by Robert Packard, President, Medical Device Academy
Responding in 15 days is one of seven steps on how to respond to an FDA 483 inspection observation. This blog post also includes advice from a former FDA investigator.
When an FDA investigator has an inspection observation, the investigator issues an FDA 483. This is the FDA’s form number. If your company receives an FDA 483, how you respond to the FDA 483 is crucial to avoiding a Warning Letter. In the words of Leo Lagrotte, a former FDA investigator I work with, “Many, many times I have seen an [Official Action Indicated (OAI)] classified inspection that had been recommended for a Warning Letter by the compliance branch be set aside based upon the response of the firm.”
The best way for your company to respond to an FDA 483 is by writing a cover letter, and then every observation needs to be addressed in the response as a separate CAPA–unless the root cause is identical for two observations. Make sure that your response includes the following seven steps:
1. Respond within 15 business days (earlier is better)
2. Use your CAPA form and a cover letter–instead of a memo
3. Document the investigation that was conducted with a concisely stated root cause
4. Identify containment measures and corrections to address each specific observation by the FDA inspector
5. Identify corrective actions planned and the date(s) you expect to complete implementation
6. Include documentation of containment, corrections and corrective actions that are completed at the time you submit the response
7. Follow-up with a memo confirming that all the corrective actions are complete and include all related documentation–including training for any new procedures or any new corrective actions that warranted training
Respond to the FDA 483 violation(s) in less than 15 business days
The FDA has always involuntarily required a medical device firm, or any firm under FDA jurisdiction that received an FDA 483, to respond in writing to the FDA 483 to the District Office within 15 business days. As of two years ago, (http://bit.ly/15Dayresponse) it became mandatory that a response from any FDA 483 must be received by the Agency within 15 business days, or an automatic Warning Letter is issued. You need to respond aggressively to FDA 483s with corrective actions, and submit your response early.
Use your CAPA forms instead of a memo
I have asked several former FDA investigators whether they would prefer to see firms submit responses in memo format or by using their CAPA forms and a cover letter. Some told me that they prefer to see firms use their CAPA forms, while others don’t seem to have a preference. Nobody from the FDA has ever indicated a preference for a memo. I see no point in doubling your work and risking transcription errors. If you have an electronic system that does not have an output format that is easy-to-follow, go ahead and copy-and-paste the information from your electronic database to your memo. If the CAPA system output is easy to follow, just use a cover letter and copies of the forms.
Document the investigation and root cause
This is definitely my pet peeve, but a one-sentence “root cause” is not enough for an FDA 483 response. Regardless of whether I am doing a mock-FDA inspection, an internal audit or a supplier audit---I expect you to document how you determined the root cause (http://bit.ly/RootCauseTraing). If it’s trivial and obvious, then it must have been something important, or I would not have written a nonconformity. Therefore, you should be looking beyond the immediate scope of the FDA 483 to ensure that a similar problem cannot occur elsewhere. In the language of the FDA, this is a preventive action, because you are preventing occurrence with another process or product. Most ISO certification auditors are purists and they won’t accept this as a preventive action. You will have to show the purists something special–maybe from your data analysis.
Don’t forget containment and correction
For every 483 observation, including the subparts, you need to identify if immediate containment is necessary and how you can correct the problem. Whenever possible, you should attempt to implement the containment and corrections during your FDA inspection. In fact, it would be fantastic to give the FDA inspector a copy of the new CAPA you initiated during the audit. The new CAPA would identify containment and corrections that have been, or will be implemented–including any nonconformity(s) you initiated to quarantine product. You may still get an FDA 483 inspection observation, but you are likely to convert a possible Official Action Indicated (OAI) into a Voluntary Action Indicated (VAI). You can also modify the CAPA wording later to include a cross-reference to the FDA 483 and quote the exact wording the inspector uses.
Explain the corrective action plans and timelines
Clarity, brevity and realistic plans are critical in this section of your response. I prefer a table that looks like the example shown below.
Target Completion Date
Retrain all personnel in the complaint handling unit on the revised SOP for MDRs.
July 31, 2014
Revise the Master Validation…
Manufacturing Engineering Manager
August 10, 2014
Show the FDA you have already taken action
Whenever possible, you want to show the FDA that you are taking action without delay. If you revised the SOP for MDRs and scheduled a group training for July 15, then you should provide the FDA a copy of the revised procedure and a copy of the agenda for your planned training session. The only caution is to only commit to actions you are certain you will implement. You can always do more, but it will be much harder to explain why you did not implement an action you submitted in your FDA 483 response.
Follow up before the FDA does
The FDA’s compliance office will be looking for a response when an FDA 483 is issued, and they will review your response. The investigator will get a copy of the FDA 483 response and the investigator will comment on the response. The compliance office and the investigator enter their comments into a CDRH database but the comments are only general as to whether the response is adequate or inadequate and will require additional review.
If you do not hear back from the FDA, do not assume that the compliance office or the investigator were satisfied. You should also follow-up several months later (earlier if possible) with a letter that includes evidence of the completed corrective actions, and your verification of effectiveness. If the verification is compelling and received in less than six months of the inspection, you may convince the compliance office to hold off a planned Warning Letter.
If you are interested in root cause analysis and improving your CAPA process, please click on this link for another webinar recording: http://bit.ly/CAPA-Webinar. A webinar recording titled “7 Steps to Respond to an FDA 483” will be available soon at the following link: http://bit.ly/FDA-483-response-webinar.
This article was republished by permission from the Medical Device Academy, which provides solution-based regulatory consulting (regulatory submissions and compliance) and the continuing education training services to medical device manufacturers. Please visit www.medicaldeviceacademy.com to learn more about how we can help your firm today.
Robert Packard is a regulatory consultant with 20 years’ experience in the medical device, pharmaceutical and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was senior manager at several medical device companies---including President/CEO of a laparoscopic imaging company. His quality management system expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications and 510(k) submissions. The most favorite part of his job is training others. Please visit his website, www.MedicalDeviceAcademy.com, if you are interested in reading his blogs or registering for a training event. You can also email him directly at: firstname.lastname@example.org.