1. Requirements for the Quality of API from FDA Perspective
Brenda Uratani, Ph.D.
FDA Assistant Country Director, China
API Conference- March Beijing

2. API Conference- March 2010- Beijing
Today’s agenda
Introducing the FDA China Office
FDA’s requirements for API manufacturing
Selected Topics and Issues of Most Concern
FDA Initiatives on API manufacturing and drug safety
API Conference- March Beijing

3. API Conference- March 2010- Beijing
Challenges
Significant demand in resources for inspections
Consequences of globalization, including more foreign manufacturing and clinical trials sites
Greater complexity associated with manufacturing
FDA concern about the state of industry compliance and insufficient investment in manufacturing and quality systems
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4. FDA International Efforts
API Conference- March Beijing

5. Beyond Our Borders Initiative
FDA in-country offices
Awareness
Capacity building
Standards/inspections
Collaboration
Leveraging opportunities
Locations:
China, India, EU, Latin America, Middle East
Leveraging projects
Pilots/Info sharing
EMEA pilot
API Conference- March Beijing

6. FDA China Office In-Country Staff
Beijing
Chris Hickey, Office Director
Mike Kravchuk, Deputy (device)
Brenda Uratani (drug)
Irene Chan (food)
Shanghai
Charles Ahn (drug inspection)
BJ Marciante (device inspection)
Guangzhou
Dennis Doupnik (food inspection)
Dennis Hudson (food inspection)
API Conference- March Beijing

7. Agreements Between HHS and SFDA: Key Provisions
Signed December 2007
Key Provisions:
All Chinese Producers of Designated Drugs and Devices Required to Register with SFDA
Goal: Certify Products Exported to the United States Meet FDA Standards
Joint Training/Capacity Building
Greater/More Rapid Information Sharing
Greater Access to Facilities
Product Integrity: Tracking System of Products Likely to Be Counterfeited
Strengthened FDA, SFDA Collaboration Under WHO Auspices
Implementation Focus on Specific Set of Drugs, Devices
API Conference- March Beijing

8. FDA China Office What Are We Doing?
Continuing to Strengthen Working Relations with SFDA
Engage in Strategic Capacity Building of, Confidence Building with SFDA, Provincial and Municipal Authorities
Work with Regulated Industry re: Exports to U.S., FDA Standards and Processes 
Monitor and Report on Conditions and Events that Might Affect the Safety and Quality of FDA- Regulated Products
Regulatory Reform/Legal Assistance
Increasing inspections at facilities that manufacture FDA-regulated goods; and
API Conference- March Beijing

9. CGMP Requirements & Principles for API Manufacturing
API Conference- March Beijing

10. API Conference- March 2010- Beijing
CGMP
C” = current dynamic and evolve over time
“GMP” = Good Manufacturing Practices
Minimal standards
Not “best” practices unless “best” is, in fact, current minimal.
API Conference- March Beijing

11. FDA Requirements for API Historical Perspectives
21 CFR 211: Current good manufacturing practice for finished pharmaceuticals
FD &C Act Sec 501 (a)(2)(B): drug
ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (November 2000)
FDA has been inspecting API for decades
API Conference- March Beijing

12. API Conference- March 2010- Beijing
ICH Q7A
Quality Management
Personnel
Buildings and Facilities
Process Equipment
Documentation and Records
Material Management
Production & In-Process Controls
Packaging & Identification Labeling of APIs & Intermediates
Storage & Distribution
Laboratory Controls
Validation
Change Control
Rejection & Re-Use of Materials
Complaints and Recalls
Contract manufacturers (including Laboratories)
Agents, Brokers, Traders, Distributors, Repackers, and Relabellers
API Manufactured by Cell Culture-Fermentation
API for Use in Clinical Trials
API Conference- March Beijing

13. Potential Problems from Non-Compliance with CGMP
Super-potency or Subpotency
Impurities
Contamination
Safety and Efficacy effects
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14. Some Issues of most concern
Day-to-day implementation of CGMP
Quality system management
Understanding the product and the process
Can’t “test” quality into the product
Material management
Equipment qualification and use
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15. Day-to-day Implementation of CGMP
Eliminate variability
Achieving Process Consistency is of utmost importance to ensure quality of each batch
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16. API Conference- March 2010- Beijing
Quality management
API Conference- March Beijing

17. Fundamental Quality Management Principles
Strong commitment to drug quality and patient safety
Strong “believer” in the value of CGMP
Understand the importance and impact of quality management, control, and implementation
API Conference- March Beijing

18. Quality System ICH Q10 Concepts
Commercial Manufacturing
“The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded”
API Conference- March Beijing

19. Pharmaceutical Quality System
The Quality System is the foundation for the drug manufacturing systems
Quality system model integrates manufacturing systems
API Conference- March Beijing

20. API Conference- March 2010- Beijing
Quality System
Deviations & investigations
Change control
Training
Audit/ review
Annual product review
Contract agreement
Document control
API Conference- March Beijing

21. Quality System Critical Commitment from Top Management
Understand & recognize the value of quality system
Strong commitment on producing safe and effective product- decision to release or reject of batch justified by data and science (responsibility of QA)
Clear communication and promotion from top management on importance of quality to all employees and units of operation
Implementation and enforcement on quality system
API Conference- March Beijing

22. Pharmaceutical Quality System Lifecycle Approach
Process performance and product quality monitoring system;
Corrective action and preventive action (CAPA) system;
Change management system;
Management review of process performance and product quality.
API Conference- March Beijing

23. API Conference- March 2010- Beijing
Lifecycle Approach
Validation, maintenance, and continuous improvement of product quality
5% pre-approval
95% Post-approval
API Conference- March Beijing

24. API Conference- March 2010- Beijing
Product Life Cycle
Comparability
Protocol
Evaluation
Risk
Assessment/
Mitigation
Propose
CGMP
Adherence
Formal
Experimental
Design (DOE)
Monitor
(CAPA
Continuous
Improvement
Innovation)
Identify
(Critical/ Key
Attributes/
Parameters)
Post-Approval
Risk
Assessment/
Mitigation
Confirm
(Control/ Predict)
PAT
PAT
Conformance/
Validation Studies
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25. Investigation & Deviations Add Value & Impact Quality
Learn from mistakes
Prevent recurrences: corrective action & preventive action (CAPA)
Build knowledge: variability reduction, continuous improvement in product quality
API Conference- March Beijing

26. API Conference- March 2010- Beijing
What is Change Control?
Changes are managed by the firm:
Evaluates everyday changes to the manufacturing facility, equipment, personnel, improvements, and minor adjustments to the process.
All changes must always be done with a written protocol under the change control system including approval by QA
Have procedures in place for the execution of the change in an orderly manner
Evaluate the impact of the change
Document the change and results
Adequacy of changes are evaluated by FDA during inspection
API Conference- March Beijing

27. API Conference- March 2010- Beijing
Change Control
Process
Process improvement /adjustment
Personnel practice
Operational procedures
Equipment/ Facility/ Utilities
Document, examples
Revision/ updating of:
SOP
Analytical worksheet
Batch record
API Conference- March Beijing

28. API Conference- March 2010- Beijing
Training
Qualified employee to perform the assigned task
Strict implementation of the established procedures
Supervision
Periodic re-evaluation
Continuing education in training
API Conference- March Beijing

29. Audit/ Review Annual Product Review
Regular trending reviews and evaluation of process and product
Evaluation of stability, recalls, OOS, product complaints, returns
Risk assessment, mitigation before occurrence of serious consequences
Ensure operation is maintained in an ongoing state of control
Knowledge gained for continuous improvement in product life cycle
API Conference- March Beijing

30. API Conference- March 2010- Beijing
Contract Agreement
Clear contractual agreements on:
Responsibilities of each party
Effective communication on all issues that potentially impact drug quality
Adequate qualification, auditing and regular periodic evaluations of contractors
Notification to FDA for changes in contractors
API Conference- March Beijing

31. API Conference- March 2010- Beijing
Document Controls
A most critical element to support acceptability of a production batch and GMP compliance
Not just a bureaucratic exercise to satisfy FDA
REQUIRE ORIGINAL RECORDS as the task (operation) is being performed, not a re-copying of the original. Data must not be altered
Production: batch records
QC: testing records
Violations: Serious Consequences
API Conference- March Beijing

32. API Conference- March 2010- Beijing
Documentation
All SOP (especially production batch record) should be in sufficient detail for the operator to carry out the task in a consistent manner
Changes in SOP must be reviewed and approved by QA
API Conference- March Beijing

33. API Conference- March 2010- Beijing
Material Management
API Conference- March Beijing

34. ICH Q7A: Materials Management
Manufacturers of intermediates and/or API should have a system for evaluating the suppliers of critical material
Materials should be purchased against an agreed specification, from a suppliers, approved by the quality unit(s)
If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.
Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.
API Conference- March Beijing

35. API Conference- March 2010- Beijing
Material Controls
Raw materials
Intermediates
Components
API
Manufacturing materials
e.g., sterilizing filters
Facility materials
e.g., HEPA filters
API Conference- March Beijing

36. API Conference- March 2010- Beijing
Equipment Management
API Conference- March Beijing

37. Qualification of Equipment
Issues especially pertain to:
Adequate IQ, OQ, PQ
Old equipment??
Instruction and training of operation for use of equipment
Establish regular maintenance, calibration and maintain documentation of these activities
API Conference- March Beijing

38. Supply Chain Management
API Conference- March Beijing

39. Supply Chain Management
Identify critical control points (areas) and implement adequate controls to ensure integrity of the supply of raw materials, component, excipients, API, drug product through procurement, manufacturing and distribution.
Tamper resistant
Serialization
testing
API Conference- March Beijing

40. Regulatory Actions for non-GMP compliant firms
Warning Letters
Withholding Approval
Import Detentions and Alerts
Seizures
Injunctions
Prosecutions
IMPACT: Product NOT suitable for use.
API Conference- March Beijing

41. API Conference- March 2010- Beijing
Thank You
Brenda Uratani
API Conference- March Beijing