Recent PAI Experiences

1
Recent PAI Experiences

• Barbara W. Unger
• Don Hill Associates, Inc.
• 317-582-1504
• bwunger_at_midlink.com
• Barnett International, Pre-Approval Inspections
• Philadelphia, PA
• June 26 28, 2002

2
Recent PAI Experience

• 5 Pre-approval Inspections in 2001
• 1 EU and 4 CBER
• Drug Substance, Drug Product and Contract
  Manufacture
• Supplemented with Additional Information from
  Another EU and 2 CDER Inspections

3
Covered in this Presentation

• Pre-requested Documents
• Documents Requested per Inspection
• Documents Requested per System
• Highlights of Observations per System
• Highlight of Observations, other Areas
• US vs EU
• Conclusions

4
Pre-Requested Documents

• SOP Index, Product Specific
• SOPs for Change Control, OOS, Deviations
• Water Quality Data
• EM Data
• In-process and Lot Release Specifications
• Laboratory Equipment
• Validation Master Plan and Summary

5
Pre-Requested Documents (cond)

• Computer Systems and Validation Status
• Lots Initiated and Disposition
• Lot Release Procedure
• Quality Agreement
• Overview of QA System
• Equipment List, Dedicated vs Multi-product

6
Pre-Requested Documents, (cond)

• Site Master File (EU)
• Batch Records for Validation Lots
• Shipping Validation

7
Documents Per Inspection

• Duration 5 days
• Requests 154 364
• Requests / Inspector
• Average 12 per Day
• Most on Days 3 and 4
• Magnitude, 285 Requests Included
• 100 1-inch Binders,
• 60 3-inch Binders,
• Batch Records,and
• Individual Documents

8
Requests per System

• SYSTEM of REQUESTS
• Quality 22 - 34
• Facility, Equipment 13 - 37
• Materials 2 -
  7
• Production 20 - 43
• Package and Label 1 - 2
• Laboratory 8 - 22

9
Requests per System
10
Quality System

• Overview of the QA system Structure, Personnel,
  Responsibilities and SOPs
• Index of Policies, Procedures, Guidance
• Vendor Audit and Qualification
• Handling of Product Complaints
• SOP for Annual Product Review

11
Facilities and Equipment

• Load Validation for Autoclave(s)
• PIDs for CIP/SIP Piping to ----- Equipment
• Engineering Study, Sanitization of Formulation
  Tank
• Dates of HVAC Qualification
• IQ / OQ of all Bioreactor Equipment
• IQ / OQ for Dewar Containing Cell Bank Vials

12
Materials

• Test Packages for Two Lots of a Raw Material
• Resulting NCMR for Raw Material
• Qualification of Media Components
• Testing of Vial and Stopper Components against
  USP Standards
• Visual Inspection of Glassware

13
Production

• In-process Hold Times Where in process,
  Temperature / Times of Hold
• Media Fill Summaries of Fill Line for Last Three
  Years
• Data to Support pH Range Batch Record and BLA
  Differ
• Validation of Mixing Time
• Batch Record for Preparation of MCB Including
  Storage, Transfer and Inventory

14
Production, (cond)

• Batch Records for Two Lots
• Batch Records for Specific Lot of PBS
• PQ for Filling Drug Substance Container
• Change Control Documentation Associated with
  Change in Process

15
Packaging and Labeling

• SOP for Label control
• SOP for Manual and Semi-automated Inspection
• Maximum Number of Rejects Before Rejecting a Lot

16
Laboratory

• Raw Data for Media Fills
• IR Data for Most Recent Lot of X Tested by
  Chemistry Lab
• Analytical Test Methods
• Lab Reports for Bioburden Samples for the PQ Lots
• Analytical Standards for WFI and Potable Water
  Testing Test Method and Specifications

17
Laboratory, (cond)

• SOP for Testing of Compressed Gasses
• Lab Manual for an Equipment Item
• Observe Endotoxin Testing Procedure
• Laboratory Certification and Assay Transfer
• Listing of QC Procedures

18
Other Requests

• Bioburden
• Control Strategy
• Data Throughout Process
• Computer Validation
• Identify all Computer Systems Used in Manufacture
• Status of Validation

19
EU Differences from FDA

• More Top Down Inspection
• Overview First, Then Specifics
• Most Interested in How/Why
• Site Master File
• Ensure this is Correct
• EM
• Duration of Plate Exposure
• Scientific Justification for Sites

20
Conclusion

• Focus on Quality, Facility, Production and Labs
• EM and Water Review Should be Part of Lot Release
• Annual Product Review SOP
• Computer Validation Status Becoming Important
• Continued Focus on Validation of the Process,
  Hold-times for Drug Substance
• Sterility Assurance Remains Critical
• Follow Own Written Procedures
• Ensure that Application, Validation, and PBR Agree