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  • 1.  Potency assay: a characterization assay instead of a release assay?

    This message was posted by a user wishing to remain anonymous
    Posted 24-Apr-2023 07:43
    This message was posted by a user wishing to remain anonymous

    Hello colleagues,

    My company is working on an enzyme for therapeutic use (in vivo and ex vivo applications). We plan to file an IND within the next 2 years, however the potency assay to be used for measuring enzyme activity is still under development. I have several questions:

    1. What impact will it have on the IND application if we have the potency assay fully developed but not qualified before the first GMP product release and before IND application?

    2. Do we need to keep the potency assay off the Certificate of analysis and specification document until the assay is qualified? We are not comfortable setting a specification for this assay yet.

    3. Can we keep the potency assay as a characterization assay (not release assay) until after the first GMP production? The intent is to qualify the assay only after the first GMP production.

    As a longer term strategy, we plan to have the potency assay qualified before phase 2 clinical trial.

    Looking forward to hearing from you. Thank you.



  • 2.  RE: Potency assay: a characterization assay instead of a release assay?

    Posted 25-Apr-2023 07:42

    In phase 1 the emphasis is on the safety of the clinical subjects, so your focus should be on the impurity profile more than on potency, unless there is reason to believe potency can be a safety issue. Analytical methods are not required to be qualified for phase 1, but if it is possible to qualify some of the methods more critical to subject safety you definitely should. For phase 1 it is not uncommon to have "report result" for non-compendial release assays until sufficient data has been obtained to establish a range for acceptance criteria. I would also recommend that you provide as much nonclinical data as possible regarding the potency of your drug, such as EC50. 

    You should also have a target range for potency in mind, and support that with as much data as possible, such as results from development batches, discussion of the MOA, and any other information you can provide that would make you feel comfortable having your product administered to a loved one. That is the acid test - if the entirety of the data you have does not support giving your product to someone you love, you need more/better data. Always keep in mind that every clinical subject is someone's loved one.

    Useful resources on this topic include ICH Q7 (see 19.8); FDA guidance Content and Format of CMC for Phase 1 INDs (old, but still valid). 



    ------------------------------
    Arvilla Trag RAC
    Principal Consultant
    CMC Compliance Services
    Iron River MI
    United States
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  • 3.  RE: Potency assay: a characterization assay instead of a release assay?

    This message was posted by a user wishing to remain anonymous
    Posted 25-Apr-2023 11:36
    This message was posted by a user wishing to remain anonymous

    For a phase 1 IND, fully developed release assay is fine, doesn't need to be validated! Assay results using the fully developed assay must be part of the COA.
    Both assay and impurity profile are equally critical and must be reported on COA even if they are not validated! 




  • 4.  RE: Potency assay: a characterization assay instead of a release assay?

    This message was posted by a user wishing to remain anonymous
    Posted 02-May-2023 07:55
    This message was posted by a user wishing to remain anonymous

    Thank you for your responses. we are working on a few orthogonal potency assays, and haven't decided on which one we will qualify and use for release.

    1. Is it OK for potency assays to be reported on a certificate of testing, separate from the CoA?
    2. is it ok if we keep all potency assays as characterization assays only (not as release assays) until phase 2?

    Thanks!




  • 5.  RE: Potency assay: a characterization assay instead of a release assay?

    This message was posted by a user wishing to remain anonymous
    Posted 02-May-2023 12:56
    This message was posted by a user wishing to remain anonymous

    What is certificate of testing???? For IND, the potency assay results must be part of release testing (for clinical trial) document even if the assay is not validated! See above the response from Anon!




  • 6.  RE: Potency assay: a characterization assay instead of a release assay?

    Posted 02-May-2023 13:16

    In my experience a Certificate of Testing has very little utility except for contract labs to confirm they performed certain tests. I have seldom seen results on a CoT; they usually refer you to the CoA for the results. I must say I am puzzled by the reluctance to put potency on the CoA. For phase 1 the FDA does not expect you to have anything validated. Qualified - yes, validated - no. But they DO expect yo to have potency.

    If you are having difficulty with your potency assay you have options. You can find a lab or consultant specializing in method development to assist you; you can try adding another potency assay while you work out the bugs in the first one, thus creating a "Plan B" option. Most of the projects I work on have two potency assays - an ELISA-based one and a cell-based assay. While regulators will accept a single potency assay, they prefer to see two potency assays for a given product.

    Don't outsmart yourself. Put the potency assay and results on the CoA and provide any necessary explanations to the agency either in a pre-meeting briefing book or in the IND. Generally speaking, the FDA likes to help with problematic assays.



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