A few comments for consideration with my opinion.
First, I think that you are trying to make a connection between two unrelated issues. Particulate formation has nothing to do with sterility. Your demonstration batch is to provide the preliminary data to demonstrate that changing the vial type has solved your particulate issue. You will confirm that it has worked with the validation batches. It is the particulate formation issue you want to focus on in your amendment. The demonstration batch simply demonstrates the fix works - it is not a full "registration" batch unless you make it one. If it didn't follow the same batch record in the same facility as the planned commercial batches, don't use it for anything other than demonstration of the fix.
Secondly, what does GMP or non-GMP have to do with sterility? Did the CMO not follow normal GMP operations in their fill where they are worried that it would not pass? (You can't do that in an ISO classed facility.) If the demonstration batch took place in the same facility as the planned NDA activities, the sterility data is irrelevant to your issue. Don't dwell on it. If the CMO outright refuses to do the test (which is puzzling), and you believe the information is critical, you can always send vials to a different CRO and have them do the test. I wouldn't think it would be worth the effort based on what you have provided in your question.
Finally, you shouldn't be asking FDA what they think you should do. It implies you don't know what you are doing. You should provide a scientifically valid justification for what you are doing, explain why what you have done is appropriate, and ask for their approval of your plan.
It is unlikely that the test results for a single test would lead to a RTF unless the results were critical to the evaluation of the submission. It appears you have already informed the FDA of the issue, explained that you have a fix, will be providing the data for the fix, and have the FDA's approval that a single demonstration of the fix is adequate for now. An additional communication regarding an issue unrelated to the problem and its fix would simply be a distraction. Discuss it in the amendment only.
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Thomas Weber
Tom Weber CMC Consulting, LLC
Santa Rosa CA
Original Message:
Sent: 01-18-2016 20:48
From: Tom Stothoff
Subject: Sterility testing of Registration Batch
During FDA review of our NDA for a parenteral product, it was discovered that particulates were forming in stability samples. Included in the NDA were stability data on 4-5 clinical batches including sterility results. Due to the particulate issue it was decided to switch to a different vial and amend the NDA with data from one demonstration batch packaged into the new vial. FDA agreed in advance to 1 batch. Is it required that sterility testing be conducted on the demo batch? Or would any sterility concerns FDA may have be addressed by the results from the previous clinical batches? We recently discovered our CMO did not test sterility and refuses to do so since this is considered a non-GMP batch. The old and new vials have the same dimensions and use the same stopper.
I am considering informing FDA prior to submitting the amendment for the new vial in order to confirm if lack of sterility data would be a refusal-to-file issue? And if not, would it even be required at all for the demo batch. If FDA says it is required, we are considering proposing to manufacture validation batches sooner so we can amend NDA during FDA review with sterility data from the PV batches.
Any comments, thoughts, suggestions on this strategy are greatly appreciated.
Tom
Chicago