Regulatory Open Forum

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

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John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

Valid point!  if it is a NCE and when you are starting a phase 1 First in Human study, manufacturing multiple batches for validation purposes is not a requirement and the FDA understands the situation! However, the material produced for the phase 1 study should follow the cGMP guidance issued by the FDA in 2008. It existed even in 1991 which was updated to this 2008 version. FDA acknowledges that certain sections of Part 211 does not apply to CTMs.

Please check this out!

https://www.fda.gov/media/70975/download

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GRSAOnline
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Original Message:
Sent: 11-May-2020 14:48
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

A fundamental cGMP requirement is that once a drug is administered to humans (i.e. Phase 1 and beyond) some level of cGMP must be applied in the manufacture of these clinical supplies - phase appropriate.  The 2008 FDA Guidance as mentioned by a previous contributor, is the correct guidance to follow which presents those cGMP controls which must be applied during Phase 1.  These controls do not require typical 211 items such as process validation and analytical method validation.  However, analytical methods must be shown to be scientifically sound and suitable, batch records must be kept, equipment must be adequately cleaned, etc.  Phase 1 cGMPs are pretty much "common sense" and likely many of the controls would be in place even without this Guidance.  GMP controls should increase in Phase 2 and onto Phase 3, where virtually all of Part 211 should apply (with the exception of drug product process validation).

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Peter Smith
Principal
Smith GMP Consulting
Narragansett, Rhode Island
USA
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Original Message:
Sent: 11-May-2020 21:12
From: Narayan Rao
Subject: GMP or non-GMP API for Phase 1-2?

Valid point!  if it is a NCE and when you are starting a phase 1 First in Human study, manufacturing multiple batches for validation purposes is not a requirement and the FDA understands the situation! However, the material produced for the phase 1 study should follow the cGMP guidance issued by the FDA in 2008. It existed even in 1991 which was updated to this 2008 version. FDA acknowledges that certain sections of Part 211 does not apply to CTMs.

Please check this out!

https://www.fda.gov/media/70975/download

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

Original Message:
Sent: 11-May-2020 14:48
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

Hi John,
Translating my experience from large molecules to your scenario, yes you must have API and the final drug product for clinical use (irrespective of phase of clinical development) manufactured using GMP standards. GMP standard refers to the quality system of the manufacturing unit i.e., controlled execution of manufacturing records, deviations/investigations, methods, certificate of analyses, release certificates etc. Final release of the API must be from site quality as well as corporate QA (or Qualified Person if your clinical trial is in EU).

That being said, the manufacturing process is not expected to be validated for earlier phases. Additionally, quality risk assessment is preferred but not required for some countries for earlier phases. phase appropriate quality management is required and need to be presented in your IND or IMPD.

Hope this helps.

-Deep

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Deep Shah
Regulatory Affairs CMC, Biologics

Seattle WA
United States
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Original Message:
Sent: 11-May-2020
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

GMP also includes your Quality Management System - QMS. There is an expectation that elements of a robust Quality system are in place, including things such as investigation of deviations and out of specification events, control of materials, laboratory controls, equipment qualification, and as noted by other respondents, batch records. The details can change as you move through the phases, but the basics need to be in place

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David W. Husman, Ph.D., ASQ CPGP, RAC
President and Principal Consultant
David Husman Consulting, LLC
Greenville, SC
USA
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Original Message:
Sent: 11-May-2020 14:48
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

This message was posted by a user wishing to remain anonymous

Dear John,

I too received similar request for Phase 1 and Phase 2 API of small molecule group. Process validation, method validation and compliance to regulatory cGMP 21CFR 210/211 is not mandatory, however enough control in manufacturing, written procedures, testing, characterization is expected for API at this stage of development.
I would like to bring one point here, if API is manufactured using 4 to 5 stages after introduction of starting material and just last stage is manufactured according to cGMP control, how would it be accepted? API need to be tested for specific tests and characterized to some extent obviously. Also this API would be converted to CTM under cGMP controls. Final CTM to be used for CT would be a GMP grade product. Suggestions from other members in group would be great to know and please share if anybody had similar experience.
thanks
Original Message:
Sent: 11-May-2020 14:48
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------

Hi John.

Simply put, I think the point here is that you need to do more than just push the product through the process and out the door.  As others have noted, you obviously won't be able to provide FDA (or anyone else!) with proof of validation of your process (unless the company has decided to invest lots more $$$$$ than most ever would with truly no reasonable assurance of ROI!) or even full verification of your expiration dating if any.  But there are lots of other things that can be done at the very beginning - testing to ensure compliance with specifications; creation of reasonably vetted specifications; investigations of any anomalies; QA oversight of the facility and processes as well as final release; CAPA implementation; etc.  So while you aren't going to be ready to pass through a PAI or full routine FDA audit for some of the longer term requirements like validation and stability you should be able to provide product that is reasonably expected to be safe for the intended use - which is a human study of a currently-unapproved drug product.

FDA has on numerous occasions referenced the need for "phased GMP compliance" commensurate with the risks and point in development for the products.  As such, at Phase 1 you likely have very little other than a documented production process (still to be validated!), a specification (still to be finalized) with some information on degradants and maybe contaminants, and maybe a few months of stability data potentially only on lab-scale.  By Phase 2 you should have a more attuned specification, potentially some additional information on degradants and contaminants, probably full accelerated stability on your lab scale and some period of time on the production scale lot(s) used for the Phase 1 trials.  Then by Phase 3 you should have nearly complete data including potentially multiple validation lots produced and on stability (even potentially having full accelerated stability completed on 1 of these) and be in a position to fairly quickly formalize your process once Phase 3 is completed in order to get through your PAI efficiently to avoid any meaningfully significant delays in approval due to GMP issues.

Remember - logic is key and being able to explain what you have done, what is missing, why it is missing and the planned path forward for any deviations/observations is ultimately going to be key to getting your product to market efficiently.  Remember, while it might be "allowable" to not have full GMP compliance at the very beginning, a well-informed, reputable IRB and even FDA may ask for further GMP/product safety details on the product before providing approval for the Phase 1 study - so you might as well build in whatever you can before submitting your study plan to them.

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Victor Mencarelli
Global Director Regulatory Affairs
MelvilleNY
United States
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Original Message:
Sent: 11-May-2020 14:48
From: John Wetzel
Subject: GMP or non-GMP API for Phase 1-2?

I have received advice that batches of a small molecule API used to make CTM for Phase 1 and Phase 2 do not need to be manufactured according to GMP. This may be a matter of semantics. Obviously, it is impossible to have a fully validated process for the first few batches of API, since validation requires making multiple batches to show consistency. So, if we define "GMP" as including all controls that would be expected for commercial API manufacturing, it would not be applicable to Phase 1-2. But it is my understanding, from reading FDA and ICH guidance documents, as well as published articles on best practices, that phase-appropriate good manufacturing practices are expected by FDA. Opinions from the group members on best practices and minimum FDA expectations would be much appreciated.

------------------------------
John M Wetzel, PhD
Wetzel Chemistry Consulting, LLC
4141 Baker Road
Albany, OH 45710
740-698-0420
www.wetzelconsulting.com
------------------------------