Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Hello,

ICH Q1A (R2) section 2.1.4. Container Closure System states that "The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution."  

My questions are
1) for phase I, does this type of study required for DS?
2) We use Pall Allegro 20 L bag for our phase I DS. I understand that Pall also provides the same line of bags in smaller sizes (such as 50 mL). In theory, we can use a 50 mL Pall Allegro bag for the stability assay of DS. But, is there any other way to do this and save samples? For example, can I use a plastic container (1mL -5 mL) size with the same material of construction to perform the DS stability testing? 

Thanks!

This message was posted by a user wishing to remain anonymous

I would suggest you propose your options to FDA with a strong scientific rationale/justification for not using the exact same container closure system as your final DP packaging for stability studies. Apart from the material of construction, you also need to take into account the product volume, headspace, etc. that could impact product stability. If you have early stability studies, during pre-clinical stage that indicate a robust profile, those might be helpful to use in support of this.  Also, you could consider reducing the number of intermediate timepoints for stability testing, to reduce the number of samples you need.

The ideal is to test in the intended container closure system, because if there are stability issues along the way, it could impact ongoing clinical studies and require additional stability. So i would recommend, use the same CCS, but propose an abbreviated stability program with reduced intermediate timepoints for the main storage condition, and propose a parallel accelerated stability program in smaller CCS with some justification for this approach.
Original Message:
Sent: 11-May-2022 19:50
From: Anonymous Member
Subject: Drug substance container closure stability for phase I

This message was posted by a user wishing to remain anonymous

Hello,

ICH Q1A (R2) section 2.1.4. Container Closure System states that "The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution."

My questions are
1) for phase I, does this type of study required for DS?
2) We use Pall Allegro 20 L bag for our phase I DS. I understand that Pall also provides the same line of bags in smaller sizes (such as 50 mL). In theory, we can use a 50 mL Pall Allegro bag for the stability assay of DS. But, is there any other way to do this and save samples? For example, can I use a plastic container (1mL -5 mL) size with the same material of construction to perform the DS stability testing?

Thanks!

Yes, you can, as long as you provide a basic scientific justification as to why the packaging of the stability sample is comparable to representative of the bulk packaging. Even better, if you can argue that the stability sample storage presents a "worst case" scenario, for instance by surface/volume ratio. This should not take more than a sentence. We should all remind ourselves that ICH Q1A is intended for marketing applications, not for clinical development (even if the gap closes as you enter Phase 3).  In a nutshell, for Phase 1 keep it simple, especially if you already have enough reasonable evidence that the DS is a stable NME.

------------------------------
Maurizio Franzini
Regulatory Affairs CMC, Director
San Francisco CA
United States
------------------------------

Original Message:
Sent: 11-May-2022 19:50
From: Anonymous Member
Subject: Drug substance container closure stability for phase I

This message was posted by a user wishing to remain anonymous

Hello,

ICH Q1A (R2) section 2.1.4. Container Closure System states that "The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution."

My questions are
1) for phase I, does this type of study required for DS?
2) We use Pall Allegro 20 L bag for our phase I DS. I understand that Pall also provides the same line of bags in smaller sizes (such as 50 mL). In theory, we can use a 50 mL Pall Allegro bag for the stability assay of DS. But, is there any other way to do this and save samples? For example, can I use a plastic container (1mL -5 mL) size with the same material of construction to perform the DS stability testing?

Thanks!

I agree with Maurizio because your response is realistic and practical given the development stage of the drug/which FDA most likely agrees with it! Thanks also for pointing out that the ICH guideline is for marketing applications! Although it is a simple thing to understand lot of executives even with experience are confused and apply incorrectly with their development pipeline and doing lot of unnecessary expensive work.

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

Original Message:
Sent: 20-May-2022 11:58
From: Maurizio Franzini
Subject: Drug substance container closure stability for phase I

Yes, you can, as long as you provide a basic scientific justification as to why the packaging of the stability sample is comparable to representative of the bulk packaging. Even better, if you can argue that the stability sample storage presents a "worst case" scenario, for instance by surface/volume ratio. This should not take more than a sentence. We should all remind ourselves that ICH Q1A is intended for marketing applications, not for clinical development (even if the gap closes as you enter Phase 3).  In a nutshell, for Phase 1 keep it simple, especially if you already have enough reasonable evidence that the DS is a stable NME.

------------------------------
Maurizio Franzini
Regulatory Affairs CMC, Director
San Francisco CA
United States

Original Message:
Sent: 11-May-2022 19:50
From: Anonymous Member
Subject: Drug substance container closure stability for phase I

This message was posted by a user wishing to remain anonymous

Hello,

ICH Q1A (R2) section 2.1.4. Container Closure System states that "The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution."

My questions are
1) for phase I, does this type of study required for DS?
2) We use Pall Allegro 20 L bag for our phase I DS. I understand that Pall also provides the same line of bags in smaller sizes (such as 50 mL). In theory, we can use a 50 mL Pall Allegro bag for the stability assay of DS. But, is there any other way to do this and save samples? For example, can I use a plastic container (1mL -5 mL) size with the same material of construction to perform the DS stability testing?

Thanks!

Although I agree that keeping it simple and scientific is important, please also consider in your risk assessment that if you are successful as you move to later stages of clinical development, you don't want CMC to be a risk down the line. Document all potential risks, probability and conclusion that saving time and money now Is worth any potential risks down the line. Mitigate as many as you identify now.  Make sure management agrees with the approach.  

The advise to get FDA buy in especially at a pre-IND meeting is critical and spot on. 

Lastly, develop your approach to bridging data to your late stage packaging and storage container including stability program so the switch is seamless and timely with no delays to a filing. 

Good luck, you received a lot of valuable input!

Dar

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

Original Message:
Sent: 20-May-2022 15:03
From: Narayan Rao
Subject: Drug substance container closure stability for phase I

I agree with Maurizio because your response is realistic and practical given the development stage of the drug/which FDA most likely agrees with it! Thanks also for pointing out that the ICH guideline is for marketing applications! Although it is a simple thing to understand lot of executives even with experience are confused and apply incorrectly with their development pipeline and doing lot of unnecessary expensive work.

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

Original Message:
Sent: 20-May-2022 11:58
From: Maurizio Franzini
Subject: Drug substance container closure stability for phase I

Yes, you can, as long as you provide a basic scientific justification as to why the packaging of the stability sample is comparable to representative of the bulk packaging. Even better, if you can argue that the stability sample storage presents a "worst case" scenario, for instance by surface/volume ratio. This should not take more than a sentence. We should all remind ourselves that ICH Q1A is intended for marketing applications, not for clinical development (even if the gap closes as you enter Phase 3).  In a nutshell, for Phase 1 keep it simple, especially if you already have enough reasonable evidence that the DS is a stable NME.

------------------------------
Maurizio Franzini
Regulatory Affairs CMC, Director
San Francisco CA
United States

Original Message:
Sent: 11-May-2022 19:50
From: Anonymous Member
Subject: Drug substance container closure stability for phase I

This message was posted by a user wishing to remain anonymous

Hello,

ICH Q1A (R2) section 2.1.4. Container Closure System states that "The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution."

My questions are
1) for phase I, does this type of study required for DS?
2) We use Pall Allegro 20 L bag for our phase I DS. I understand that Pall also provides the same line of bags in smaller sizes (such as 50 mL). In theory, we can use a 50 mL Pall Allegro bag for the stability assay of DS. But, is there any other way to do this and save samples? For example, can I use a plastic container (1mL -5 mL) size with the same material of construction to perform the DS stability testing?

Thanks!