1. FIELD COMPLIANCE UPDATE CDR Thomas R. Berry, RPh FDA, Investigator RAL-RP / ATL-DO

2. Information Disclaimer: The information provided is only intended to be general summary information. It is not intended to take the place of either the written law or regulations. Opinion Disclaimer: The comments and opinions expressed are those solely of the presenter. They are not intended to take the place of either the written law or regulations

3. CRISSP Score  CDER/ORA Risk-based Inspection Site Selection Prioritization  Larger the score – higher priority  “High” priority = “Tier 1” establishments  Developed by the Division of Manufacturing and Product Quality, OC/CDER

4. CRISSP Score  Derived from three categories of risk:  Product  Process  Facility

5. FY 06  Approximately 500 establishments identified by CDER as high-risk sites  Includes the following programs:  56002 – Drug Process Inspections (DPI)  56002a – DPI / Small Volume Parenterals  56002b – DPI / Drug Repackers and Relabelers  56002c – DPI / Radioactive Drugs  56002f – API Process Inspections  56002m – DPI / Therapeutic Biological Product Inspections

6. CRISSP Score Exclusions  Medical Gas Establishments  PADE Inspections  Therapeutic biological-only sites  Pharmacies  Positron-Emission Tomography

7. FY 06 – ATL-DO Drug Cadre  Tier 1 = 44 inspections  Tier 2 = 133 inspections  Pre-Approval Inspections  Directed Inspections  Complaint Investigations

8. FY 06 – ATL-DO Drug Cadre  Drug Surveillance Samples = 29  Collected during GMP Inspections  Surveillance vs Compliance

9. FACTS  Field Accomplishments and Compliance Tracking System  Creates the assignments for the investigator  Provides firm status and historical investigatory information

10. Investigator Example  High Risk GMP Inspections = 8  Downgraded High Risk Inspections = 1  PADE Inspections = 2  District Investigations = 4  Drug Surveillance Samples = 15

11. Other Assignments  OCI Investigations = 1  Pharmacy = 1  Seizure = 1  Destruction = 2  Katrina (MS + LA) x 1 month  Training x 1 month

12. Turbo EIR  Provides more consistency between inspections and investigators  Provides specific citations and examples of violations  Provides information for statistical analysis and identifies potential investigator / FDA / industry trends

13. Top 10 Drug Observations Used in Turbo EIR CY 05 CY 05 & CY 04 Turbo Cite ID Count

14. FDA Top 10 (CY 05) 1.21 CFR 211.22 (d) – Quality Control Unit Responsibilities and Procedures 2.21 CFR 211.110 (a) – Process Validation 3.21 CFR 211.100 (b) – Written Production & Process Controls 4.21 CFR 211.192 – CAPA 5.21 CFR 211.100 (a) – SOPs / Process Validation

15. FDA Top 10 (CY 05) 6.21 CFR 211.160(b) – Laboratory controls 7.21 CFR 211.25(a) – Employee Training 8.21 CFR 211.165(a) – Laboratory Testing & Release 9.21 CFR 211.180(e)(2) – APRs 10. 21 CFR 211.188 – Batch Production & Control Records

16. Investigator’s Top Ten 1.21 CFR 211.192 (4) – CAPA 2.21 CFR 314.80 – PADE Program 3.21 CFR 211.160 (6) – Laboratory Controls 4.21 CFR 211.100 (3) – Written production and process controls 5.21 CFR 211.25 (7) – Employee Training

17. Investigator’s Top Ten 6.21 CFR 211.166 – Stability Program 7.21 CFR 211.67 – Written Procedures Not Followed for Cleaning & Maintenance of Equipment 8.21 CFR 211.188 (10) – Batch Production & Control Records 9.21 CFR 211.22 (1) - Quality Control Unit Responsibilities and Procedures 10. 21 CFR 211.110 (2 +5) – Process Validation

18. FDA 483 Disclaimer This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact the FDA at the phone number and address listed above.

19. Investigator’s Significant Issues #5 - 21 CFR 211.22(a) - There is no quality control unit. Must be independent of production. Must prevent innovative “Marketing Strategies”

20. Investigator’s Significant Issues #4 - 21 CFR 211.110 Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in- process material and the drug product. The manufacturing and cleaning processes should be validated to assure that each batch of drug product produced meets pre-defined written specifications for identity and strength.

21. Investigator’s Significant Issues #3 - 21 CFR 211.166 Results of stability testing are not used in determining expiration dates. Must provide data that supports expiration dates. Must provide data to continuously support the expiration date included in the Application.

22. Investigator’s Significant Issues #2 -21 CFR 211.160(b) Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. Test incoming materials and test finished product with scientifically sound methods.

23. Investigator’s Significant Issues #1 - 21 CFR 211.165(f) - Drug products failing to meet established standards, specifications, and quality control criteria are not rejected. If your active ingredient has not arrived and you receive an immediate order for a product containing that active ingredient, FDA still expects you to wait for the active ingredient to arrive from the supplier and put it in the product.

24. Investigator’s Concerns 1.Sterilization – –Pyrogenic reaction case 2.Position Papers – –Explanation of why specific regulation does not apply to the firm –Explanation of why the firm has elected not to follow a specific regulation

25. Investigator’s Concerns 3.Corrective Actions / Preventative Actions – –Implementations of CAPA –Review of the potential impacts the event may have on other products / lots. –Retraining 4.Cleaning & Maintenance of Equipment – –Log Documentation –Hold times 5.100 % Visual Inspection of Sterile Products

26. Investigator’s Limited Vision 1.High Priority Large Firms – Inspections annually of different product classes. 2.More Cascade Assignments – Inspections resulting from findings at another firm. 3.Compounding Pharmacies – Manufacturing and/or evaluation of how the pharmacy is ensuring the safe and effective use of the compounded product

27. Investigator’s Limited Vision Corporation Responsibility – Holding corporate officers responsible for making sure problems at one facility are not occurring at any of the firm’s other facilities.

28. Field Compliance Update Questions ???