1. Kyle McDuffie, Vice President Beckman User Meeting 2001 Delaware. Orlando. Holland. UK Instrument Integration and Regulatory Compliance

2. Fact or Fiction the FDA is targeting laboratories in inspections I can buy a validated, 21 CFR Part 11 compliant software product There have been several recent warning letters related to laboratory systems Web or browser based systems are inherently more compliant than classic client server systems As long as I have the raw data, I can delete other electronic copies of the results I need to be able to re-analyze the data for the full retention period

3. Agenda  Brief review of cGMP requirements for laboratories  Brief review of 21 CFR Part 11  Promise of instrument integration with LIMS  Our approach  Fact or Fiction  Conclusion

4. cGMP  Overall FDA objectives Protect the public health Prevent fraud Since 1997, to assist getting lifesaving drugs to market faster  FDA Inspections For cause –Be able to reconstruct what occurred including all steps from raw materials through distribution Routine –Verify compliance & control

5. cGMP Requirements - Labs  FDA 21 CFR Part 211 (Finished Pharmaceuticals) Adequate laboratory facilities Each lot must be sampled and tested –Conformance with specifications Specific tests required –Dissolution –Content Uniformity –Assay –Stability Quarantine –Control of retesting –Rejected lots Responsibilities –Approval, rejection Documentation, documentation, documentation

6. cGMP Requirements  Record Keeping (211.180 through 211.198) Complete record of all data secured during the test Record of all calculations Statement of the results Signature or initials and date Second level review / approval and evidence Calibration records Method modifications records  Record Retention Minimum of 1 year post expiration of the batch Must be available for inspection Can be paper or computer records

7. 21 CFR Part 11 Electronic Records; Electronic Signatures  For cGMP environments Specifies requirements for electronic records to be considered equivalent to handwritten records for those records required by cGMP  Key aspects Validation Audit Trail Security –Authority checks –Operational checks –Limit access to authorized individuals Accountability Archival and retrieval

8. 21 CFR Part 11  Technical Controls About 50% of the regulation requirements Primary focus of software vendors  Procedural Controls About 50% of the regulation requirements Focused on the end-user and the environment  Software Products Should provide technical functionality to allow the system to be operated in a compliant manner A vendor can not validate a system for you Technically compliant products can be operated in a non- compliant manner!

9. Promise of Instrument Integration - cGMP Requirements Promise of Instrument Integration - cGMP Requirements  Improved Record Keeping (211.180 through 211.198) Complete records Record of all calculations Electronic or printed Statement of the results Electronic Signature Electronic Second level review / approval and evidence Calibration records Method modifications records  Record Retention Minimum of 1 year post expiration of the batch Must be available for inspection

10. Promise of Instrument Integration  Automate the laboratory workflow  Prevent multiple instances of the same data  Prevent manual transcription and related errors  Simplify / enhance the review and approval processes Leading to…..  Streamlined lot release  Faster decision making (Quarantine, reject, re-test)  Lower overall cost  Better compliance / ease of demonstrating compliance

11. Instrument Integration Instrument Integration  “ … Any instrument to Beckman LIMS in any application” Gas / liquid chromatography (Waters Millennium 32 ) Quality Control / Quality Assurance R&D / Drug Discovery  Unidirectional or Bi-directional Continuous Operation (Polling) Interactive Mode –Setup Autosampler runs –Review results –Calculations, spec checking, rounding, dilution –Advanced applications

12. Example

13. Our Approach  Seamless integration to LabManager Maintain data integrity by utilizing TPO  Validation Following GAMP recommendations for development and implementation  Audit Trail Includes reason for change Includes all user actions within the software  Archive and retrieve Can reconstruct all activities from the audit trail Includes all files to / from the LIMS / Instrument Independent archive from LabManager for flexibility  Security Username / password Access control by job title Inactivity timeout

14. Fact or Fiction the FDA doesn’t like file based architectures Closed systems are inherently better than open systems the vendor validated the system for me If I keep paper copies of the chromatograms, I’ll be fine A discrepancy between the data in the ERP, the LIMS and CDS is not a major problem as long as I can prove which one is right I only need to worry about new systems I put in Web or browser based systems can’t be validated There is no installation or operational qualification required if I use a browser based system There is consensus within the FDA regarding the interpretation of all key aspects of 21 CFR Part 11

15. Fact or Fiction the FDA is targeting laboratories in inspections I can buy a validated, 21 CFR Part 11 compliant software product There have been several recent warning letters related to laboratory systems Web or browser based systems are inherently more compliant than classic client server systems As long as I have the raw data, I can delete other electronic copies of the results I need to be able to re-analyze the data for the full retention period

16. Conclusions  Instrument Integration Is a key part of laboratory automation Excellent tools are available now Regulatory compliance is improved Easier to demonstrate compliance with a computer than with paper files  Regulatory compliance Beware the fiction, keep up to date Interpretations still evolving (FDA has promised additional guidance)

17. For More Info / Copy of Presentation  Send an email to kylem@csols.com Phone 302-731-4686  Other sources www.fda.gov www.pda.org Institute of Validation Technology (www.ivthome.org)www.ivthome.org