1. The Top 10 List – Best Lessons Learned from FDA Warning Letters Walter Nowocin Medtronic, Inc./Minneapolis, Minnesota Measurement Science Conference 23 March, 2012

2. Objectives Review metrology related warning letters over the past five years – the best of the best Have discussions involving best practices on avoiding similar occurrences Pass along lessons learned Learn about new FDA search site

3. Source of Data All data in this presentation was taken from the ‘FDA Electronic Freedom of Information Reading Room – Warning Letter and Responses’ http://www.fda.gov/foi/warning.htm In the past I used the FDA site to search the past twelve months of warning letters containing the words calibrate, calibrated, or calibration. For example in 2010, I searched a total of 437 warning letters with 15 having calibration issues.

4. FDA Warning Letter Search Site http://www.fda.gov/foi/warning.htm

5. FDA Form 483 ‘Reading Room’ http://www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm

6. General Observations Over five years, warning letters have increased while calibration specific issues have decreased. Calibration issues tend to be basic; i.e. past due dates, no procedures, etc. If there are calibration issues, they are usually associated with many other quality system issues. Rarely a warning letter just for calibration. Most violations are to company specific requirements and not FDA requirements.

7. FDA Warning Letter Categories Quality System Regulation - 820 Medical Devices Current Good Manufacturing Practice – Finished Pharmaceuticals Good Laboratory Practice Regulations - Nonclinical Laboratory Studies Current Good Manufacturing Practice – API (Active Pharmaceutical Ingredient) FDA 501k Product Approval Process

8. 820.72(a) – No Annual Cal; Failed on Demo of Cal – 7 Jan 08 Number 10

9. 501(a)(2)(B) – Incorrect Use of ‘N/A’ – 28 April 2008 Number 9

10. 820.70(i) Failure to Validate Computer Software – 25 Mar 2008 Number 8

11. cGMP for API – Failed to Calibrate within Intended Range (7 April 2011) Number 7

12. 820.72 (b) – Cal Procedures; Accuracy and Precision (18 Sep 08) Validation of Heat Sealer No Calibration of Temperature Gauges for monitoring heat sealer Number 6

13. 211 – Overdue Cal Trending (23 Dec 09) What Calibration Metrics are you monitoring for quality trends? Do you have established ‘trigger’ points for investigation action? Number 5

14. 211.192 – Out of Specification Investigation (22 Apr 09) Analytical Lab finding, but is a lesson learned for Cal Labs. Number 4

15. 820.72(b)(1) – Traceability to Reference Standard – 8 Dec 06 Number 3

16. 211.68 – Original Calibration Data (7 May 09) Number 2

17. 820.72(b)(2) – Self Calibration Program (26 Feb 09) Number 1

18. Any questions on these warning letters or Form 483s?