It is Dr. D’s personal belief and strong opinion (yes – all of the doctor’s opinions are strong), the importance of an effective CAPA system equates to the basic blocking and tackling skills exhibited by good football teams. Additionally, FDA will always take a quick peek at CAPA during one of their friendly visits. Ok, I am sorry, the doctor just mislead the readers. Correction: FDA will take a long-hard look at CAPA during one of their visits; and use the results as a starting point for their investigation.
Furthermore, CAPA should actually result in a problem being permanently resolved or a potential problem averted. Finally, ensure each step of the CAPA process is well-defined. Dr. D recommends pursuing a Five-Step Model encompassing (a) problem definition, analysis, and scope; (b) initial investigation; (c) problem solution and implementation; (d) verification of effectiveness; and (e) disseminating the results, including management review. Remember to keep in mind the potential impact to product safety and efficacy, regulatory compliance, and overall quality system effectiveness, resulting from CAPA driven changes to product, processes, and procedures.
Warning letter violations
As with most editions of Devine Guidance (DG), the warning-letter issues identified in this edition expose the lack of procedures and/or effective procedures. Device manufacturers not having written procedures continues to be a salient thread linking compliance issues and violations. The two warning-letter recipients highlighted in this edition of DG are no exception, and as far as Dr. D is concerned, that is a problem. I am at a loss as to how to motivate device manufacturers to understand and grasp two basic concepts:
- DG Rule # 1 – compliance to regulations is not optional it is mandatory and dictated by law; and
- DG Rule # 6 – all procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled within a defined document control system.
What concerns Dr. D greatly is that the medical device industry is expanding rapidly in an effort to keep up with an aging population. Let’s face it boomers, we are not getting any younger. However, ongoing compliance to the QSR continues to be a growing problem, as evidenced by the significant increase in the issuance of warning letters. Maybe making DG a mandatory reading assignment for device manufacturers (Devine Guidance – 101) could help stem the flow of current and future compliance problems. Yes, the doctor is delusional. Forcing offending device manufacturers to read DG is probably not going to happen, but Dr. D just cannot help himself as I have never been accused of being a milquetoast (look-it up if you must).
Warning Letter One (August 2010): Observation 1 of 2 – Failure to establish and maintain procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100(a). Specifically, although product quality problems were identified and corrections were made associated with Correction Removal numbers 9 and 10, the corrective action reports were not generated for these corrections and associated activities as specified by SOP 1401 Revision B.
Warning Letter One (FDA Response): We have reviewed your response dated March 31, 2010, and have concluded that the adequacy of the response cannot be determined at this time. Your firm states that SOP 1401 Rev B will be revised, employees retrained, etc., but the firm did not provide copies of the revised procedure and did not provide evidence that employees had received training on the revised procedure because the promised corrective actions had not occurred at the time of the firm’s response.
Warning Letter Two (July 2010): Observation 1 of 5 – Failure to establish and maintain procedures for implementing corrective and preventive actions, as required by 21 CFR § 820.100(a). For example, you do not have a written corrective and preventive action procedure.
Warning Letter Two (FDA Response): We have reviewed your response and have concluded that it is inadequate. Your firm has not adequately addressed the requirements of 21 CFR § 820.100(a) nor have you informed us of any specific plan or provided evidence of immediate corrections and systemic corrective actions.
Quality System Regulation – 21 CFR, Part 820
QSR – Subpart J – Corrective and Preventive Action 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.
Procedures for CAPA are required and need to be effective
As evidenced by the two warning-letter excerpts selected for this DG edition, procedures for CAPA are required and need to be effective. When designing and implementing an approach to CAPA, the QSR is very descriptive in regards to what elements are required to be addressed. The QSR specifically calls out seven salient points that shall be addressed in an effective CAPA procedure. Yes, Dr. D presented a 5-Step Model in the introduction; however, the doctor has taken professional liberty and combined a couple of steps. In fact, device manufacturers have the freedom to tailor their approach to CAPA, to fit their specific business model, providing compliance to all of the QSR requirements is achieved.
What is FDA looking for in regards to analysis? In short, the FDA wants device manufacturers to continually monitor all aspect of their operation and use the results, if warranted, as quality inputs into the CAPA system. For example, unfavorable trends in yields discovered on the manufacturing floor, a nonconformance discovered during an internal quality audit, returned product, and product complaints are a few examples of quality inputs requiring input into the CAPA system. The QSR specifically adds a callout for “other sources of data” and “other quality problems.” These catchall phrases equate to considering all potential and actual quality problems for inclusion into the CAPA system or an “all encompassing approach.” Remember two of the salient purposes of CAPA are; (a) to prevent problems from occurring, and (b) prevention of problem recurrence once a problem has occurred.
Cut and dry investigation
The investigation piece associated with CAPA is pretty cut and dry. The QSR requires device manufacturers to investigate the cause of ALL product issues (nonconformities), process issues, and quality system issues. Remember, device manufacturers are not free to pick and choose the problems they want to resolve. Device manufacturers need to fix all nonconformities that have been identified. Additionally, device manufacturers need to exhibit a sense of urgency in executing investigations. One year, or even longer, is just too damned long to complete an initial investigation. Furthermore, if the agency determines the approach to CAPA investigations is unsatisfactory, the device manufacturer can expect a From 483. Finally, please ensure your management representative is contrite as he or she apologizes for your organization’s indiscretions and asks the investigator, “Where do I sign the form?” One final comment from Dr. D, ensure the investigation is to root-cause. One area of CAPA investigation, that I continue to see as problematic, is a lack of in-depth analysis capable of resulting in the identification of the real root cause.
The expectation of the FDA is that once a CAPA investigation is complete, the appropriate actions needing to correct nonconformities should be identified. The doctor would like to warn the readers against using too many concessions such as “no-further action is required due to an isolated incident” or and oldie but a goody “no obvious trend.” Device manufacturers that frequently invoke concessions are typically awarded with Form 483s. That said, once the appropriate actions have been identified, Dr. D strongly recommends moving into implementing the recommended actions.
Validation and verification
Although device manufacturers are typically pretty confident when they move into their implementing solution phase, they must first determine if the proposed action is going to have a negative impact on product safety and efficacy of finished devices. Dr. D is pretty positive, well maybe somewhat positive; device manufacturers do a good job performing in-depth root-cause analysis, while identifying potential corrections to problems. However, the FDA wants device manufacturers to be absolutely sure there is no potential impact to finished devices, prior to implementing changes.
Moving into the implementing-solution phase, device manufacturers need to ensure all changes are documented. Dr. D’s not so secret approach is to employ the change request process that feeds the document control system. All changes need to be reviewed and approved. Additionally, changes made to product need to be captured within the Design History File (DHF). Furthermore, ensure FMEAs are reassessed for potential changes in levels of risk and/or occurrences. Finally, all corrections made that change the design or a process associated with a Class 3 device, will probably require a formal review and approval by the FDA. Can you say PMA supplement?
Information is and always will be a powerful tool. It should be incumbent upon all device manufacturers to ensure information associated with quality problems, nonconforming product, and potential quality issues be disseminated amongst the proverbial ranks. Successful dissemination of information, i.e., Kaizen circles, etc, will result in the prevention of problem recurrence. For example, if there have been MDRs identifying tip separation from a catheter, and the failure investigation determines the root-cause is process related, the operators on the manufacturing floor need to be made aware of the process problem. Otherwise, trust Dr. D when I say, “history will repeat itself.”
Ensure CAPA is an integral part of management review. All problems, issues, preventive actions, and corrective actions, shall be incorporated into the management review process. Guess what? If the CAPA system is deemed to be ineffective by the agency, during one of their friendly visits, the ineffectiveness of management responsibility may also come into question. For example, not closing CAPAs on-time, or prolonging closures due to multiple extensions, or claiming a lack of resources to work on CAPAs, will result in two Form 483s observations; one observation written against the CAPA system, and one observation written against management responsibility.
Once again, Dr. D must invoke DG Rule # 3 – Document the results of all events in writing, because if it is not documented in writing, the event did not occur. Now climbing onto my soapbox, I will ask you to repeat after Dr. D, “Documented evidence is your best defense during a friendly visit from the FDA.” I cannot over emphasize the importance of accurate documentation. Besides, documenting the results is a salient requirement of the QSR.
I think the most important takeaway, for this edition of DG, is to use the CAPA system to fix all of your quality problems. A strong CAPA system will allow organizations to track quality problems to closure. Additionally, when problems are identified or potential problems noted, device manufacturers need to act quickly. If you ever want to see Dr. D angry, one way to do it quickly is to place a problem or other nonconformance into the CAPA system; and then take over a year to resolve an issue that should have been corrected in a few days or worst case a couple of weeks. In fact, that type of performance will quickly grab the attention of the agency as well. Remember CAPA is not rocket science. You identify problems and you fix problems.
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, when I evaluate Subpart – K (Labeling and Packaging Control), specifically (820.120 – Device Labeling and 820.130 – Device Packaging) – cheers from Dr. D. and best wishes for continued professional success.
Code of Federal Regulation. (2009, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
Devine. C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ.
- FDA – U.S. Food and Drug Administration Website. (2010). Warning letters. Retrieved August 24, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/