Regulatory Open Forum

Please remember that the NDA is about your commercial supply and supplier and therefore should focus on your commercial manufacturer and capability to manufacture the product as identified in Module 3 for approval.  Of course the commercial supplier must perform process validation, typically clinical trial manufacturers don't conduct a process validation as expected for NDA review and approval. It will be your commercial supplier that will be inspected as part of PAI as stated by Peter, therefore the commercial manufacturer will have to demonstrate readiness which should include some data.  In addition, you will need to place the commercial material on stability to establish expiry dating of the commercial material unless you get agreement from FDA during your pre-NDA that your clinical process and commercial process are "the same" and therefore you can use the clinical supply data as "commercial" material. Your clinical supplier is not considered a second supplier unless you plan to supply commercial product with it, then you have two submit two DP sections in Module 3 which does create risk.  You should submit any compatibility protocol to the FDA or discuss your strategy at the pre-NDA meeting.

Before you transfer the clinical process to the commercial supplier and to define your pre-NDA meeting strategy, conduct a risk assessment to ensure that you have captured any potential differences and possible risks between the two manufacturer's  process. In my experience no two manufacturer's conduct the process "the same" or are "identical" there are always differences that need to be considered and mitigated if needed.  Always have some data when you discuss this type of strategy with FDA, that is some feasibility data or a feasibility batch and supportive stability from the "commercial supplier" to show FDA some "sameness".

As suggested by Peter, you want to minimize any risk to your NDA approval and to meet approval in 10 months unless a priority review.  Most importantly, as I indicated above, the FDA is interested in your commercial process and supplier, make that the focus of your NDA. Your clinical supplier and process is in the IND.

Good luck,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States

Original Message:
Sent: 04-Jun-2022 07:25
From: Peter Smith
Subject: NDA approval of two API suppliers

In answer to your questions about 2 API suppliers: 1) Each API supplier must validate their own processes as they are 2 totally different facilities, equipment , personnel, procedures, etc.  There is no process for "co-validation".
2) Comparability is generally made at the API (physical and chemistry) level.  However, there should be drug product test runs with the second API to show that the tablets are comparable.  Unless requested by the Center, the second API would not need to be used in clinical studies.

Another piece of advice.  Submitting the original NDA with 2 API suppliers presents a risk in that should one supplier fail a PAI, the entire NDA will receive a Complete Response Letter.  The more facilities/sites in an NDA, the greater the chance on will fail. Many companies submit one supplier in the NDA, and do all the prep for the second supplier (validation, comparability, product test runs, etc.), and then immediately upon NDA approval submit an sNDA for the second supplier.  This reduces PAI-failure risk.   ​

------------------------------
Peter Smith
Principal
Smith GMP Consulting
Narragansett, Rhode Island
USA

Original Message:
Sent: 02-Jun-2022 15:17
From: Anonymous Member
Subject: NDA approval of two API suppliers

This message was posted by a user wishing to remain anonymous

We are entering Phase 3 and will use drug substance from supplier A to manufacture tablets for the clinical studies. We are considering qualification of a second API supplier and submit both suppliers in the NDA.  A tech transfer of the process with be performed from supplier A to supplier B so both will use same process and controls and same/similar equipment

1) For validation purposes, does each API site need to validate independently (i.e. 3 batches at each site)?  Or could we perform a "co-validation", for example make 2 batches at site A and 1 batch at site B since same process?

2) Can the comparability between the two API sites be demonstrated at the API level? Or would we need to make tablets with API from site B and compare tablets used in the clinical studies using API from site A? I know in the past when I've submitted sNDA's post approval to qualify a second API supplier we did make tablets and include release testing results on the tablets, but I don't if that is a requirement vs just being conservative.

We are focusing on US market for now, but could pursue ex-US approvals afterward.

Thank you

Please remember that the NDA is about your commercial supply and supplier and therefore should focus on your commercial manufacturer and capability to manufacture the product as identified in Module 3 for approval.  Of course the commercial supplier must perform process validation, typically clinical trial manufacturers don't conduct a process validation as expected for NDA review and approval. It will be your commercial supplier that will be inspected as part of PAI as stated by Peter, therefore the commercial manufacturer will have to demonstrate readiness which should include some data.  In addition, you will need to place the commercial material on stability to establish expiry dating of the commercial material unless you get agreement from FDA during your pre-NDA that your clinical process and commercial process are "the same" and therefore you can use the clinical supply data as "commercial" material. Your clinical supplier is not considered a second supplier unless you plan to supply commercial product with it, then you have two submit two DP sections in Module 3 which does create risk.  You should submit any compatibility protocol to the FDA or discuss your strategy at the pre-NDA meeting.

Before you transfer the clinical process to the commercial supplier and to define your pre-NDA meeting strategy, conduct a risk assessment to ensure that you have captured any potential differences and possible risks between the two manufacturer's  process. In my experience no two manufacturer's conduct the process "the same" or are "identical" there are always differences that need to be considered and mitigated if needed.  Always have some data when you discuss this type of strategy with FDA, that is some feasibility data or a feasibility batch and supportive stability from the "commercial supplier" to show FDA some "sameness".

As suggested by Peter, you want to minimize any risk to your NDA approval and to meet approval in 10 months unless a priority review.  Most importantly, as I indicated above, the FDA is interested in your commercial process and supplier, make that the focus of your NDA. Your clinical supplier and process is in the IND.

Good luck,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States

Original Message:
Sent: 04-Jun-2022 07:25
From: Peter Smith
Subject: NDA approval of two API suppliers

In answer to your questions about 2 API suppliers: 1) Each API supplier must validate their own processes as they are 2 totally different facilities, equipment , personnel, procedures, etc.  There is no process for "co-validation".
2) Comparability is generally made at the API (physical and chemistry) level.  However, there should be drug product test runs with the second API to show that the tablets are comparable.  Unless requested by the Center, the second API would not need to be used in clinical studies.

Another piece of advice.  Submitting the original NDA with 2 API suppliers presents a risk in that should one supplier fail a PAI, the entire NDA will receive a Complete Response Letter.  The more facilities/sites in an NDA, the greater the chance on will fail. Many companies submit one supplier in the NDA, and do all the prep for the second supplier (validation, comparability, product test runs, etc.), and then immediately upon NDA approval submit an sNDA for the second supplier.  This reduces PAI-failure risk.   ​

------------------------------
Peter Smith
Principal
Smith GMP Consulting
Narragansett, Rhode Island
USA

Original Message:
Sent: 02-Jun-2022 15:17
From: Anonymous Member
Subject: NDA approval of two API suppliers

This message was posted by a user wishing to remain anonymous

We are entering Phase 3 and will use drug substance from supplier A to manufacture tablets for the clinical studies. We are considering qualification of a second API supplier and submit both suppliers in the NDA.  A tech transfer of the process with be performed from supplier A to supplier B so both will use same process and controls and same/similar equipment

1) For validation purposes, does each API site need to validate independently (i.e. 3 batches at each site)?  Or could we perform a "co-validation", for example make 2 batches at site A and 1 batch at site B since same process?

2) Can the comparability between the two API sites be demonstrated at the API level? Or would we need to make tablets with API from site B and compare tablets used in the clinical studies using API from site A? I know in the past when I've submitted sNDA's post approval to qualify a second API supplier we did make tablets and include release testing results on the tablets, but I don't if that is a requirement vs just being conservative.

We are focusing on US market for now, but could pursue ex-US approvals afterward.

Thank you

Please remember that the NDA is about your commercial supply and supplier and therefore should focus on your commercial manufacturer and capability to manufacture the product as identified in Module 3 for approval.  Of course the commercial supplier must perform process validation, typically clinical trial manufacturers don't conduct a process validation as expected for NDA review and approval. It will be your commercial supplier that will be inspected as part of PAI as stated by Peter, therefore the commercial manufacturer will have to demonstrate readiness which should include some data.  In addition, you will need to place the commercial material on stability to establish expiry dating of the commercial material unless you get agreement from FDA during your pre-NDA that your clinical process and commercial process are "the same" and therefore you can use the clinical supply data as "commercial" material. Your clinical supplier is not considered a second supplier unless you plan to supply commercial product with it, then you have two submit two DP sections in Module 3 which does create risk.  You should submit any compatibility protocol to the FDA or discuss your strategy at the pre-NDA meeting.

Before you transfer the clinical process to the commercial supplier and to define your pre-NDA meeting strategy, conduct a risk assessment to ensure that you have captured any potential differences and possible risks between the two manufacturer's  process. In my experience no two manufacturer's conduct the process "the same" or are "identical" there are always differences that need to be considered and mitigated if needed.  Always have some data when you discuss this type of strategy with FDA, that is some feasibility data or a feasibility batch and supportive stability from the "commercial supplier" to show FDA some "sameness".

As suggested by Peter, you want to minimize any risk to your NDA approval and to meet approval in 10 months unless a priority review.  Most importantly, as I indicated above, the FDA is interested in your commercial process and supplier, make that the focus of your NDA. Your clinical supplier and process is in the IND.

Good luck,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States

Original Message:
Sent: 04-Jun-2022 07:25
From: Peter Smith
Subject: NDA approval of two API suppliers

In answer to your questions about 2 API suppliers: 1) Each API supplier must validate their own processes as they are 2 totally different facilities, equipment , personnel, procedures, etc.  There is no process for "co-validation".
2) Comparability is generally made at the API (physical and chemistry) level.  However, there should be drug product test runs with the second API to show that the tablets are comparable.  Unless requested by the Center, the second API would not need to be used in clinical studies.

Another piece of advice.  Submitting the original NDA with 2 API suppliers presents a risk in that should one supplier fail a PAI, the entire NDA will receive a Complete Response Letter.  The more facilities/sites in an NDA, the greater the chance on will fail. Many companies submit one supplier in the NDA, and do all the prep for the second supplier (validation, comparability, product test runs, etc.), and then immediately upon NDA approval submit an sNDA for the second supplier.  This reduces PAI-failure risk.   ​

------------------------------
Peter Smith
Principal
Smith GMP Consulting
Narragansett, Rhode Island
USA

Original Message:
Sent: 02-Jun-2022 15:17
From: Anonymous Member
Subject: NDA approval of two API suppliers

This message was posted by a user wishing to remain anonymous

We are entering Phase 3 and will use drug substance from supplier A to manufacture tablets for the clinical studies. We are considering qualification of a second API supplier and submit both suppliers in the NDA.  A tech transfer of the process with be performed from supplier A to supplier B so both will use same process and controls and same/similar equipment

1) For validation purposes, does each API site need to validate independently (i.e. 3 batches at each site)?  Or could we perform a "co-validation", for example make 2 batches at site A and 1 batch at site B since same process?

2) Can the comparability between the two API sites be demonstrated at the API level? Or would we need to make tablets with API from site B and compare tablets used in the clinical studies using API from site A? I know in the past when I've submitted sNDA's post approval to qualify a second API supplier we did make tablets and include release testing results on the tablets, but I don't if that is a requirement vs just being conservative.

We are focusing on US market for now, but could pursue ex-US approvals afterward.

Thank you

Please remember that the NDA is about your commercial supply and supplier and therefore should focus on your commercial manufacturer and capability to manufacture the product as identified in Module 3 for approval.  Of course the commercial supplier must perform process validation, typically clinical trial manufacturers don't conduct a process validation as expected for NDA review and approval. It will be your commercial supplier that will be inspected as part of PAI as stated by Peter, therefore the commercial manufacturer will have to demonstrate readiness which should include some data.  In addition, you will need to place the commercial material on stability to establish expiry dating of the commercial material unless you get agreement from FDA during your pre-NDA that your clinical process and commercial process are "the same" and therefore you can use the clinical supply data as "commercial" material. Your clinical supplier is not considered a second supplier unless you plan to supply commercial product with it, then you have two submit two DP sections in Module 3 which does create risk.  You should submit any compatibility protocol to the FDA or discuss your strategy at the pre-NDA meeting.

Before you transfer the clinical process to the commercial supplier and to define your pre-NDA meeting strategy, conduct a risk assessment to ensure that you have captured any potential differences and possible risks between the two manufacturer's  process. In my experience no two manufacturer's conduct the process "the same" or are "identical" there are always differences that need to be considered and mitigated if needed.  Always have some data when you discuss this type of strategy with FDA, that is some feasibility data or a feasibility batch and supportive stability from the "commercial supplier" to show FDA some "sameness".

As suggested by Peter, you want to minimize any risk to your NDA approval and to meet approval in 10 months unless a priority review.  Most importantly, as I indicated above, the FDA is interested in your commercial process and supplier, make that the focus of your NDA. Your clinical supplier and process is in the IND.

Good luck,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States

Original Message:
Sent: 04-Jun-2022 07:25
From: Peter Smith
Subject: NDA approval of two API suppliers

In answer to your questions about 2 API suppliers: 1) Each API supplier must validate their own processes as they are 2 totally different facilities, equipment , personnel, procedures, etc.  There is no process for "co-validation".
2) Comparability is generally made at the API (physical and chemistry) level.  However, there should be drug product test runs with the second API to show that the tablets are comparable.  Unless requested by the Center, the second API would not need to be used in clinical studies.

Another piece of advice.  Submitting the original NDA with 2 API suppliers presents a risk in that should one supplier fail a PAI, the entire NDA will receive a Complete Response Letter.  The more facilities/sites in an NDA, the greater the chance on will fail. Many companies submit one supplier in the NDA, and do all the prep for the second supplier (validation, comparability, product test runs, etc.), and then immediately upon NDA approval submit an sNDA for the second supplier.  This reduces PAI-failure risk.   ​

------------------------------
Peter Smith
Principal
Smith GMP Consulting
Narragansett, Rhode Island
USA

Original Message:
Sent: 02-Jun-2022 15:17
From: Anonymous Member
Subject: NDA approval of two API suppliers

This message was posted by a user wishing to remain anonymous

We are entering Phase 3 and will use drug substance from supplier A to manufacture tablets for the clinical studies. We are considering qualification of a second API supplier and submit both suppliers in the NDA.  A tech transfer of the process with be performed from supplier A to supplier B so both will use same process and controls and same/similar equipment

1) For validation purposes, does each API site need to validate independently (i.e. 3 batches at each site)?  Or could we perform a "co-validation", for example make 2 batches at site A and 1 batch at site B since same process?

2) Can the comparability between the two API sites be demonstrated at the API level? Or would we need to make tablets with API from site B and compare tablets used in the clinical studies using API from site A? I know in the past when I've submitted sNDA's post approval to qualify a second API supplier we did make tablets and include release testing results on the tablets, but I don't if that is a requirement vs just being conservative.

We are focusing on US market for now, but could pursue ex-US approvals afterward.

Thank you