1. Walter Nowocin, PEM Medtronic, Inc., Minneapolis, Minnesota NCSL International Workshop and Symposium, Nashville, TN 16 July, 2013

2.  Review metrology related warning letters over the past twelve months  Have discussions involving best practices on avoiding similar occurrences  Pass along lessons learned  Learn about new FDA search site

3.  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 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. http://www.fda.gov/foi/warning.htm

5. http://www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm

6.  Over five years, warning letters have increased while calibration specific issues have decreased. However, after hitting a five year low last year, we have doubled the calibration findings this year.  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.  Quality System Regulation for Medical Devices – 21 CFR Part 820  Current Good Manufacturing Practice for Finished Pharmaceuticals – 21 CFR Part 211  Good Laboratory Practice for Nonclinical Laboratory Studies – 21 CFR Part 58

8.  Search the FDA warning letter web site for calibration related key words: calibrate, calibrated, and calibration  Save the warning letter as a PDF  Use a screen capture utility to copy only the areas of the warning letter that pertains to calibration  Provide a summary of what the finding describes  Describe what best practices would prevent this issue from reoccurring  NOTE: Newer warning letters are now in a web page view and you can ‘copy’ and ‘paste’ what you need

9. Number 10 Basic Calibration Issues – FDA 483 Inspection – 27 Sep 11 6. Initial qualification and routine calibration, maintenance and cleaning of automatic, mechanical, and electronic equipment is not performed according to a written program designed to assure proper performance. Specifically, c) The bench-top incubator used for the incubation of media fills and environmental monitoring samples has not been qualified, maintained or cleaned according to a written program. Visual inspection of the incubator showed a ¼ inch gap between the door and the chamber when closed and the temperature dial only showed a single handwritten setting of 30 º C. d) The analytical balance model (x) used to weigh all components for compounding lacked calibration records for the most recent calibration performed by a contractor on 8/4/11. In addition, there was no documentation demonstrating the minimum weight that could be accurately weighed on this balance. Furthermore, daily checks with certified weights are not conducted. c) All thermometers used in the refrigerator, incubator, autoclave, and compounding processes lacked calibrations against an NIST-standard. The temperatures of your refrigerator and freezer used to store components and finished drug products are not monitored daily to ensure that proper storage conditions are maintained. d) The magnehelic gauges used to measure differential pressure between areas in the clean room lacked calibration records. Comment: Basic examples of not having adequate calibration records.

10. Number 9 Analytical Calibrations – 211.160(b)(4) - 26 Jul 12 3. Your firm has failed to calibrate instruments and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met [21 C.F.R. § 211.160(b)(4)]. Two examples of violations of § 211.160(b)(4) are as follows: a. Your firm does not have an established written program to calibrate/qualify the Perkin Elmer Clarus gas chromatograph (GC) at suitable intervals. b. Your firm did not calibrate and qualify the Jasco high performance liquid chromatography (HPLC) instrumentation adequately, in that there is no periodic qualification or evaluation of the pump, oven, injector, or detector. The “Use and Calibration of HPLC” procedure does not include criteria to define adequate calibration of the instrument. Your response indicates that a use, maintenance, and qualification procedure for the GC will be separated from the procedure for the “Determination of (b)(4) and (b)(4) by Gas Chromatography” by March 2012. Additionally, your response indicates that the HPLC procedure will be revised to include operational performance and acceptance criteria by March 2012. Comment: Does your calibration lab get involved with Analytical Lab calibrations or do you allow them to ‘user’ calibrate their specialized equipment?

11. Number 8 OEM Disclaimer – 820.72(a) - 2 Nov 12 10. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a). For example: Your firm continues to use the patient simulator as part of final acceptance testing activities for the ANX 3.0 Autonomic Nervous System Monitor, when the testing equipment manufacturer disclaims in their operating and service manual the use of this product as a certification test instrument for medical devices. Also, a review of the Ansar Master Equipment List revealed that the patient simulator required an annual calibration that had not been done. Comment: Not following supplier recommendations for intended use. The company’s own requirements identified calibration, contradicting the suppliers recommendation. How do you handle IMTE that has no supplier specifications and your customer requests a calibration?

12. Number 7 Pressure and Flow Meters – 820.75(b) – 20 May 13 Comment: A typical issue in manufacturing, which pressure and flow gages require calibration and which can be labeled No Calibration Required (NCR). Notice the timing of the ‘Completed Actions,’ Calibrated before the activity to define the equipment specifications.

13. Number 6 Electrostatic Discharge Program– 820.70(c) - 22 Oct 12 5. Failure to establish and maintain adequate procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality and failure to periodically inspect environmental control systems to verify that the system is adequate and functioning properly, as required by 21 CFR 820.70(c). For example: a. Procedure No. MSOP-240-Manufacture, Revision H, dated 3/22/2012, provides instructions within Section 7 to “Use static electricity reduction mats during the burn-in process.” However, Procedure No. MSOP-240 does not provide instruction to conduct periodic monitoring of the two Electrostatic Discharge/ESD mats (Equipment ID No.: (x) and (y) located within the (z) area to ensure common point ground connections. In addition, the subject procedure is not defined in that it provides no instructions for operators/personnel to be grounded (e.g., via the use of wrist straps, conductive flooring, conductive shoes/foot straps, ESD clothing or a combination thereof) and the methodologies used to ground personnel must be monitored. Finally, the two subject ESD mats were not included on your firm’s periodic monitoring schedule and a common point ground challenge was not conducted on the mats until 3/12/2012, which is nine days after the start of the current inspection. We have reviewed your firm’s response and conclude that it is not adequate. Your firm has changed procedure MSOP- 240, Manufacture, to require personnel to wear a wrist strap during (x). Your firm has placed the ESD stations under the calibration program. The response is not adequate because your firm has not completed a comprehensive program to enhance the current ESD controls which includes: 1) implementing an ESD monitoring process that will allow for periodic monitoring of the ESD controls; 2) changing the gowning procedure to define appropriate ESD gowning and testing; 3) requiring ESD smocks to be worn by employees handling (y); and 4) provide training on ESD and ESD controls for all employees that handle the (z). Comment: How do you monitor ESD processes, calibrate, periodic inspection, preventive maintenance? A very specific expectation from the FDA on what is expected from an ESD Program.

14. Number 5 Software Validation – 820.70(i) - 9 May 12 7. Failure to adequately validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i). For example, upon request for the protocol used during the validation of your firm’s software- controlled audiometer device calibration system, your firm stated that it did not have a pre- established protocol for conducting the validation. We reviewed your firm’s response and conclude that it is not adequate. Your firm did not submit supporting documentation indicating that it will create a requirement that protocols be used during future software validations. Your firm’s response did not address why no protocol was used during the validation of the audiometer testing equipment software. Your firm’s response also did not include evidence to indicate that a corrective action was implemented or that a systemic corrective action was considered (including reviewing all software validations to ensure that the validations were conducted as required). Comment: It seems we get a calibration software validation example each year. The company failed in three different areas to meet the FDA’s expectations on what should have been corrected: future validations, past reason, and expanded search to find other software gaps.

15. Number 4 Oven Specifications – 820.75(a) - 22 Oct 12 1. Failure to adequately ensure, when the results of a process cannot be fully verified by subsequent inspection and test, that the process shall be validated with a high degree of assurance and approved according to established procedure, as required by 21 CFR 820.75(a). For example: a. Per Procedure No. MSOP-214 – Application Solution, Set-up Operations and Maintenance, Revision R, your firm via an (x) process applies a (y) solution to its Triage quantitative (these are the (z) for the Triage Cardiac Marker tests; these tests have a (v) component). Per Procedure No. MSOP-214, the application process requires an oven set-point temperature of (m) degrees Celsius and a drying time of (n). However, the earliest validation documentation (VP-98-04 – Process Qualification Report Cardiac Assembly, dated 4/23/1998) does not provide objective evidence of how your firm established the oven specifications. Instead, report No. VP-98-04 only indicates, “After dispensing, the (y) are cured in a calibrated oven for a set duration.” We reviewed your firm’s response and conclude that it is not adequate because your firm has not completed an engineering study that determines the optimal settings for the oven set point and the duration of the drying process. Your firm also will need to complete a re-validation of the drying process after the engineering study is completed. In addition, your firm must review and, as needed, revise its product development and process validation procedures to require that objective evidence be generated to justify how process parameters are set. Comment: Ovens are getting close scrutiny by the FDA because they are typically older ovens without supplier defined specifications. The FDA expects a documented engineering determination for defining specifications. How are your legacy ovens?

16. Number 3 Resetting Temperature Set Point – 820.90(a) - 22 Oct 12 3. Failure to establish and maintain adequate procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). For example, on 3/14/2012, during a walk-through of the facility, it was observed that two cardiac marker products, Part No. (x) and Part No. (y), were found in convection oven with a set point temperature reading of (z) degrees Celsius. However, review of Procedure No. PN: (m) – Device Bases, and Procedure No. PN: (n) Cardiac, Revision C, revealed set point temperature specifications of (j) degrees Celsius. Your firm’s initial response was to immediately reset the temperature to its specifications of (k) degrees Celsius and no other quality system actions were performed. After a discussion with management, Non-Conformance Report (NCR) No. NC-12-114 was generated in response to the out-of-specification condition. However, NCR No. 114 is inadequate in that it does not address the following: a. The operator who reset the set point temperature from (j) to (k) was not notified of the nonconformance; and b. An investigation into how long the set point temperature had been outside the specification of (k). We reviewed your firm’s response and conclude that it is not adequate. Your firm has provided proof that the operator who reset the set point has been counseled regarding his action. You also responded that a NCR should have been generated when the set point temperature was reset. An investigation of how the set point was changed was conducted and your firm has supplied that information. The response is not adequate because you have not completed the non‑conformance compliance training records for all manufacturing and QA personnel who are involved in the processing of non-conformances. Comment: First example of someone changing a set point while the FDA Inspector is observing the process. A pretty glaring mistake. Then above all else when dealing with FDA findings, consider training, training, training.

17. Number 2 Thermometer and Single Point Cal – FDA 483 Inspection - 24 Aug 12 Comment: First, ‘suitable interval’ can be confusing. Does it mean time or range? In this instance it appears that the use is in terms of ‘range of readings’ and not frequency of calibration (21 CFR Part 211.160(b)(4)). USP Ice Bath procedure may discuss how to setup a proper ice bath, but may not provide rationale for a one point calibration. NIST SP 1088 ‘Maintenance, Validation, and Recalibration of Liquid-in-Glass Thermometers’ does provide rationale for single-point recalibration at the ice point (0º C). ASTM E563-11 ‘Standard Practice for Preparation and Use of an Ice-Point Bath as a Reference Temperature,’ is another resource.

18. Number 1 Calibration versus Verification – FDA 483 Inspection - 20 May 13 Comment: To be honest, I am not sure what the issue is here. I have reviewed it many times. We might need more information to come to a conclusion. Maybe the ‘verifications’ discussed are on the manufacturing line and if found out of specification they are sent to the calibration lab for a ‘calibration.’ By reading the completed actions, it seems that they are including adjustment instructions into their calibration procedures and at a higher level. Could it be that the FDA Inspector does not know what the definition of ‘calibration’ really is? Or does the company define the definition a certain way and has misapplied it? What do you think? For consideration: calibration confirms measurement uncertainty with traceability and verification confirms specified requirements which may be manufacturing specifications.

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