Studies
of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-derived Products
F.2.d Drug Substance

• However, for some well characterized, therapeutic
  biotechnology-derived products, preliminary
  specifications and additional validation data may
  be needed in certain circumstances to ensure
  safety in Phase 1.

F.3.e Drug Product
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Limits vs Specifications

• Specification an acceptance criterion that
  product must meet and is registered with the FDA
  and other regulatory agencies.
• Change must be approved by FDA
• Limit an acceptance criterion that product
  should meet and is registered with the FDA and
  other regulatory agencies
• Product can be used without prior FDA approval if
  appropriate investigation is made

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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Types of Specifications
Safety (narrow to undetectable)

• General
• Quantity
• Identity
• Purity
• Potency

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Safety Specifications

• Purity
• adventitious agents
• other toxic contaminants
• known toxic product variants
• Potency/Quantity
• toxin-linked or radio-labeled
• narrow therapeutic index
• Mixed Safety/Consistency
• endotoxin
• safety lt5 EU/kg/dose
• lower levels may be specified based on experience

• Potency/Quantity
• meaningful dose escalation
• futility

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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Evolution of Specifications
Acceptance criteria

• Limited lots
• Narrow with increased manufacturing experience
• Safety risks early

• Avoid meaningless criteria
• Widen with increased manufacturing experience
• Safety risks later

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IND Specifications Through Development
21 CFR 312.23 (a)(7)(iii)

• As drug development proceedsthe sponsor should
  submitamendmentson the
• Chemistry
• manufacturing,
• and control processes
• with information appropriate to the expanded
  scope of the investigation.

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IND Specifications Through Development
Guidance for Industry IND Meetings for Human
Drugs and Biologics EOP2 Biotech

• Adequacy of physicochemical and biological
  characterization (e.g., peptide map, amino acid
  sequence, disulfide linkages, higher order
  structure, glycosylation sites and structures,
  other post-translational modifications, and plans
  for completion, if still incomplete)
• Bioassay (e.g., appropriateness of method,
  specificity, precision)
• Removal of product- and process-related
  impurities (e.g., misfolded proteins, aggregates,
  host cell proteins, nucleic acid)
• Bioactivity of product-related substances and
  product-related impurities relative to desired
  product

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Specification Characterization Experience
ICH Q6B SPECIFICATIONS TEST PROCEDURES AND
ACCEPTANCE CRITERIA FOR BIOTECHNOLOGICAL
/BIOLOGICAL PRODUCTS

• Characterization of a biotechnological or
  biological productis necessary to allow relevant
  specifications to be established.
• Acceptance criteria should be established and
  justified based on data obtained from lots used
  in
• preclinical and/or clinical studies
• demonstration of manufacturing consistency
• stability studies
• relevant development data.
• This document does notapply to the regulation of
  preclinical and/or clinical research material.

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Product Life-cycle
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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Hypothetical Example

• Phase II and pivotal studies tx for 6 mo
• 1.3 aggregates by SEC
• 0.3 aggregates first clinical lot next lot
  0.51

• Antibody developed for chronic use
• Pre-clinical lot for tox studies
• Initial pilot scale lots made for phase I II
  studies

Sponsor initially has no specifications for
aggregates agrees to set spec at gt90 monomer
Same spec set for stability
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Stability Data
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Aggregate Safety Data

• Patients received 3X and 9X the planned dosing (3
  per group)
• 0.3 aggregates by SEC upon release used between
  3 and 6 months (0.5-1)
• Equivalent to 4.5-9 aggregates in planned dosing

• Tox study in animal model with relevant antigen
  50X planned dosing
• 1.3 aggregates
• Equivalent to 65 aggregates in planned dosing

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Utility Safety/Clinical Data

• Tracking lot ages used in studies
• Immunogenicity risk may not be revealed in
  pre-clinical models and small clinical studies
• In high dose studies ratio of variant to product
  monomer may be as important as variant absolute
  levels
• PK/PD changes
• Specific mechanistic issues

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Mechanistic Issues
Antibody is a receptor antagonist

• Purified aggregates bind at 50 of reference
• Purified aggregates act as a receptor agonist
• High ratio of monomer to aggregate may block
  aggregate signaling

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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Mab Acceptance Ranges/Limits
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Common MAb Release Specs
BioProcess International Vol 2 (2) 2004
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Overview

• Regulatory basis for IND specifications/limits
• Types of specifications
• Evolution of specifications through development
• Hypothetical example
• Monoclonal Ab specifications
• Specification endgame/ Summary

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Selection of Acceptance Criteria

• Limited experience even at licensure
• Multiplicity of assays favor failures
• Many strategies have been proposed
• 3 SD
• Tolerance intervals
• Clinical lot ranges
• Importance of measured parameter
• Stability criteria

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Specification Poker

• Know when to hold them
• Know when to change them
• Know when you need another assay

• DONT BLUFF
• SHOW ALL YOUR CARDS

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Summary

• Initial IND submissions need specifications for
  safety related issues
• Product characterization and stability combined
  with clinical and preclinical data are used to
  develop and refine specifications
• Discussion of the strategies used for this
  refinement with the agency can facilitate
  appropriate specifications at licensure

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Acknowledgments

• Patrick Swann, Ph.D.
• Barry Cherney, Ph.D