ACPS Manufacturing Subcommittee Report

1
ACPS Manufacturing Subcommittee Report

• October 19, 2004
• Judy P. Boehlert, Ph.D.
• Chair

2
Meeting Dates and Topics

• July 20, 2004
• Quality by Design Topic Updates
• Introduction to Bayesian Approaches
• Research and Training Needs The
  Industrialization Dimension of the Critical Path
  Initiative
• Manufacturing Science and Quality by Design as a
  Basis for Risk-based CMC Review
• Risk-based CMC Review Paradigm

3
Meeting Dates and Topics

• July 21, 2004
• Introduction to Pharmaceutical Industry Practices
  Research Study
• Pilot Model for Prioritizing Selection of
  Manufacturing Sites for GMP Inspection
• cGMPs for the Production of Phase I INDs
• Applying Manufacturing Science and Knowledge
  Regulatory Horizons

4
Quality by Design Topic Updates

• ICH Q8
• Guidance on pharmaceutical development section of
  the CTD
• Will describe baseline expectations and optional
  information
• Requires FDA and industry to think differently
• Process understanding and predictive ability
  can lead to regulatory flexibility
• Framework for continuous improvement
• Step 2 expected November 2004

5
Quality by Design Topic Updates

• ICH Q9 - Quality Risk Management
• Risk identification should link back to
  potential risk to the patient
• Risk assessment What can go wrong? What is the
  likelihood? What are the consequences?
• Risk control Options for mitigating, reducing
  and controlling risks
• Risk communication Between decision makers and
  other shareholders
• Step 2 November, 2004?

6
Quality by Design Topic Updates

• Quality Systems needed to realize potential of Q8
  and Q9 (ICH Q10?)
• Monitor and evaluate processes with feedback
  loops in a manner to identify trends and
  demonstrate control or the need for action
• Manage and rectify undesirable occurrences
• Handle improvements
• Manage/implement/monitor change
• Q10 on hold

7
Quality by Design Topics

• ASTM E55 Committee
• Development of standards for PAT
• Consensus standards with input from industry,
  academia and regulators
• Established process with an umbrella set of rules
• ASTM recognized worldwide
• Three functional committees
• Management (Sub 1)
• Implementation and practices (Sub 2)
• Terminology (Sub 91)
• Avoid duplication with other initiatives?

8
Introduction to Bayesian Approaches

• Reliability for the Analysis of Risk
• Reliability the quantification of uncertainty
• Utility costs and rewards that occur as a
  consequence of any chosen decision
• Risk Analysis process assessing reliabilities
  and utilities including identification of
  consequences
• Scales for measuring uncertainty, e.g.,
  probability

9
Introduction to Bayesian Approaches

• When the quantification of uncertainty is solely
  based on probability and its calculus, the
  inference is said to be Bayesian.
• Discussion of use of Bayesian approaches for ICH
  Q8, Q9, Q10 and use of prior information

10
Industrialization Dimension - Critical Path
Initiative

• Examining innovational stagnation
• Critical path inadequate attention in areas of
  new or more efficient methodologies and
  development research
• Industrialization goes from physical design of
  prototype up to commercial mass production
• Education and research infrastructure needs
  improvement

11
Industrialization Dimension - Critical Path
Initiative

• FDA strong interest in computational
  methodologies to support CMC
• Putting together a chemometrics group
• New FDA research program focusing on
  industrialization dimension
• Training needs, e.g., pharmaceutical inspectorate
  training program

12
Manufacturing Science and Quality by Design

• Basis for risk-based CMC review
• Companies share product/process understanding
  with regulators
• Base specifications on mechanistic understanding
• Continuous improvement
• Real time quality assurance

13
Science Perspective on Manufacturing

• Define current and the desired state and steps to
  go from here to there
• Define terms manufacturing science,
  manufacturing system and manufacturing capability
• Real case studies will help
• Testing is mostly non-value added quality be
  design is the desired state

14
Risk-Based CMC Review - ONDC

• Provide regulatory relief by incorporating
  science based risk assessment
• More product/process knowledge shared by industry
• More efficient science based inspections
• Focus resources on critical issues
• Specifications based on risk based assessment

15
Risk-Based CMC Review - ONDC

• Quality Assessment rather than a Chemistry Review
• Conducted by interdisciplinary scientists
• Risk-based assessment
• Focus on critical quality attributes and their
  relevance to safety and efficacy
• Reliance on knowledge provided by applicants
• Comparability Protocols

16
Risk-Based CMC Review - ONDC

• Role of process capability in setting
  specifications will need to be addressed there
  may be no clinical relevance
• Knowledge base at time of submission
• Specifications should not be used as a tool to
  control the manufacturing process
• Expand the Quality Overall Summary in the future

17
Risk-Based CMC Review - OGD

• Extent of product knowledge is key
• Risk-based decisions based on supportive data
• Voluntary!
• Supplement need based on knowledge of the risk of
  the change
• Clear rationale for selection of specifications

18
Risk-Based CMC Review - OGD

• Identify critical parameters for product
  manufacturing and stability
• Train FDA staff and regulated industry
• Yields greater flexibility in optimizing the
  process
• Lessened supplement burden
• Real examples would be an asset

19
Risk-Based CMC Review - OGD

• Generic industry focus is on a bioequivalent
  product
• Often patent issues to design around
• Workload in OGD a significant issue
• Provide advice to industry on improving quality
  of DMFs

20
Risk-Based CMC Review Asking the Right Questions

• Desired State
• Include needed data in filing
• Process and product design
• Identify critical attributes
• Identify process critical control points
• Analyze data to produce meaningful summaries and
  scientific rationales
• Reviewers assess adequacy of submission by asking
  the right questions

21
Additional Committee Comments Day 1

• ICH and ASTM activities appear to be synergistic
  but ICH needs to be aware of ASTM focus
• Is FDA getting ahead of ICH Q8, 9,10?
• Need concrete examples
• Need to clearly demarcate minimum and optional
  information necessary
• Optional information comes in degrees as more
  is learned

22
Additional Committee Comments Day 1

• Need to avoid implying two different quality
  approaches
• Will need training programs and case studies
  form a working group under the Manufacturing
  Subcommittee?
• Need to find better terms than minimal and
  optional
• Focus on process and then the tools

23
FDA Research Project

• Identify attributes that impact inspection
  outcomes
• Compile and link FDA databases
• Look at variables for product/process, facility,
  firm and FDA
• Status collecting data CDER completed, CBER
  ongoing
• Georgetown University Washington University

24
Pharmaceutical Manufacturing Research Study

• Focus - Are cGMP violations related to
  managerial, organizational and technical
  practices
• Interview manufacturers
• Internet based questionnaire in Fall 2003
• U.S. and EU Manufacturers
• Data collection near completion
• Georgetown University Washington University

25
Pharmaceutical Industry Practice Comments

• Concern with just looking at numbers of
  deviations or field alerts, particularly, when
  investigation may have shown little concern
• Also, very detailed SOPs can lead to more
  deviations
• India and China not included in API manufacturers

26
Risk Ranking and Filtering

• Risk ranking series of decisions to start to
  rank within a class or across classes
• Tools may be customized for each application
• Filters may be used to reflect resource
  limitations and/or program goals

27
Pilot Risk-Ranking Model to Prioritize Sites for
GMP Inspections

• Using ICH Q9 concepts of defining risk
• Site Risk Potential (SRP) includes product,
  process and facility components
• Look at probability and severity components that
  make up harm
• Looking at other risk ranking models, e.g., EPA
  and USDA
• Using the CDER Recall database

28
Pilot Risk-Ranking Model to Prioritize Sites for
GMP Inspections

• Comments
• Focusing on volume at a site may be misleading
  the risk could actually be lower
• Need to also consider risk of the loss of
  availability
• Consider hard to fabricate products or products
  with difficulty controlling uniformity
• Investigator consistency will be an issue
• Look at high personnel turnover

29
Pilot Risk-Ranking Model to Prioritize Sites for
GMP Inspections

• Will sites know how they are ranked?
• Self-inspections are a critical part of the
  Quality System but the value to the company is
  diminished if information is available to FDA

30
GMPs for the Production of Phase I Drugs

• CMC review to ensure the identity, strength,
  quality and purity of the investigational new
  drugs as they relate to safety
• Draft guidance for GMPs in process (CDER, CBER,
  ORA)
• Risk-based approach
• No regular inspection program looked at on a
  for cause basis

31
Process Understanding and PAT

• Update on the PAT initiative
• Guidance recently finalized
• Expand to biotech products
• Continue training of FDA staff

32
Comparability Protocol

• Update on guidances
• Goal is to provide regulatory relief for
  postapproval changes
• A detailed plan describing a proposed change with
  tests and studies to be performed, analytical
  procedures to be used and acceptance criteria to
  demonstrate lack of adverse effect on product
• Many comments received from the public

33
Comparability Protocol

• Committee Comments
• Single use protocol has limited utility more
  utility for repetitive changes
• Specificity of the protocol may limit repetitive
  use
• How much specificity is needed?
• For a well defined protocol, an AR should be
  sufficient

34
General Conclusions

• General principles are good but case studies are
  needed to facilitate understanding
• Case studies should cover all industries, e.g.,
  dosage form, API, Pioneer and Generic
• Committee expressed concern on what appears to be
  understaffing in OGD

35
General Conclusions

• Failure Mode Effect Analysis (FEMA) can be
  linked with risk based decision making wherein
  the results feed into decision trees
• Training and education of both regulators and the
  industry in the new approaches is key
• Historical inconsistency in regulator findings
  may limit the utility of surveys