Let’s face it, receiving a Form 483 letter (Notice of Inspectional Observations) from the FDA has never been much fun. And since the September 2009 change to the statutory response time (now 15 days) there isn’t that much time to react. What to do?
1. Don’t panic. I know, I know – these words usually have the opposite effect. Beyond the cliché, however, you will find that keeping a detached attitude and cool head, even if the response deadline is so short, will help you in the long run. The 483 letter wording will cite specific observations and then generalize non-compliance back to the high level provisions of the Code of Federal Regulations (21 CFR Part 820, Part 11, etc.) Even though this might imply that your firm is completely out of control in those areas, in reality it just puts the onus on you to argue to the FDA’s satisfaction that the letter’s implied inference was incorrect as the inconsistencies (if accurate) will be removed in a timely fashion. And that is the purpose of the response letter.
2. Immediately appoint a “Response Manager” (RM) and assemble a response team. Your response team should include representatives from all the functional areas cited (manufacturing, operations, engineering, etc.), quality / regulatory leadership staff, external consultants, etc.
3. Your RM should prepare a tracking spreadsheet with the following content:
a. The observation as worded in the 483 letter
b. Name of responsible individual
c. Due date for response draft
d. Summary of the internal investigation
e. Root cause (if applicable) related to each of the specific observation(s)
f. Plan to eliminate root cause (action items, people responsible, due dates)
g. Systemic issue (if applicable) related to the result of the internal investigation
h. Plan to implement systemic change to prevent similar non-conformances in the future
i. Plan to verify the effectiveness of the correction and of the systemic change
j. The response as worded in the response letter
4. Some 483 observations might be related to FDA recommendations and might not cite violations. You might want to consider improvement plans in those areas, or explain why not based on a documented risk assessment (or other viable considerations).
5. For observations which you believe were based on incomplete or inaccurate evidence, it is best to prevent such observations during the audit if at all possible (how to prevent inaccurate 483 observations during an audit is the topic for another discussion). Failing that, however (and if you still believe that the observation is inaccurate), you can try to argue your point in the response letter, but only if you can produce new factual evidence that supports your claim. You should include copies of the factual evidence as attachments to your response.
6. Your correction and improvement plans will be much more believable to the FDA if you retain the assistance of qualified external consultants to plan, manage, and / or execute the action items contained therein. After all, if your employees had the requisite knowledge and expertise already, why did your firm exhibit the non-conformance(s) in the first place?
7. Your RM should start assembling a Proof Book to show the FDA when they return, with the following entries:
a. A copy of the original 483 letter
b. A copy of your response and any subsequent correspondence with the FDA
c. Proof of remedial activity (plans, dates, status reports, protocols, decisions, training records, proof of task completion, internal audit reports, proof of effectiveness, etc.)
d. Traceability of findings to responses, plans, CAPAs, recalls, customer letters, etc.
8. Your quality system might require that a CAPA and / or a complaint be raised for each 483 observation, or just for the ones with a higher level of risk. Make sure to follow all your internal procedures as well.
9. Your action plans should be believable, achievable for your level of corporate resources, and timely. Have your Legal department (or your external legal counsel) review your response letter before you send it in. Your response letter is a legal document and you will be held to it when the FDA returns.
10. Send your response to arrive no later than 1 day before the deadline via a traceable delivery system with proof of delivery. USPS Express Mail overnight usually works best, FedEx overnight a close second.
Each regulated area is different, and not all consultants and consulting companies are equally qualified in all areas of compliance (even if you or someone you know did business with them in the past). If you would like urgent external assistance and you are not sure who to call, we can help you quickly locate the best consultant or consulting firm for your very specific situation. Please visit www.priusmedical.com for details.
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