1. Quality System

2. PAT Initiative
July 2001
CGMP for 21st
Century Initiative
Medical Innovation
Critical Path
Initiative
“Desired State”

3. policies and standards
Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21st Century
Strong
Public Health
Protection
Integrated quality
systems orientation
Science-based
policies and standards
Risk-based orientation
International
cooperation
Time

4. Directional Vectors
Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science
Encourage new technological advances
Encourage risk-based approaches that focus both industry and Agency attention on critical areas
Facilitate modern quality management techniques, including implementation of quality systems
Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities

5. Covering the Space Defined by the Directional Vectors
Preapproval Inspection Compliance Program
Risk
Dispute Resolution Process
Pharmaceutical Inspectorate
Product Specialists on Inspection Process
Systems/Integration
Guidance on CFR Part 11
Aseptic Processing
Comparability Protocol
ICH P2, QbD, & Risk
PAT
Science

6. The Scientific Opportunity
Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based.
Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes.

7. The Risk Mitigation and Communication Opportunity
Intuitive/Subjective to Quantitative
HCCP
FMEA
Quality by Design
“Reliability is a design engineering discipline which applies scientific knowledge to assure a product will perform its intended function for the required duration within a given environment. This includes designing in the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best described as product performance over time.”

8. The Quality Systems Opportunity A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad?
Sampling Plans (‘50s)
Zero-Defect Movement (‘60s)
ISO-9000 (‘80s)
QS-9000
Malcolm Baldrige Award
European Quality Award
Total Quality Management
Six Sigma
The Ultimate Six Sigma - “The Big Q”
cGMPs
Pharmaceutical
Quality
System
for the 21st
Century
K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN

9. A Two Year Journey? What is the Destination?
“Vision I can see clearly now”
The “Desired State”

10. Desired State
Product quality and performance achieved and assured by design of effective and efficient manufacturing processes
Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
Continuous "real time" assurance of quality

11. Desired State
Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability
Risk based regulatory scrutiny relate to the:
level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and
the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

12. Meeting Objectives
Seek input and advise on charting the most efficient path towards the “desired state”
Review assessment of Chemistry, Manufacturing, and Controls (CMC) sections of submissions
Risk based cGMP Inspections: Selection of Manufacturing sites for inspections

13. What do we wish to accomplish with ICH Q8
Ensure Q8 facilitates movement towards the “desired state” we have articulated
This will
Help us better understand the proposed product and process design and its relation to the intended use
improve process of establishing regulatory specifications
Improve our ability to identify and understand critical product and process factors
improve our understanding and confidence in risk mitigation strategies
Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement
Improve communication and systems thinking
More efficient review and inspection process
Be a “win win win” for public health, regulators and industry

14. ICH Q8: Integrating QbD and Risk Mitigation Dimensions
Illustrative Examples of points to consider
Development Objectives
Intended Use
Route of administration
Patient population
…..
Product Design
Design Specifications
(Customer requirements)
Manufacturing Process
and its Control
Regulatory
Specs.
Risks to Quality
Risk of incorrect identity
Poor product & process
Changes in clinical trial product
(Bridging studies)
Inadequate Design Specifications
(e.g., TDS adhesive attribute)
Critical to quality and performance?
Risk of unqualified impurities
Risk of poor bioavailability
Risk of incorrect expiry date
Risk of inadequate controls
Risks After Approval
[Risk of SUPAC,..]
[Risk of unrepresentative test samples]
[Risk of Inadequate Facility and QS]
Tests & Controls -Risk Mitigation
ICH Q9

15. Continuous Improvement – Emerging ICH Q8 “Design Space” Concept
Multi-dimensional space defined by critical vectors of product quality and performance
Examples of critical vectors
Robust manufacturing process – consistent, reproducible delivery of product meeting its specifications
Manufacturing options
Stability (shelf-life) and
Bioavailability

16. Risk cGMP ICH Q8 regulatory oversight Company’s Quality system Process
Understanding
Post
approval
change
CMC
regulatory
oversight
ICH Q8&9

17. Risk (P/R) CMC regulatory oversight Company’s Quality system cGMP
Process
Understanding
Risk
(P/R)
CMC
regulatory
oversight
Company’s
Quality system
cGMP
Post
approval
change
ICH Q8 + Q9
PAC to
Continuous
Improvement
Process
Understanding
Risk
CMC
regulatory
oversight
Company’s
Quality system
cGMP
Continuous
Improvement
Process
Understanding
Risk
CMC
regulatory
oversight
Company’s
Quality system
cGMP
Proposed
ICH Q 10

18. Moving towards the “Desired State” Day 1
Update on Current Efforts
ICH Q8, Q9 and proposed Q10
ASTM
Awareness topic: Filling the gaps – Research planning
Bayesian approaches in CMC?
Critical Path Initiative
Implementing the concepts developed in ONDC and OGD
Manufacturing Science
Quality by Design

19. Moving towards the “Desired State” Day 2
Risk based CGMP Inspections
Update on research study on pharmaceutical industry practices
Pilot model for prioritizing selection of manufacturing sites for inspections
CGMPs for the Production of Phase I INDs
Efforts on facilitating continuous improvement through reduction in the need for “Prior Approval Supplements”
PAT Example
Comparability protocol concept