CMC Aspects of Various Clinical Phases of Study First Dose in Humans to Phase IV Clinical Supply Req

1
CMC Aspects of Various Clinical Phases of Study-
First Dose in Humans to Phase IV Clinical Supply
Requirements

• Robert Jerzewski
• Bristol-Myers Squibb Co.
• August 17, 2004

2
Outline

• Introduction
• Phase 1 Requirements
• Phase 2 Requirements
• Phase 3/4 Requirements
• Summary

3
Introduction

• CFR 312.23(7) CMC Information
• In each phase of the investigation sufficient
  information is required to be submitted to assure
  the proper identification, quality, purity and
  strength of the investigation drug

4
Introduction

• EC Annex 13, July 2003
• manufacturing formulae and processing and
  packaging instructions should be a comprehensive
  as possible given the current state of knowledge

5
Introduction

• Regulatory Authorities require CMC information to
  insure the safety and purity of investigational
  drugs, but
• recognize that CMC information and knowledge
  evolves along with clinical experience
• Recognize that most drugs dont make it past
  phase I

6
Introduction

• Regulatory Authorities require CMC information to
  insure the safety and purity of investigational
  drugs, but
• Emphasis on phase 1 is safety
• Emphasis on phase 2/3/4 is on clinical studies
  yielding reliable and interpretable data

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Phase 1 CMC Requirements Drug Substance

• A brief description of drug substance and some
  evidence to support its proposed structure (such
  as NMR and MS)
• name and address of the manufacturer(s)
• a brief description of manufacturing process
• flow diagram
• list of reagents, solvents and catalysts used

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Phase 1 CMC RequirementsDrug Substance

• Analytical methods
• brief description of methods
• proposed limits supported by simple analytical
  data
• certificate of analysis
• validation data not needed for most cases

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Phase 1 CMC RequirementsDrug Substance

• Stability
• brief description of study test methods
• preliminary tabular data on representative lot
• not needed full protocol or detailed stability
  data

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Phase 1 CMC RequirementsDrug Product

• Component list (reference compendia)
• quantitative composition including variations
• name and address of manufacturer
• brief description of manufacturing/packaging
  procedures (flow diagrams suggested)

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Phase 1 CMC RequirementsDrug Product

• Analytical methods and specifications
• brief description of methods/specifications
• certificate of analysis of a clinical batch
• validation data not required for most cases

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Phase 1 CMC RequirementsDrug Product

• Stability
• brief description of study test methods
• preliminary tabular data on representative lot
• not needed full protocol or detailed stability
  data

13
Phase 2 CMC Requirements

• FDA Guidance for Industry INDs for Phase 2 and
  Phase 3 Studies Chemistry, Manufacturing and
  Controls Information (May 2003)
• sponsor to access changes that directly/indirectly
  affect product safety
• update IND before phase 2/3 (safety)
• update IND during phase 2/3 (corroborating data)

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Phase 2 CMC Requirements

• CMC modifications that can affect safety
• change in synthetic pathway/impurity profile
• change in material source
• method of sterilization
• composition of drug product

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Phase 2 CMC Requirements Drug Substance

• Manufacturing Process/Controls
• update flow diagram as applicable with
• sterochemical information of starting materials
  and intermediates
• identify significant side products
• identify unique or critical steps in
  manufacturing process

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Phase 2 CMC Requirements Drug Substance

• Control of Materials
• structures, source, methods and test results
  should be available upon request
• list new reagents, solvents and auxiliary
  materials
• provide information on controls for critical
  steps/intermediates

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Phase 2 CMC Requirements Drug Substance

• Characterization
• additional evidence to support chemical structure
  (e.g. IR, UV)
• Data on particle size and other relevant physical
  properties

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Phase 2 CMC Requirements Drug Substance

• Control of Drug Substance
• specification sheet
• identify critical quality attributes
• update analytical methods with validation
  available on request
• identification and qualification of new
  impurities

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Phase 2 CMC Requirements Drug Substance

• Reference Standards
• Additional characterization of working standard
  (reference standard) beyond batch release tests
• Container Closure System
• brief description of system and subsequent
  changes

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Phase 2 CMC Requirements Drug Substance

• Stability
• description of stability program to support phase
  2 including analytical methods, acceptance
  criteria, and study protocol
• update of stability from phase 1
• development of stability indicating assays

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Phase 2 CMC Requirements Drug Products

• Description and Composition of Drug Product(s)
• list any changes from phase 1
• Manufacture of Drug Product(s)
• list any changes in manufacturers
• provide a representative batch formula
• update description of manufacturing process
• flow diagram
• brief step by step description of manufacturing
  process (focus on unit operation not granular
  details

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Phase 2 CMC Requirements Drug Products

• Control of Excipients (noncompendial)
• provide specification sheet
• a complete description of analytical methods
• a brief description of manufacture and control
  with an appropriate reference (e.g. DMF)
• novel excipients require information equivalent
  to that submitted for new drug substances

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Phase 2 CMC Requirements Drug Products

• Control of Drug Product
• update specifications with physicochemical and
  microbiological tests (added or deleted)
• certificate of analysis of representative batch
  with updated specifications
• update of analytical methods
• complete description/validation data for
  analytical procedures not from an FDC-recognized
  standard reference

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Phase 2 CMC Requirements Drug Products

• Container Closure System
• updates and new systems
• Stability
• description of stability program to support phase
  2 clinical studies
• list of tests, acceptance criteria, and testing
  protocol
• update stability data from phase I study
• provide stability data for representative batches
  used in phase 2 in annual reports

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Phase 3/4 CMC Requirements Drug Substance

• Focus on CMC safety information to support phase
  3 studies
• Scale and knowledge have increased significantly
  since phase 1
• phase 1 kg of DS/thousands of units
• phase 2 10s of kgs/10s of thousands of units
• phase 3 100s of kgs/millions of units
• Opportunity to have End-of-Phase-2 Meeting with
  FDA

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Phase 3/4 CMC Requirements Drug Substance

• Update of General Information (not provided
  previously)
• solubility, partition coefficient, pKa, pI
• crystal properties and morphology
• steriochemistry
• Manufacturers
• list of all firms including contract
  facilities

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Phase 3/4 CMC Requirements Drug Substance

• Description of Manufacturing Process
• update flow diagram and process description with
  relevant information
• batch size (range)
• ratios of reagents, solvents and auxiliary
  materials
• process controls and brief analytical procedures
  and general operating conditions (time, temp,
  etc.)
• controls of critical steps and intermediates
• control of crystalline forms
• literatures references
• reprocess procedures

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Phase 3 / 4 CMC Requirements Drug Substance

• Control of Materials
• update information from phase 1/2
• provide procedures and acceptance criteria for
  starting materials
• table of reagents, solvents and catalysts
  including
• reference to quality standard
• specific identity test

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Phase 3/4 CMC Requirements Drug Substance

• Characterization
• provide additional information to support
  elucidation and characterization
• additional spectra (IR, UV)
• single crystal X-ray diffraction data

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Phase 3/4 CMC Requirements Drug Substance

• Control of Drug Substance
• update test procedures and acceptance criteria
• test results for representative clinical
  materials
• new impurities should be identified and qualified
  as appropriate suitable limits should be
  established
• microbial limits for non-sterile products as
  appropriate
• update information on primary reference standard
  (synthesis, purification, test procedures,
  etc.)

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Phase 3/4 CMC Requirements Drug Substance

• Stability
• Update with data from phase 2
• provide data on special stress studies (oxygen,
  light, temp and humidity)
• protocol for NDA stability study

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Phase 3/4 CMC Requirements Drug Product

• Manufacturer
• update listing of all firms associated with
  manufacturing, packaging/labeling and testing
• Batch Formula
• update any new compositions

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Phase 3/4 CMC Requirements Drug Product

• Description of Manufacturing Process/Controls
• update flow diagram and description of
  manufacturing process
• provide brief description of packaging/labeling
  process for clinical supplies

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Phase 3/4 CMC Requirements Drug Product

• Description of Manufacturing Process/Controls
• provide information on reprocessing with controls
• update on changes in the drug product
  sterilization process
• Control of Excipients
• provide update if necessary

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Phase 3/4 CMC Requirements Drug Product

• Control of Drug Product
• Summary table of test results and data (e.g.
  chromatograms) from batch release of
  representative clinical trial material
• Summary table of test results and data (e.g.
  chromatograms) from batch release of
  representative clinical trial material
• Data on particle size and/or polymorphic form of
  drug substance, when appropriate

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Phase 3/4 CMC Requirements Drug Product

• Control of Drug Product
• Updates on the degradation profile of drug
  product
• Identify, qualify and report new degradants as
  appropriate
• Results of USP antimicrobial preservative
  effectiveness test
• Dissolution test method development studies for
  to-be-marketed formulation (obtain concurrence
  with FDA before primary stability studies are
  initiated)

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Phase 3/4 CMC Requirements Drug Product

• Container Closure System
• update with information for phase 3 container
  closure system
• package component compliance statements and/or
  authorization letter from the DMF holder
• additional information for atypical delivery
  systems (MDIs, disposable injection devices)

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Phase 3/4 CMC Requirements Drug Product

• Stability
• Changes in stability program for phase 2
• Update data from phase 2 stability program
• Stability protocol for formal stability studies
• One-time stress testing to asses physical (e.g.,
  precipitation, aggregation, etc.) and/or chemical
  (e.g., interaction of components) characteristics
  of the drug product

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Summary

• Regulatory Authorities recognize that CMC
  information and knowledge evolves over the
  development phases
• Emphasis on phase 1 CMC information is to assure
  patient safety
• Emphasis on phase 2/3/4 CMC information is to
  assure patient safety and clinical study quality