1. Walter Nowocin, PEM Medtronic, Inc., Minneapolis, Minnesota NCSL International Workshop and Symposium, Orlando, FL July, 2014

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 2014, I searched a total of 539 warning letters with 6 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 generally 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.  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 8 No Work Instructions – 820.70(a) – 4 Jan 2013 10. Failure to establish and maintain procedures to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specification, as required by 21 CFR 820.70(a). For example, during a tour of the facility, production workers were observed carrying out the functional and calibration testing, assembly, and final acceptance testing of the Accoson Greenlight 300 device. However, the production workers did not have work instructions for the work that they were performing. Your firm’s Works Manager indicated that all instructions are stored (b)(4) and (b)(4) and that the operators know how to perform their job; therefore, there is no need for them to have work instructions. We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that a copy of each authorized work instruction has been placed with the production worker trained for the task. However, it is unclear whether your firm conducted a review to ensure that operators have approved work instructions for all manufacturing processes. Comment: Unbelievable that 40 years after the first release of the FDA cGMPs that we still have companies that fail to comply with the most basic of requirements. The FDA keeps stressing a ‘holistic’ view of responses.

10. Number 7 Draft Document – 820.40 - 28 Jan 13 4. Failure to establish and maintain procedures to control all documents that are required by 21 CFR 820, as required by 21 CFR 820.40. Specifically, documents that were not approved and obsolete were observed at a location where they were used. For example: a) The following documents have an Effective Date of "Draft" and are not approved per your firm's Document Format and Control SOP 050-015-4: i.Calibration, Cleaning, and Maintenance Log-(b)(4); Comment: First time that we have seen a ‘Draft’ status document actually in use. Another pretty basic failure.

11. Number 6 No Temperature or Humidity Monitoring – 211.42(c) - 24 Sep 12 13. Failure to assure an adequate control system for temperature and humidity is in place to prevent contamination during aseptic processing [21 CFR211.42(c)(10)(ii)]. Specifically, there is no system for the monitoring of temperature or humidity of the processing rooms at your Sugarland, Texas facility, where you manufacture the AdMSC product. The manufacturer's manual for your (b)(4) BSCs states that they should be operated in environmental conditions of a maximum relative humidity of (b)(4) 20. There are no procedures designed to assure proper performance of equipment used in the culture/expansion of your AdMSC intermediates. For example: a. You did not calibrate your (b)(4) for temperature and (b)(4) to assure that their displays are accurate. Your manufacturing record specifies that culture is to be performed at (b)(4) degrees Celsius and (b)(4) b. There is no indication that the temperature of the refrigerators and freezers used to store culture media, (b)(4), and reagents used to manufacture the AdMSC product is consistently monitored. Comment: The FDA likes citing Manufacturing Manuals for violations. Temperature and Humidity monitoring is a continuing focus for the FDA.

12. Number 5 Inconsistent Weight Readings – 820.72(a) – 19 Dec 13 10. Failure to establish procedures to ensure equipment is routinely calibrated, inspected, checked and maintained, as required by 21 CFR § 820.72(a). For example, B. Your firm’s Irvine procedure for calibration of (b)(4), (b)(4), (b)(4) and (b)(4), IR-04-02-045, effective 01/09/2009, 31 May 2011, 08 March 2012 and 01 March 2013 were not implemented. Your procedure requires: 1. The use of weight that is at least (b)(4)% of the scale range. The (b)(4), (b)(4) and (b)(4), dated revealed the weight readings taken from 2.2 lbs to 20 lbs on 1/14/12 but only 2.2 lbs. to 5.0 lbs. on 7/3/12 and on 12/31/12. 2. The procedure IR-04-02-045 included calculation and verification of (b)(4). Your firm does not document this in your calibration records. We reviewed your firm’s response and concluded that it is not adequate. Your firm provided no objective evidence that there is no product impact because of the deficiencies above. Comments: Inconsistent data will always get you in trouble. A classic example of not following your own procedures.

13. Number 4 CAPA Failure– 820.100(a) – 1 Nov 11 1) Failure to establish and maintain adequate procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). Specifically, your firm failed to implement the Corrective and Preventive Action (CAPA) procedure (BCP0046, effective dates 04/15/09 and 01/11/11) to ensure that existing and/or potential events related to product, process, or the quality management system that had failed to meet requirements or expectations were evaluated to determine CAPA eligibility, root causes, failure investigation, risk assessment, and eventually establish a status of the investigation. For example: a) Failure investigations were not always extended to determine the underlying cause of the problem in order to determine an appropriate implementation of corrective actions. For example: i) CAPA 15082 was generated to investigate (b)(4) assay value assignment performed using the incorrect calibration reference. Investigation into the causes disclosed that at the time the (b)(4) Calibrator value assignment process was converted from the (b)(4) to the (b)(4) series, the (b)(4) instrument calibration procedures had not been implemented. Corrective actions included update of procedures to ensure proper escalation of failures and document the calibration of records. However, this CAPA was not extended to evaluate the lack and/or inadequacy of established controls and procedures that allowed the transfer of value assignment process to an instrument for which no calibration procedures had been implemented for that specific value. Furthermore, no investigation was conducted to determine the decision of using the previous S-Cal values as the (b)(4) Calibrator instead of the (b)(4) reference (b)(4) as established by procedures and the lack of a planned deviation request in order to depart from the established manufacturing process. Comment: CAPAs are a Top 5 concern for FDA auditors. Has the CAPA determined the correct Root Cause? In this case the company concentrated on future issues and not on addressing the past issue.

14. Number 3 Calibration Specifications – 820.72(b) - 2 May 12 8. Failure to maintain adequate calibration procedures that include specific directions and limits for accuracy and precision, as required by 21 CFR 820.72(b). For example, your firm’s calibration procedure, (b)(4) does not contain specification limits for accuracy and precision. Also, the testing records, (b)(4) do not contain specification limits or a record of the results of calibration testing. Lastly, your firm’s process engineer, (b)(4), however, this specification is not established in your firm’s calibration procedure. We reviewed your firm’s response and conclude that it is not adequate. Your firm did not submit evidence or supporting documentation to correct the issue of not documenting calibration specifications. Your firm did not provide documentation to indicate that it revised the testing procedure to include specification limits for finished product and that it will begin to maintain records of all calibration results that include specification limits. Your firm’s response did not include evidence to indicate that a corrective action was implemented or that a systemic corrective action was considered. Comment: Three main issues, (1) undocumented calibration specifications, (2) records of calibration testing results, and (3) evidence of a systematic corrective action not just singular.

15. Number 2 Chart Recorder OOT Investigation – 211.192 – 4 Sep 2013 1. Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.192]. For example: b. PAC-021-081312 was opened on 8/10/12 due to the out of tolerance temperature recorder of the (b)(4) Oven. The recorder was found to be displaying readings 25°C higher than the referenced temperature which resulted in vial depyrogenation below (b)(4). Your Standard Operation Procedure (SOP) 3020.08 entitled "(b)(4)" requires that the oven cycle run for (b)(4) hours at a minimum of (b)(4). The investigation determined that the reading errors were due to a bent chart pen and corrective actions included chart pen repair and probe recalibration. Approximately (b)(4) lots of aseptically filled drug products were manufactured using the vials processed in this oven and were released for distribution. You conducted a product assessment; however, it only included products manufactured from July 2010 to July 2012. Your assessment should have included products manufactured from July 2009 to July 2012, which represents the time frame between the last two calibration dates of the temperature recorder. Comment: A basic failure not to investigate back to the previous calibration date. Of particular interest is that this chart recorder must have a calibration interval of three years. That is too long of a time to potentially impact product. What is your max cal interval in this situation?

16. Number 1 Not Following Metrology Recommendation – FDA 483 Inspection Update - 18 Apr 06 OBSERVATION 3 The use of instruments and apparatus not meeting established specifications was observed. Specifically, In December 2005, the Quality Control Unit (QCU) determined the need to replace the flow rate valves of all [REDACTION] apparatuses as a result of frequent clogging, flow rate problems, and increased bubble formation that randomly caused "erratic" dissolution results. [REDACTION] valves were purchased and received in January 2006; however, the QCU failed to adequately monitor the implementation of this corrective action and, as a result, the valves were not installed and the use of these dissolution baths with potentially malfunctioning valves continued for dissolution testing of all Cartia, Diltia, Taztia, Metformin, Naproxen Sodium, and Ketoprofen drug products. Subsequent to the determination of performance problems with the [REDACTION] dissolution apparatuses, the Metrology Department, responsible for laboratory equipment maintenance and calibration, conducted an investigation (date not documented & investigation not tracked) to determine the root cause of the problems in the dissolution apparatuses. The investigation concluded that "due to a blockage on the pores caused by crystal deposits (salts interference), air bubbles may form cause false readings in the middle of the run that do not represent a true absorbance reading of the sample" and recommended more frequent maintenance schedules to prevent flow valve problems. However, the QCU reported that the problem had been fixed in January 2006 with the replacement of the valves (that didn't take place) and failed to implement the recommended corrective and preventive/maintenance actions in a timely manner. Comment: The QCU had two opportunities to implement recommended solutions and failed each time. However, many companies do not rely on just one safety net. Where are all of the other functions helping to ensure actions are being implemented correctly?

17. BONUS 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.

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