warning letters

This blog reviews 5 of the most common reasons for why CDRH issues FDA warning letters, and preventive actions are suggested for each of the five reasons.

The following is a quote from an interview I conducted with a former FDA inspector:

“You’re in deep trouble if the [FDA 483] response is excellent, and the corrective actions are excellent, but when the FDA comes back, you never bothered to implement those corrective actions. Now you know that you have that warning letter coming at you.”

#1 – No actions implemented for CAPAs

The former inspector is describing one of the most common reasons for FDA warning letters. If an FDA investigator issues an FDA 483, you are required to respond with a corrective action plan (http://bit.ly/FDA-483). However, you must implement your plan to close the FDA 483 inspection observation(s) during the next FDA inspection. CDRH’s QSIT inspection manual (http://bit.ly/QSITManual) requires that the CAPA process be evaluated during every inspection–even during abbreviated inspections, where only two of the four major quality subsystems are sampled (i.e., “CAPA + 1”). Therefore, the FDA investigator will notice if no actions have been taken for CAPAs that were initiated since the last inspection. If the CAPAs are specific to the FDA 483–CDRH requires the FDA investigator to review those records first. To ensure that corrective actions are being implemented and documented, I recommend three ways of controlling the process:

1. monitor the “aging” of CAPAs and establish a quality objective for average days aging
2. have an independent expert perform a desktop audit of your CAPA process
3. ensure that you carefully review each CAPA that is behind schedule during Management Reviews (which should be at least quarterly)

#2 – FDA 483 response submitted late

A second common reason for receiving an FDA warning letter is a failure to submit an FDA 483 response to the district office within 15 business days. The FDA has always involuntarily required a medical device firm to respond to an FDA 483 within 15 business days, but in 2009, a post-inspection review program (http://bit.ly/15Dayresponse) was initiated where it became mandatory that response from any FDA 483 must be received by the Agency within 15 business days, or FDA warning letters are automatically issued. This is an automatic issuance that results in a very quick response from your CDRH district office. Therefore, you need to respond aggressively to FDA 483s with corrective actions and submit your response early.

Note: The FDA warning letters are only issued when inspection observations result in “Official Action Indicated” (OAI). However, inspectors will not tell you if the outcome is OAI or Voluntary Action Indicated (VAI). This determination is made by the District Office of the FDA. Therefore, all device manufacturers should assume that the outcome may be OAI. 

#3 – Submitting a response without evidence of implementing changes

This past Saturday, I recorded a webinar on the “7 Steps to Respond to an FDA 483 Inspection Observation” (http://bit.ly/FDA-483-response-webinar). The title of the third slide in that presentation is “The FDA may be late…”. I mentioned that it is not uncommon for FDA warning letters to be issued six months after the actual inspection occurred. The following warning letter is an example (http://bit.ly/fda-warning-letters-example1).

I don’t personally know this firm, but I found this example by searching through the FDA warning letters database: http://bit.ly/fda-warning-letter-search. The company received an FDA 483 with multiple inspection observations on November 4, 2010. The company was non-compliant in the following areas: CAPA (21 CFR 820.100), complaint handling (21 CFR 820.198), and design controls (21 CFR 820.30). The company responded to CDRH on November 23. This was 13 business days after the FDA 483 was received, and with FedEx shipping, it probably arrived at the FDA barely in time–November 29 (the Monday after Thanksgiving).

Unfortunately, the response did not include evidence of correcting the existing procedure deficiencies. The plan indicated changes were going to be made, but the FDA expects you to revise procedure deficiencies quickly (i.e., before you mail the response to the FDA 483). If it is not possible to make corrections in this timeframe, a risk-based approach is recommended. For example, the complaint handling process is the most critical of the three processes identified as deficient in the warning letter. Therefore, the company should have enclosed a revised complaint handling procedure and promised to revise the CAPA and design control procedures within a few weeks.

The FDA warning letter was not issued for this example until April 6, 2011–almost exactly six (6) months from the date of the FDA 483 issuance. CDRH offices are ghost towns in December. Therefore, it was important for the company to contact CHRH early in November and identify an email address and contact to send documentation regarding the implementation of corrective actions. The company could have revised the other two procedures in December and implemented all three procedures in December. Evidence of thorough implementation of corrections and corrective actions by email is often adequate to prevent FDA warning letters.

For international firms, this is extremely important because a second warning letter for an international firm results in a warning letter with automatic detention (i.e., the company cannot import a product into the USA). In this example, the second warning letter was issued on November 26, 2012 (http://bit.ly/fda-warning-letters-example2).

#4 – Failure to remove objectionable marketing communications

The FDA does not routinely visit companies that only manufacture Class 1 (i.e., low-risk) devices. However, they routinely visit companies that manufacture medium-risk, Class 2 devices. The FDA reviews websites and other marketing communications for marketing claims that are not within the scope of an issued 510k. Typically, the claims that are allowed are almost verbatim from 21 CFR (i.e., Title 21 Code of Federal Regulations). Therefore, many companies receive an FDA 483 indicating that they are claiming an indication for the use of which the device does not have clearance (i.e., a 510k) for. In these cases, the company is expected to remove the claims and/or submit a 510k. In these cases, often CDRH will wait a year or more before taking additional action to give the firm ample time to obtain clearance for the indications. Here is a link to an example of a warning letter of this type: http://bit.ly/fda-warning-letters-example3.

#5 – Design controls are not implemented at all

Design controls are the most common reason for the issuance of an FDA 483 (http://bit.ly/FY2013-483-Data-Analysis). If you read the blog, Medical Device Academy wrote on the data analysis of FDA 483 inspection observations issued in FY2013 by CDRH, and you may have wondered how design controls are the #1 most common FDA 483. Still, the highest individual clause reference is #8 [i.e., 21 CFR 820.30(i)]. If you review this next warning letter example (http://bit.ly/fda-warning-letters-example4), it should become clear that some companies do not have a design control process implemented at all. In this situation, the FDA investigator is likely to issue a separate FDA 483 against each of the required elements:

1. 21 CFR 820.30(e) – design reviews
2. 21 CFR 820.30(f) – design verification
3. 21 CFR 820.30(g) – design validation
4. 21 CFR 820.30(h) – design transfer
5. 21 CFR 820.30(i) – design changes

In this specific example, the FDA investigator issued the FDA 483 on August 16, 2012, and the warning letter was issued immediately after the FDA returned from the holidays–January 4, 2013. This firm had a narrow window of time between August and November to submit an FDA 483 response and then follow-up with documentation of completing the CAPA plan. The warning letter indicates that the corrective action plan was not adequate, but the FDA still took several months to issue the warning letter.

If you recently had an FDA inspection and received an FDA 483, make sure you don’t make any of the mistakes above. You might also want to take the webinar on this topic: http://bit.ly/FDA-483-response-webinar.

If it’s been a year since you received an FDA inspection, you might want to watch the video on this webpage: http://bit.ly/regulatory-compliance-services