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API Conference- March 2010- Beijing 1 Requirements for the Quality of API from FDA Perspective Brenda Uratani, Ph.D. FDA Assistant Country Director, China.

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Presentation on theme: "API Conference- March 2010- Beijing 1 Requirements for the Quality of API from FDA Perspective Brenda Uratani, Ph.D. FDA Assistant Country Director, China."— Presentation transcript:

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

2 API Conference- March Beijing 2 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

3 API Conference- March Beijing 3 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

4 API Conference- March Beijing 4 FDA International Efforts

5 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

6 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)

7 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

8 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

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

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

11 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

12 API Conference- March Beijing 12 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

13 API Conference- March Beijing 13 Potential Problems from Non-Compliance with CGMP Super-potency or Subpotency Impurities Contamination Safety and Efficacy effects

14 API Conference- March Beijing 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

15 API Conference- March Beijing 15 Day-to-day Implementation of CGMP –Eliminate variability –Achieving Process Consistency is of utmost importance to ensure quality of each batch

16 API Conference- March Beijing 16 Quality management

17 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

18 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”

19 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

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

21 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

22 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.

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

24 API Conference- March Beijing 24 FormalExperimental Design (DOE) Conformance/ Conformance/ Validation Studies Validation Studies Post-Approval Propose Product Life Cycle Evaluation Identify (Critical/ Key Attributes/Parameters) Confirm Confirm (Control/ Predict) Monitor ( CAPA ContinuousImprovementInnovation) Risk Assessment/ Assessment/Mitigation ComparabilityProtocol Risk Mitigation CGMPAdherence PAT PAT

25 API Conference- March Beijing 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

26 API Conference- March Beijing 26 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

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

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

29 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

30 API Conference- March Beijing 30 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

31 API Conference- March Beijing 31 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

32 API Conference- March Beijing 32 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

33 API Conference- March Beijing 33 Material Management

34 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.

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

36 API Conference- March Beijing 36 Equipment Management

37 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

38 API Conference- March Beijing 38 Supply Chain Management

39 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

40 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.

41 API Conference- March Beijing 41 Thank You Brenda Uratani


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