Folks, for this week’s guidance Dr. D is going to dive into a warning letter awarded to a sterilization service provider in May. Now as the doctor has stated on many occasions, my experience with germs, bugs, and other micro-organisms is that these are bad things that have ability to leave their tiny-little skeletal remains on medical devices. Can you say pyrogen?Now it is a given that the device industry has created a variety of effective ways for killing these little critters: (a) gassing them with Ethylene Oxide; (b) nuking them with radiation; (c) or cooking them with an autoclave.

However, what happens when one of these sterilization facilities runs afoul of FDA for failing to comply with Quality System Regulation? If you answered warning letter, you would be correct.

This week’s warning letter contains so much of the proverbial cannon fodder as to how not operate an establishment supporting the medical device industry; Dr. D will execute his best Sigmund Freud and analyze it for the next few weeks. Seriously, people, the warning letter observations are that toxic, no pun intended. When the FDA finds compliance issues premised on the “bricolage” (look-it-up) of potentially falsified data, things are always going to end badly. Bright orange jumpsuits and shiny stainless-steel bracelets just might be in someone’s future. Enjoy.

FDA Warning Letter – 22 May 2014

Now Dr. D has never been to Libertyville, IL. However, FDA spent parts of four months there from October 29th to January 8th of this year, and left their hosts with nine Form 483 observations that resulted in an award winning prize, a world-famous agency warning letter. I am assuming the investigators just might have been Bears, Bulls, and Blackhawks fans, but that is probably a stretch. The doctor thinks the concerns relating to the potential incorrect dosing of finished medical devices with gamma radiation caught FDA’s attention. Regardless, Dr. D’s objective is not to disparage an establishment that has been the focus of an intense agency inspection but to educate industry so the same mistakes are not repeated. Dr. D says, “a wise man learns from the mistakes of others.”

Observation Three (3) “Failure to ensure that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems, as required by 21 CFR 820.100(a)(6). For example, on July 29, 2013 your firm’s Libertyville North facility initiated an investigation, NC-05731, into product runs that were overdosed and were subsequently made to appear within customer specification by employee data falsification and manipulation of dosimetric equipment. This investigation identified approximately 89 runs as potentially affected. Your firm did not inform all of the identified customers that the dosimetric testing of their products may have been subject to falsification of dosimetric data. In addition, your firm’s failure to notify customers extends to all customers of runs that were not properly identified by your firm as being potentially affected during your initial investigation of NC-05731 (see Warning Letter point 1b).

We have reviewed your responses and have determined that they are inadequate. Specifically, your responses did not include evidence to support your statement that customers were notified after the inspection concluded and to show what information was reported to customers. In addition, your responses indicated that PROC-00034, “(b)(4) Processing Review and Approval”, was updated to state that communication to the customers is required if re-read data is accepted as the final read to release product; however, this revised document was not included with the response to allow for FDA review. It is unclear what the timeframe for customer communication is in the revised PROC-00034.”

Observation Four (4) “Failure to establish and maintain procedures for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100(a)(2), and to adequately document all activities required under Corrective and Preventive Action, and their results, as required by 21 CFR 820.100(b). Specifically, your firm’s procedures, including PROC-00036, “Routine Use – (b)(4) Dosimetry System”, allow for previously measured results and calculated dose values to be changed without a documented investigation.

We have reviewed your responses and have determined that they are inadequate because the responses indicated that PROC-00034, “(b)(4) Processing Review and Approval”, will be updated to ensure that there is a thorough review of any discrepancy that arises between initial and re-read dosimeter calculations; however, this document was not included with the response to allow for FDA review. In addition, the responses do not indicate what revisions, if any, are going to be made to PROC-00036, “Routine Use – (b)(4) Dosimetry System”, which currently allows re-reads to be taken without a documented investigation.”

21 CFR, Part 820

Section 820.100 – Corrective and preventive Action

(a) Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. The procedures shall include requirements for:

1. Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems. Appropriate statistical methodology shall be employed where necessary to detect recurring quality problems; 
2. Investigating the cause of nonconformities relating to product, processes, and the quality system;
3. Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;  
4. Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;  
5. Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;  
6. Ensuring that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems; and
7. Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented.

Compliance for dummies

Now the doctor has covered CAPA multiple times over the years so jumping up onto the old soapbox to pontificate is probably not going to provide a whole lot of value for you old timers. However, there is always value in providing a quick refresher course in what FDA actually expects from a reasonably robust CAPA program, so please read on. Not wanting to state the obvious but obliged to do so, device establishments must actual script a well-written SOP for CAPA and actually adhere to it. Input into the CAPA system can come from:

(a) manufacturing operations;
(b) audit reports (internal, external, and supplier);
(c) customer complaints;
(d) management review meetings;
(e) other non-conformances, e.g., product or process issues; and
(f) statistical trends negatively reflecting product performance or the effectiveness of the QMS.

In short, all organizational problems (opportunities) are candidates for the CAPA system. Additionally, CAPA is not a single-step process. It is a series of steps that organizations pursue to prevent a recurrence of product non-conformances, QMS issues, or unwanted process performance issues. That being said, the QSR requires device establishments to:

• Perform immediate containment activities to stop the proverbial bleeding and prevent the non-conformance form further expansion (e.g., locking down violative product to prevent further exposure to potential patient and user risk);
• Investigate non-conformities (e.g., it better be to root-cause);
• Identify all of the steps pursued prevent a recurrence;
• Revise processes, procedures, work instructions, etc. to preclude future non-conformances (please note: design changes may require a new or abbreviated 510(k) for Class II devices and will require a supplemental PMA for a Class III device);
• Validate that the corrective action pursued is actually effective, including the assurance that actions taken are not negatively impacting the overall safety and effectiveness of finished medical devices (a.k.a., Verification of Effectiveness);  
• Disseminate relevant information on quality problems and problems resulting in product non-conformances with individuals responsible for product quality (in Dr. D’s book that is everyone, assemblers, inspectors, engineers, etc.);
• Ensure CAPA activities, including status, is an integral part of management review; and
• Document all CAPA activities in writing. Why? If an event or activity is not documented in writing, in the eyes of FDA, it simply did not occur.

Takeaways

For this week’s guidance, Dr. D is going to leave the readers with just one takeaway. The doctor is clairvoyant and sees a future full of pain for the owners of this week’s warning letter. Whenever phrases such as “data falsification” are referenced by FDA in a warning, the offending organization will probably become familiar with the acronym DOJ, as in investigation. Falsifying data that may have resulted in the overall compromising of product safety and efficacy is a serious accusation.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. FDA’s enforcement page. (2014, May). FDA.gov Website. Retrieved June 4, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm399011.htm