Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Hello Everyone,

I would like to get some clarifications about sampling changes post or as a result of completing validation batches. 

Our company is planning to start manufacturing validation batches for the product for US market. The plan is to have large sampling pull for IPC testing for validation batches. After validation will be completed and successful, we would like to modify batch records and reduce the number of samples that are collected IPCs. 
In out submission we have specified that post-approval batches will have reduced IPC sampling comparing to registration batches. However, is it acceptable to implement this change after validation, or validation batches must have IPC sampling exactly as commercial batches will?

Thank you!

For biologics it not uncommon to have additional IPC testing during validation (e.g. additional testing for impurity clearance and/or at certain steps for informational purposes to gain a deeper understanding of your process) and for the IPC testing program to be reduced for the commercial lots. Commercial lots will be subject to the approved IPCs called out and justified in S.2.4. The justification for the commercial IPCs will also be linked to your pharm dev (S.2.6), describing how you arrived at these commercial IPCs through early development, scale up etc. In short, it will be acceptable to change after validation as long as you are still testing the IPCs you listed in S.2.4. and FDA have approved these. I hope I understood your question correctly.

------------------------------
Barbara Hoey
Senior Manager, CMC Regulatory Sciences
Limerick
Ireland
------------------------------

Original Message:
Sent: 19-Jan-2023 14:13
From: Anonymous Member
Subject: Changing IPC sampling after validation

This message was posted by a user wishing to remain anonymous

Hello Everyone,

I would like to get some clarifications about sampling changes post or as a result of completing validation batches.

Our company is planning to start manufacturing validation batches for the product for US market. The plan is to have large sampling pull for IPC testing for validation batches. After validation will be completed and successful, we would like to modify batch records and reduce the number of samples that are collected IPCs.
In out submission we have specified that post-approval batches will have reduced IPC sampling comparing to registration batches. However, is it acceptable to implement this change after validation, or validation batches must have IPC sampling exactly as commercial batches will?

Thank you!

This message was posted by a user wishing to remain anonymous

Thank you Barbara,

Yes your reply really helps! I just wanted to know if this is a standard practice in the industry.
Original Message:
Sent: 20-Jan-2023 07:55
From: Barbara Hoey
Subject: Changing IPC sampling after validation

For biologics it not uncommon to have additional IPC testing during validation (e.g. additional testing for impurity clearance and/or at certain steps for informational purposes to gain a deeper understanding of your process) and for the IPC testing program to be reduced for the commercial lots. Commercial lots will be subject to the approved IPCs called out and justified in S.2.4. The justification for the commercial IPCs will also be linked to your pharm dev (S.2.6), describing how you arrived at these commercial IPCs through early development, scale up etc. In short, it will be acceptable to change after validation as long as you are still testing the IPCs you listed in S.2.4. and FDA have approved these. I hope I understood your question correctly.

------------------------------
Barbara Hoey
Senior Manager, CMC Regulatory Sciences
Limerick
Ireland

Original Message:
Sent: 19-Jan-2023 14:13
From: Anonymous Member
Subject: Changing IPC sampling after validation

This message was posted by a user wishing to remain anonymous

Hello Everyone,

I would like to get some clarifications about sampling changes post or as a result of completing validation batches.

Our company is planning to start manufacturing validation batches for the product for US market. The plan is to have large sampling pull for IPC testing for validation batches. After validation will be completed and successful, we would like to modify batch records and reduce the number of samples that are collected IPCs.
In out submission we have specified that post-approval batches will have reduced IPC sampling comparing to registration batches. However, is it acceptable to implement this change after validation, or validation batches must have IPC sampling exactly as commercial batches will?

Thank you!

Good day,

What you are describing sounds more like PPQ than validation. Additional samples are pulled during PPQ to confirm process limits and establish PARs, NORs, KPPs, CPPs and CQAs; many parameters are tested that are not normally tested or monitored during routine production. It is acceptable to reduce the extra sampling and testing after PPQ.

Conversely, process validation is repeated execution of a process at the established parameters and ranges to demonstrate the results are reproducible. Validation by definition must be done with the exact process intended for commercial manufacture, and the batch record must be the one intended to use for commercial production. The process you validate is the one you must use going forward; it is not acceptable to reduce sampling and testing after validation. You may simply have the wrong term in place to describe these activities.

If the FDA has been told what you are doing is validation they will have different expectations than they would for PPQ. You may need to explain to them that the wrong term was used in the past, but I suggest you immediately start referring to these activities as PPQ.

Best of luck,


------------------------------
Arvilla Trag RAC
Principal Consultant
CMC Compliance Services
Iron River MI
United States
------------------------------

Original Message:
Sent: 19-Jan-2023 14:13
From: Anonymous Member
Subject: Changing IPC sampling after validation

This message was posted by a user wishing to remain anonymous

Hello Everyone,

I would like to get some clarifications about sampling changes post or as a result of completing validation batches.

Our company is planning to start manufacturing validation batches for the product for US market. The plan is to have large sampling pull for IPC testing for validation batches. After validation will be completed and successful, we would like to modify batch records and reduce the number of samples that are collected IPCs.
In out submission we have specified that post-approval batches will have reduced IPC sampling comparing to registration batches. However, is it acceptable to implement this change after validation, or validation batches must have IPC sampling exactly as commercial batches will?

Thank you!

I do have to quibble on one point.

Process validation, as defined by the FDA guidance and adopted by other agencies as well (e.g., EMA), is "the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. Process validation is therefore not limited only to the exact commercial manufacturing process, since definition of the commercial process through design studies is part of the exercise. What you are describing is more aligned with Stage 3 of process validation, namely the process verification stage.

But I agree with the point that what the OP called process validation is most likely the process performance qualification stage, as described in the FDA PV guidance. I think part of the problem is that the CTD section and most, if not all, of the ICH guidelines still say process validation when they mean PPQ.

------------------------------
Rachel Thornton
Associate Director
Smyrna GA
United States
------------------------------

Original Message:
Sent: 23-Jan-2023 06:25
From: Arvilla Trag
Subject: Changing IPC sampling after validation

Good day,

What you are describing sounds more like PPQ than validation. Additional samples are pulled during PPQ to confirm process limits and establish PARs, NORs, KPPs, CPPs and CQAs; many parameters are tested that are not normally tested or monitored during routine production. It is acceptable to reduce the extra sampling and testing after PPQ.

Conversely, process validation is repeated execution of a process at the established parameters and ranges to demonstrate the results are reproducible. Validation by definition must be done with the exact process intended for commercial manufacture, and the batch record must be the one intended to use for commercial production. The process you validate is the one you must use going forward; it is not acceptable to reduce sampling and testing after validation. You may simply have the wrong term in place to describe these activities.

If the FDA has been told what you are doing is validation they will have different expectations than they would for PPQ. You may need to explain to them that the wrong term was used in the past, but I suggest you immediately start referring to these activities as PPQ.

Best of luck,


------------------------------
Arvilla Trag RAC
Principal Consultant
CMC Compliance Services
Iron River MI
United States

Original Message:
Sent: 19-Jan-2023 14:13
From: Anonymous Member
Subject: Changing IPC sampling after validation

This message was posted by a user wishing to remain anonymous

Hello Everyone,

I would like to get some clarifications about sampling changes post or as a result of completing validation batches.

Our company is planning to start manufacturing validation batches for the product for US market. The plan is to have large sampling pull for IPC testing for validation batches. After validation will be completed and successful, we would like to modify batch records and reduce the number of samples that are collected IPCs.
In out submission we have specified that post-approval batches will have reduced IPC sampling comparing to registration batches. However, is it acceptable to implement this change after validation, or validation batches must have IPC sampling exactly as commercial batches will?

Thank you!