Kyle McDuffie, Vice President Beckman User Meeting 2001 Delaware . Orlando . Holland . UK

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

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 • 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 • “ … Any instrument to Beckman LIMS in any application” • Gas / liquid chromatography (Waters Millennium32) • 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)