上海CMC培训EnsuringDrugQualityforPublicHealthTheImplementation.ppt

1,Ensuring Drug Quality for Public Health The Implementation,Brenda Uratani, Ph.D. Assistant Country Director FDA China Office, Beijing,2,Overview,Challenges to Globalization of Drug Manufacturing FDAs Work in China GMP Principles: Issues of the most concern,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,FDA International Efforts,FDA Overseas Efforts Long-Term Goal,Products coming to the U.S. meet U.S. requirements. Strengthened Regulatory Counterparts Industry Responsibility: Supply Chain Management at Point of Manufacture, Point of Export, and When Presented for Importation,5,FDA Overseas Presence Current Locations,China India Latin America Europe Middle East (2010),6,FDAs Work in China,7,8,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),FDA/SFDA Agreement: Key Provisions,Key Provisions: Registration of designated drugs and devices Joint Training/Capacity Building Greater/More Rapid Information Sharing Greater Access to Facilities Product Integrity/Anti-counterfeiting Strengthened FDA, SFDA Collaboration Under Multilateral Auspices,9,Drugs in China: What Has FDA Done?,FDA-SFDA Collaboration Inspections Engagement of Industry Capacity-Building,10,What Is China Doing?,Updating Standards, Methods Revision of China CGMP Working to Improve Drug Adverse Event Reporting Training Elite Group of Inspectors Re: International Standards Attempting to Strengthen Drug Application Review Process Taking More Active Role in International Standard-Setting Shifting Focus to Conduct More Pre-Approval Inspections Utilizing Tools to Detect Counterfeiting Supply Chain: Developing Tools and Standards for Tracking/ Tracing,11,Chinas Role in Drug Development: Challenges for China,Need for Regulatory Reform Uniformity of implementation of CGMP across all provinces Regulatory Authorities Working to Strengthen Capacity, Authority, Streamline Reporting Structures Counterfeits Economically-Motivated Adulteration “Show” and Shadow Factories Supply Chain Integrity Bulk Chemicals Excipient Quality Raw Material Processing Where There is no Oversight Adverse Drug Reaction Reporting Different Standards for Domestic, Exported Products Data Integrity Process Inspects Firms Generally, Not Capacity to Produce Specific Products,12,13,CGMP Requirements & Principles Issues of Most Concern,14,CGMP,C” = current dynamic and evolve over time “GMP” = Good Manufacturing Practices Minimal standards Not “best” practices unless “best” is, in fact, current minimal.,15,Potential Problems from Non-Compliance with CGMP,Super-potency or Subpotency Impurities Contamination Safety and Efficacy effects,16,Some Issues of most concern,Day-to-day implementation of CGMP Understanding the product and the process Cant “test” quality into the product Quality system management Material management Equipment qualification and use Supply chain management,17,Day-to-day Implementation of CGMP,Eliminate variability Achieving Process Consistency is of utmost importance to ensure quality of each batch,18,Process Understanding Inadequate Development Work,Reaction parameters are often too wide and not supported by development work Either extremity of an executed range of parameters is often selected as optimal condition Gaps in knowledge management in progressing from one stage to another stage Lack of formalized structure for process development,19,Quality System,20,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,21,Firms should not work only to pass an FDA inspection Firm should operate the facility under quality system,22,Pharmaceutical Quality System,The Quality System is the foundation for the drug manufacturing systems Quality system model integrates manufacturing systems,23,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,24,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.,25,Lifecycle Approach,Validation, maintenance, and continuous improvement of product quality 5% pre-approval 95% Post-approval,26,Formal Experimental Design (DOE),Conformance/ Validation Studies,Post-Approval,Propose,Product Life Cycle,Evaluation,Identify (Critical/ Key Attributes/ Parameters),Confirm (Control/ Predict),Monitor (CAPA Continuous Improvement Innovation),Risk Assessment/ Mitigation,Comparability Protocol,Risk Assessment/ Mitigation,CGMP Adherence,PAT,PAT,27,Quality System ICH Q10 Concepts,3.1.3 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”,28,Quality System,Deviations & investigations Change control Training Audit/ review Annual product review Contract agreement Document control,29,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,30,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,31,Training,Qualified employee to perform the assigned task Strict implementation of the established procedures Supervision Periodic re-evaluation Continuing education in training,32,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,33,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,34,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,35,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,36,Material Management,37,Material Controls,Raw materials Intermediates Components API Manufacturing materials e.g., sterilizing filters Facility materials e.g., HEPA filters,38,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 know