Ajaz S. Hussain, Ph.D.

1
Update on Pharmaceutical Manufacturing Initiative

• Ajaz S. Hussain, Ph.D.
• Deputy Director
• Office of Pharmaceutical Science, CDER, FDA

2
Outline

• Pharmaceutical Manufacturing Initiatives
• Process Analytical Technology Initiative
• CGMP for the 21st Century Initiative
• PAT Progress report and Strategy for Moving
  Forward
• CGMPs for the 21st Century
• Defining the desired state
• Questions for the Science Board

3
PAT Initiative

• FDA Science Board Meetings (11/01, 4/02)
• Emerging Science Issues in Pharmaceutical
  Manufacturing
• Current state of Pharmaceutical Manufacturing
• G. K. Raju (M.I.T) and Doug Dean
  (PriceWaterHouseCoopers)
• Opportunities for improvements
• Norman Winskill and Steve Hammond (Pfizer)
• New Technology - Dont Use or Dont Tell
  approach
• Ray Scherzer (CAMP/GlaxoSmithKline)
• Challenge to Phrama Industry - Quality By Design
• Science Board support for FDAs proposal to
  facilitate innovation

http//www.fda.gov/cder/OPS/PAT.htmscienceboard
4
PAT Progress

• Advisory Committee for Pharmaceutical Science
  (PAT Subcommittee) deliberations
• Definitions, benefits, and scope
• Perceive/real regulatory hurdles
• Internal (with-in company) hurdles
• Need for across discipline communication
• PharmacyChemistryEngineering Pharmaceutical
  Engineering
• Approaches for removing these hurdles
• Case studies
• General approaches for validation
• PAT Training curriculum for FDA staff

5
PAT Teams ORA, CDER CVM
PAT Steering Committee Doug Ellsworth,
ORA/FDA Dennis Bensley, CVM/FDA Mike Olson,
ORA/FDA Joe Famulare, CDER/FDA Yuan-yuan Chiu,
CDER/FDA Frank Holcomb, CDER/FDA Moheb Nasr,
CDER/FDA Ajaz Hussain Chair, CDER/FDA
PAT Review - Inspection Team Investigators Rober
t Coleman (ORA/ATL-DO) Rebecca Rodriguez
(ORA/SJN-DO) Erin McCaffery (ORA/NWJ-DO) George
Pyramides (PHI-DO) Compliance Officers Albinus
DSa (CDER) Mike Gavini (CDER) William Bargo
(CVM) Reviewers Norman Schmuff (CDER) Lorenzo
Rocca (CDER) Vibhakar Shah (CDER) Rosario
DCosta (CDER) Raafat Fahmy (CVM)
PAT Policy Development Team Raj Uppoor,
OPS/CDER Chris Watts, OPS/CDER Huiquan Wu,
OPS/CDER (Ali Afnan, OPS/CDER)
PAT Training Coordinators John Simmons, Karen
Bernard and Kathy Jordan
6
Why Process Analytical Technologies?

• PAT provides an opportunity to move from the
  current testing to document quality paradigm to
  a Continuous Quality Assurance paradigm that
  can improve our ability to ensure quality was
  built-in or was by design - ultimate
  realization of the true spirit of cGMP!
• Greater insight and understating of processes
• At/On/In-line measurement of performance
  attributes
• Real-time or rapid feedback controls (focus on
  prevention)
• Potential for significant reduction in production
  and development cycle time
• Minimize risks of poor process quality and reduce
  (regulatory) concerns

7
PAT Conceptual Framework for Regulatory Policy
Development
8
Regulatory Framework

• PAT tools not a requirement
• Research exemption
• Continuous improvement without the fear of being
  considered non-compliant
• Regulatory support and flexibility during
  development implementation
• Eliminate the fear of delayed approval
• Dispute avoidance/resolution
• Science Risk based regulatory approach
• Low risk categorization based on a higher level
  of process understanding

9
Strategy for Moving Forward

• Scientific Workshops
• Several FDA co-sponsored and other workshops
  conducted (US and Europe)
• Scientific discussion and debate
• across disciplines (pharmacy, chemistry, chemical
  engineering)
• organizational units (development, manufacturing,
  quality control, and regulatory departments)
• General guidance on PAT to be released
• Training workshop
• Bring together different Associations
  (disciplines)

10
Strategy for Moving Forward

• Champions to drive this initiative towards a
  shared vision or desired state
• Industry Pfizer, GSK, BMS, Aventis, Lilly,
  Novartis,...
• Academia MIT, Purdue, Washington, Tennessee,
  Michigan, Rutgers, Maryland, Minnesota,
  Connecticut, Puerto Rico, Duquesne.., London,
  Bradford, Basel, (planned - Gifu and other
  universities in Japan)
• PAT introduced in Pharmaceutical Engineering
  programs at Purdue, Michigan and Rutgers
• (Instrument vendors - moving towards a
  association to address common issues)

11
Strategy Moving forward

• Improving the FDA knowledge base for technical
  policy development
• Several experts recruited
• Intramural research refocused to address
  technical needs and for in-house training
• Significant increase in peer reviewed
  contributions
• Learn from other industries (e.g., link with
  ASTM)
• CRADA with Pfizer developed, awaiting final FDA
  approval (focus on chemical imaging)
• Collaborate with NSF (Center for Pharmaceutical
  Processing Research)

12
Strategy Moving forward

• PAT Initiative a part of the broader cGMP
  Initiative for the 21st Century (announced 12
  August 2002)
• An example of science and risk-based systems
  approach to product quality regulations

13
A Drug Quality System for the 21st Century Goals

• ..it is time to step back and evaluate the
  currency of these programs so that
• the most up-to-date concepts of risk management
  and quality systems approaches are incorporated
  while continuing to ensure product quality
• the latest scientific advances in pharmaceutical
  manufacturing and technology are encouraged
• management of the program encourages innovation
  in the pharmaceutical manufacturing sector

http//www.fda.gov/oc/guidance/gmp.html
14
A Drug Quality System for the 21st Century Goals

• the submission review program and the inspection
  program operate in a coordinated and synergistic
  manner
• regulations and manufacturing standards are
  applied consistently
• FDA resources are used most effectively and
  efficiently to address the most significant
  health risks.

http//www.fda.gov/oc/guidance/gmp.html
15
Scope and Timeline

• Veterinary drugs and human drugs, including human
  biological drug products
• Organizations
• ORA, OC, CBER, CDER, CVM
• CFSAN and CDRH for issues that impact these
  centers (e.g., electronic records,..)
• 14 Task groups (13 groups active)
• Chair, Dr. Janet Woodcock
• 2 years (immediate - 2/03, intermediate - 8/03,
  and long term projects)

16
Current Progress

• Issued a draft Guidance on 21 CFR Part 11
  implementation
• The draft guidance clarifies the scope and
  application of the regulation and provides for
  enforcement discretion in certain areas that have
  been problematic
• Issued a draft guidance entitled "Comparability
  Protocols-Chemistry, Manufacturing and Controls
  Information."
• Encouraging innovation within the existing
  framework
• Under appropriate circumstances, use of a
  comparability protocol can allow manufacturers to
  implement changes to their processes without
  submission of a prior approval supplement to the
  FDA.

17
Current Progress

• Center review of drug cGMP warning letters
• Technical dispute resolution process for cGMP
  disputes
• Emphasizing a risk-based approach to the work
  planning process
• Including product specialists on inspection teams
• Improving the operations of Team Biologics
• Enhancing expertise in pharmaceutical
  technologies
• Pharmaceutical Inspectorate
• Quality management system
• International collaboration
• Holding scientific workshops with stakeholders

18
Defining the desired state

• As we move forward with this initiative it is
  essential to define what we wish to achieve
• What should be the desired state of
  pharmaceutical manufacturing and associated
  regulatory policies in the 21st Century?
• A shared vision to guide further evolution of
  this initiative
• Enroll all stakeholders in this journey to better
  serve the patients
• Highlight, for the academic and research
  community, the scientific needs in pharmaceutical
  engineering

19
A Drug Quality System for the 21st Century

• Pharmaceutical 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.
• This initiative is designed to do just that
  through an integrated systems approach to product
  quality regulation founded on sound science and
  engineering principles for assessing and
  mitigating risks of poor product and process
  quality in the context of the intended use of
  pharmaceutical products.

http//www.fda.gov/cder/gmp/21stcenturysummary.htm
20
Desired State
http//www.fda.gov/cder/gmp/21stcenturysummary.htm

• 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

21
Desired State
http//www.fda.gov/cder/gmp/21stcenturysummary.htm

• 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

22
Question for the Science Board

• Please recommend
• how we may improve our articulation of the
  desired state
• considerations for communicating the desired
  state with stakeholders
• public, health care providers, academia and
  industry
• additional considerations for aligning our
  activities to ensure efficient progress