Regulatory Open Forum

We are in Phase 3. Our current API manufacturer has also been doing micronization and we have already made our 3 registration batches of API for the NDA, but their equipment capacity is not ideal for our planned commercial batch size needs so we are in the process of identifying an alternate CMO for micronization. This 2^nd CMO will likely be the primary site for micronization going forward. Our plan is to qualify the 2^nd CMO during Process Validation. Plan would be to have current API manufacturer micronize 1 or 2 PV lots (I suggest 1 since they will be the backup site for micronization) and alternate CMO micronize 1 or 2 PV lots (I suggest 2 since this CMO will be primary site for micronization). API specification and PSD acceptance criteria would be the same for API micronized at either site. We'll need to manufacture the API PV batches before NDA submission in order to have ready to make tablet PV batches after NDA submission. 

Appreciate any thoughts/opinion on this strategy.

Thank you.

Tom,

The plans seems reasonable, as you would have to do process validation at both micronization sites if plan to use both commercially. You could delay the PV of your secondary site if you do not plan to use that site immediately. Of course, the key here is to show that the API registration batches are comparable to the 2nd CMO's  API batches and presenting this data in your NDA. I do not know the details, but this might include comparison of the micronization process, specifications, and stability (possibly drug product as well). In addition, it would be helpful to have a  2nd CMO's with a strong FDA inspection history. You might want to discuss the move to another micronization site and the comparison data you will be presenting with the FDA in your pre-NDA meeting or earlier.

Regards,

We are in Phase 3. Our current API manufacturer has also been doing micronization and we have already made our 3 registration batches of API for the NDA, but their equipment capacity is not ideal for our planned commercial batch size needs so we are in the process of identifying an alternate CMO for micronization. This 2^nd CMO will likely be the primary site for micronization going forward. Our plan is to qualify the 2^nd CMO during Process Validation. Plan would be to have current API manufacturer micronize 1 or 2 PV lots (I suggest 1 since they will be the backup site for micronization) and alternate CMO micronize 1 or 2 PV lots (I suggest 2 since this CMO will be primary site for micronization). API specification and PSD acceptance criteria would be the same for API micronized at either site. We'll need to manufacture the API PV batches before NDA submission in order to have ready to make tablet PV batches after NDA submission. 

Appreciate any thoughts/opinion on this strategy.

Thank you.

Hi Tom,

What you describe is quite typical to change manufacturers to meet market needs after NDA approval.  Clearly the NDA has been submitted with the initial micronizer.  If (when) the NDA is approved, the approval will be based on the initial micronizer.  In order to introduce the 2nd micronizer, a supplement will need to submitted upon NDA approval.  Do all the background work for the 2nd micronizer (qualification, equivalence testing, etc.) and prepare the supplement for submission immediately after NDA approval.  To try to introduce the 2nd micronizer before NDA approval (by an amendment) would the delay approval process and raise the prospect to withhold approval if a PAI should fail.  Product using the 2nd micronizer can be marketed only after the s-NDA is approved.

Tom,

The plans seems reasonable, as you would have to do process validation at both micronization sites if plan to use both commercially. You could delay the PV of your secondary site if you do not plan to use that site immediately. Of course, the key here is to show that the API registration batches are comparable to the 2nd CMO's  API batches and presenting this data in your NDA. I do not know the details, but this might include comparison of the micronization process, specifications, and stability (possibly drug product as well). In addition, it would be helpful to have a  2nd CMO's with a strong FDA inspection history. You might want to discuss the move to another micronization site and the comparison data you will be presenting with the FDA in your pre-NDA meeting or earlier.

Regards,

We are in Phase 3. Our current API manufacturer has also been doing micronization and we have already made our 3 registration batches of API for the NDA, but their equipment capacity is not ideal for our planned commercial batch size needs so we are in the process of identifying an alternate CMO for micronization. This 2^nd CMO will likely be the primary site for micronization going forward. Our plan is to qualify the 2^nd CMO during Process Validation. Plan would be to have current API manufacturer micronize 1 or 2 PV lots (I suggest 1 since they will be the backup site for micronization) and alternate CMO micronize 1 or 2 PV lots (I suggest 2 since this CMO will be primary site for micronization). API specification and PSD acceptance criteria would be the same for API micronized at either site. We'll need to manufacture the API PV batches before NDA submission in order to have ready to make tablet PV batches after NDA submission. 

Appreciate any thoughts/opinion on this strategy.

Thank you.