Regulatory Open Forum

Dear friends,

One question regarding in vitro dissolution test in support of in vivo waiver request per 21 CFR 320.22(d)(2) for approval following NDA 505(b)(2) pathway. Here the RLD is a gel product for non-oral use and the test product is for oral use. The product has multiple strengths and the lower strengths are dose proportional by virtue of the manufacturing process. Therefore, the goal is to request for bio- waiver for the lower strength approval meeting 320.22(d)(2) requirements . However, the dissolution method for the test product is very different from the FDA approved RLD dissolution method due to significant change in formula composition. Therefore, in vitro dissolution testing of the RLD and test product cannot be performed using the same method.  How do we approach the situation? The company is planning for PIND meeting with FDA. What should be the appropriate question to FDA?  Much appreciate your guidance.

Best regards,

Mercy

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Mercy James PHD, RAC, SCD
Warren NJ
United States
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Why do dissolution comparison if you have a different delivery? Keep in mind you have to justify your dissolution based on your delivery not the RLD. In this case the RLD provides no real data. Now with that said, I would use the FDA recommended dissolution method and compare and it the results are not identical I would not submit the data from the RLD and justify your specification.

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John Lay
Director, Regulatory and Quality
Vistapharm Inc.
Largo FL
United States

Original Message:
Sent: 11-09-2015 22:19
From: Mercy James
Subject: In vitro dissolution test: RLD Vs. Test for NDA 505(b)(2) pathway

Dear friends,

One question regarding in vitro dissolution test in support of in vivo waiver request per 21 CFR 320.22(d)(2) for approval following NDA 505(b)(2) pathway. Here the RLD is a gel product for non-oral use and the test product is for oral use. The product has multiple strengths and the lower strengths are dose proportional by virtue of the manufacturing process. Therefore, the goal is to request for bio- waiver for the lower strength approval meeting 320.22(d)(2) requirements . However, the dissolution method for the test product is very different from the FDA approved RLD dissolution method due to significant change in formula composition. Therefore, in vitro dissolution testing of the RLD and test product cannot be performed using the same method.  How do we approach the situation? The company is planning for PIND meeting with FDA. What should be the appropriate question to FDA?  Much appreciate your guidance.

Best regards,

Mercy

------------------------------
Mercy James PHD, RAC, SCD
Warren NJ
United States
------------------------------

Hi Mercy,

The most fundamental aspect of a 505(b)(2) is bridging all the changes of the new product to the RLD.  This means that anything like impurities, degradation products etc. need to be compared to the RLD and any differences evaluated, discussed etc.  There are often different methods for 505(b)(2) applications.  From my perspective, deciding you are  a 505(b)(2) and raising this at a P-IND is quite early in the development process.  What makes you a 505(b)(2)? Are you relying on nonclinical and clinical data from the RLD? If you have a stand alone non-clinical and clinical program to support your product and indication you may want to rethink this approach. Maybe this is really the question for FDA at some point, "we plan to submit the application as a 505(b)(2) and rely on the following information from the RLD......Do you agree?

For your questions, since you are going to an oral dose, then I would propose you need to meet USP and/or EP dissolution methods as appropriate. I would imagine that oral delivery vs. non oral would require different methods depending on the formulation and characteristics of the tablet, capsule, gel, etc. 

Just some thoughts,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principal Consultant RA, Quality and Compliance
Velocity Consulting
Ventura CA
United States

Original Message:
Sent: 11-09-2015 22:19
From: Mercy James
Subject: In vitro dissolution test: RLD Vs. Test for NDA 505(b)(2) pathway

Dear friends,

One question regarding in vitro dissolution test in support of in vivo waiver request per 21 CFR 320.22(d)(2) for approval following NDA 505(b)(2) pathway. Here the RLD is a gel product for non-oral use and the test product is for oral use. The product has multiple strengths and the lower strengths are dose proportional by virtue of the manufacturing process. Therefore, the goal is to request for bio- waiver for the lower strength approval meeting 320.22(d)(2) requirements . However, the dissolution method for the test product is very different from the FDA approved RLD dissolution method due to significant change in formula composition. Therefore, in vitro dissolution testing of the RLD and test product cannot be performed using the same method.  How do we approach the situation? The company is planning for PIND meeting with FDA. What should be the appropriate question to FDA?  Much appreciate your guidance.

Best regards,

Mercy

------------------------------
Mercy James PHD, RAC, SCD
Warren NJ
United States
------------------------------

Thank you John and Darlene for the swift response.

I think I need to explain a little bit more. The approval of the new product for buccal delivery is sought solely by establishing Bioequivalence with the RLD (gel). The RLD dosing regimen includes several doses and thus the new product includes several strengths matching with the RLD. The plan is to do the clinical study to establish BE with the RLD using the highest strength only. The lower strengths are dose proportional by virtue of the unique manufacturing process. Thus intent is to seek in vivo waiver request per 320.22(d)(2). Therefore, I thought in vitro dissolution data comparing test Vs. RLD using FDA approved method is a requirement (one of three criteria to be met). Due to the differences between the two formulations (test Vs. RLD), is it possible to get waiver of the comparative in vitro dissolution testing requirement?  In summary, what should be the data package to request in vivo study waiver for the lower strengths.

Thanks again for the help. Mercy

------------------------------
Mercy James PHD, RAC, SCD
Warren NJ
United States

Original Message:
Sent: 11-10-2015 10:30
From: Darlene Rosario
Subject: In vitro dissolution test: RLD Vs. Test for NDA 505(b)(2) pathway

Hi Mercy,

The most fundamental aspect of a 505(b)(2) is bridging all the changes of the new product to the RLD.  This means that anything like impurities, degradation products etc. need to be compared to the RLD and any differences evaluated, discussed etc.  There are often different methods for 505(b)(2) applications.  From my perspective, deciding you are  a 505(b)(2) and raising this at a P-IND is quite early in the development process.  What makes you a 505(b)(2)? Are you relying on nonclinical and clinical data from the RLD? If you have a stand alone non-clinical and clinical program to support your product and indication you may want to rethink this approach. Maybe this is really the question for FDA at some point, "we plan to submit the application as a 505(b)(2) and rely on the following information from the RLD......Do you agree?

For your questions, since you are going to an oral dose, then I would propose you need to meet USP and/or EP dissolution methods as appropriate. I would imagine that oral delivery vs. non oral would require different methods depending on the formulation and characteristics of the tablet, capsule, gel, etc. 

Just some thoughts,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principal Consultant RA, Quality and Compliance
Velocity Consulting
Ventura CA
United States