Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release? If one is limited by the number of DP vials that can be made for a given DP lot and most of the DP vials are being used up in release/stability tests leaving few for use in clinical trials, one way to make more vials available for the clinic is to only perform a subset of release/stability tests on subsequent lots  after the "lead" lot is released. Is this acceptable?

Hi anon,

What you are describing sounds a little bit like 'pooling' drug product batches/lots. Under certain circumstances this might be acceptable, but you would need to have alignment with your regulator about it beforehand, especially when it concerns drug product release and stability testing for clinical material. For instance, your in-process testing would need to be thorough with tight acceptance criteria and provide a very high degree of certainty about the purity, potency, quality, and sterility of the individual DP lots that are pooled through the final steps of manufacturing. Also, all manufacturing activity would likely need to take place in serial or within a very short period of time (probably less than a week total) using starting materials from the same origin/lot. At the end of processing all lots, you might be able to perform release testing on a random sampling of the cumulative vialed DP material. But even under these circumstances it may be challenging to get FDA to agree to pooled release and stability testing for clinical DP (not sure about EMA). 

On the other hand, only performing release and stability testing material from a single initial "lead" DP lot sounds like a non-starter to me, based on my experience with regulators, although maybe another poster has had more experience with this. Either way, I can certainly empathize with you on the burdensome material requirements for certain tests of vialed DP, which is often in short supply early in development. Good luck!

Best,
Marshall

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Marshall Hoke
Director of Regulatory Affairs
Lafayette CO
United States
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Original Message:
Sent: 09-Mar-2022 23:20
From: Anonymous Member
Subject: "Lead" lot

This message was posted by a user wishing to remain anonymous

In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release? If one is limited by the number of DP vials that can be made for a given DP lot and most of the DP vials are being used up in release/stability tests leaving few for use in clinical trials, one way to make more vials available for the clinic is to only perform a subset of release/stability tests on subsequent lots  after the "lead" lot is released. Is this acceptable?

To clarify to the initial responder, the situation described by the OP is not considered pooling!  
OP: Let me know if my interpretation is not right!
Good luck

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GRSAOnline
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Original Message:
Sent: 10-Mar-2022 12:01
From: Marshall Hoke
Subject: "Lead" lot

Hi anon,

What you are describing sounds a little bit like 'pooling' drug product batches/lots. Under certain circumstances this might be acceptable, but you would need to have alignment with your regulator about it beforehand, especially when it concerns drug product release and stability testing for clinical material. For instance, your in-process testing would need to be thorough with tight acceptance criteria and provide a very high degree of certainty about the purity, potency, quality, and sterility of the individual DP lots that are pooled through the final steps of manufacturing. Also, all manufacturing activity would likely need to take place in serial or within a very short period of time (probably less than a week total) using starting materials from the same origin/lot. At the end of processing all lots, you might be able to perform release testing on a random sampling of the cumulative vialed DP material. But even under these circumstances it may be challenging to get FDA to agree to pooled release and stability testing for clinical DP (not sure about EMA).

On the other hand, only performing release and stability testing material from a single initial "lead" DP lot sounds like a non-starter to me, based on my experience with regulators, although maybe another poster has had more experience with this. Either way, I can certainly empathize with you on the burdensome material requirements for certain tests of vialed DP, which is often in short supply early in development. Good luck!

Best,
Marshall

------------------------------
Marshall Hoke
Director of Regulatory Affairs
Lafayette CO
United States

Original Message:
Sent: 09-Mar-2022 23:20
From: Anonymous Member
Subject: "Lead" lot

This message was posted by a user wishing to remain anonymous

In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release? If one is limited by the number of DP vials that can be made for a given DP lot and most of the DP vials are being used up in release/stability tests leaving few for use in clinical trials, one way to make more vials available for the clinic is to only perform a subset of release/stability tests on subsequent lots  after the "lead" lot is released. Is this acceptable?

"In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release?"

The key word is the "subsets of DP lots"

Yes, this is done for lot of biologics where one lead DS lot is used for making several DP subsets of main DP lot. Make sure full testing is done on the primary/lead DP lot and key tests for subset DP lots. 

------------------------------
GRSAOnline
------------------------------

Original Message:
Sent: 09-Mar-2022 23:20
From: Anonymous Member
Subject: "Lead" lot

This message was posted by a user wishing to remain anonymous

In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release? If one is limited by the number of DP vials that can be made for a given DP lot and most of the DP vials are being used up in release/stability tests leaving few for use in clinical trials, one way to make more vials available for the clinic is to only perform a subset of release/stability tests on subsequent lots  after the "lead" lot is released. Is this acceptable?

I agree with Narayan Rao that this is not pooling.

The only personal experience I have with such a scenario is when the same bulk DP (meaning tank of thawed & filtered DS) was filled into separate lots of varying fill volumes. Specifically, it was a commercial batch where, at the end of the filling run, the product was filled into smaller fill volumes to be used in clinical studies. So the only thing different among the batches was the fill volume - same equipment, same processing parameters, etc. So only microbial testing and extractable volume was tested on the sub-batches. But in that case the fill step was the only thing different, and even then it was just a couple changes in fill settings, and it was a validated process before that point.

If you're filling the same lot of DS into multiple DP batches in separate filling runs, I'm skeptical that would be allowed unless you have a really good reason for doing it that way. For example, if you're working with an orphan drug situation and you can't make too many doses at one time b/c most of them will expire before it can be used, then they'll probably be willing to work with you. But you should at least have a risk assessment documented to show the risk of the non-tested attributes being impacted by the process is low.

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Rachel Thornton
Associate Director
Smyrna GA
United States
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Original Message:
Sent: 09-Mar-2022 23:20
From: Anonymous Member
Subject: "Lead" lot

This message was posted by a user wishing to remain anonymous

In gmp manufacturing of biologics, is there such a thing as a "lead" lot? If one lot of DS is used to generate multiple lots of DP, can all release tests be done on the first "lead" DP lot for release and only a subset of tests done for the remaining lots, for release? If one is limited by the number of DP vials that can be made for a given DP lot and most of the DP vials are being used up in release/stability tests leaving few for use in clinical trials, one way to make more vials available for the clinic is to only perform a subset of release/stability tests on subsequent lots  after the "lead" lot is released. Is this acceptable?