Regulatory Open Forum

Hi RAPS forum,

I'm looking for input on the appropriateness/acceptability of a strategy to reduce product waste in early development of a parenteral biologic protein, which can be described as follows:

For the Phase 1 product presentation, using a higher API concentration and volume is highly desirable to minimize the number of product containers that is required for treatment of adult patients (e.g. at a 20 mg/kg dose). However, running a stability program on the same large containers of highly-concentrated drug product means that a considerable amount of product is wasted as excess due to sampling requirements (e.g. number of containers needing to be tested). Is it appropriate/acceptable to run a stability program on smaller containers, if: the primary and secondary containers and closures for the stability samples are constructed of the same materials as the full-size clinical containers; the drug product is identical (e.g. same concentration, manufacture) and filled in parallel for clinical and stability materials; and, other attributes (e.g. headspace) are made to be highly representative of the clinical presentation?

Thanks,
Marshall Hoke

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

Good morning, Marshall.

My first question is have you raised this with FDA at your pre-IND meeting? Second - have you done any proof of concept studies on this approach? Some of this may depend also on your excipients and storage conditions. Is your bulk DS formulated, or is it formulated in the DP process?  Generally speaking, it is not uncommon for container closure systems for drug substance stability to be smaller but made of the same materials as for the bulk, as many DS containers are quite large. That being said, if your bulk DS is formulated and on stability in smaller containers you should be OK with a similar approach for DP. Per ICH Q5C 4.2:

"In addition, the drug substance (bulk material) made at pilot-plant scale should be produced by a process and stored under conditions representative of that used for the manufacturing scale. The drug substance entered into the stability program should be stored in containers which properly represent the actual holding containers used during manufacture. Containers of reduced size may be acceptable for drug substance stability testing provided that they are constructed of the same material and use the same type of container/closure system that is intended to be used during manufacture."

Unfortunately, Q5C doesn't really address different container sizes for DP. You may want to consider submitting your stability protocol design to FDA and asking if the agency agrees, which is what I would do if the DP is extremely expensive, unusual and/or difficult to produce.  Best of luck.

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

Original Message:
Sent: 11-Aug-2022 14:27
From: Marshall Hoke
Subject: Stability vs Clinical Container Closures for Phase 1

Hi RAPS forum,

I'm looking for input on the appropriateness/acceptability of a strategy to reduce product waste in early development of a parenteral biologic protein, which can be described as follows:

For the Phase 1 product presentation, using a higher API concentration and volume is highly desirable to minimize the number of product containers that is required for treatment of adult patients (e.g. at a 20 mg/kg dose). However, running a stability program on the same large containers of highly-concentrated drug product means that a considerable amount of product is wasted as excess due to sampling requirements (e.g. number of containers needing to be tested). Is it appropriate/acceptable to run a stability program on smaller containers, if: the primary and secondary containers and closures for the stability samples are constructed of the same materials as the full-size clinical containers; the drug product is identical (e.g. same concentration, manufacture) and filled in parallel for clinical and stability materials; and, other attributes (e.g. headspace) are made to be highly representative of the clinical presentation?

Thanks,
Marshall Hoke

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

Thank you Arvilla for the very concise and helpful answer! We do plan to detail this proposal in our pre-IND interaction and conduct a 'risk assessment' to support the proposal. Luckily in this case the bulk DS is formulated.  Thank you also for the reference to the passage in Q5C, which is supportive of this approach.

Best,
Marshall

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

Original Message:
Sent: 12-Aug-2022 07:36
From: Arvilla Trag
Subject: Stability vs Clinical Container Closures for Phase 1

Good morning, Marshall.

My first question is have you raised this with FDA at your pre-IND meeting? Second - have you done any proof of concept studies on this approach? Some of this may depend also on your excipients and storage conditions. Is your bulk DS formulated, or is it formulated in the DP process?  Generally speaking, it is not uncommon for container closure systems for drug substance stability to be smaller but made of the same materials as for the bulk, as many DS containers are quite large. That being said, if your bulk DS is formulated and on stability in smaller containers you should be OK with a similar approach for DP. Per ICH Q5C 4.2:

"In addition, the drug substance (bulk material) made at pilot-plant scale should be produced by a process and stored under conditions representative of that used for the manufacturing scale. The drug substance entered into the stability program should be stored in containers which properly represent the actual holding containers used during manufacture. Containers of reduced size may be acceptable for drug substance stability testing provided that they are constructed of the same material and use the same type of container/closure system that is intended to be used during manufacture."

Unfortunately, Q5C doesn't really address different container sizes for DP. You may want to consider submitting your stability protocol design to FDA and asking if the agency agrees, which is what I would do if the DP is extremely expensive, unusual and/or difficult to produce.  Best of luck.

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

Original Message:
Sent: 11-Aug-2022 14:27
From: Marshall Hoke
Subject: Stability vs Clinical Container Closures for Phase 1

Hi RAPS forum,

I'm looking for input on the appropriateness/acceptability of a strategy to reduce product waste in early development of a parenteral biologic protein, which can be described as follows:

For the Phase 1 product presentation, using a higher API concentration and volume is highly desirable to minimize the number of product containers that is required for treatment of adult patients (e.g. at a 20 mg/kg dose). However, running a stability program on the same large containers of highly-concentrated drug product means that a considerable amount of product is wasted as excess due to sampling requirements (e.g. number of containers needing to be tested). Is it appropriate/acceptable to run a stability program on smaller containers, if: the primary and secondary containers and closures for the stability samples are constructed of the same materials as the full-size clinical containers; the drug product is identical (e.g. same concentration, manufacture) and filled in parallel for clinical and stability materials; and, other attributes (e.g. headspace) are made to be highly representative of the clinical presentation?

Thanks,
Marshall Hoke

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