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  • 1.  Forced Degradation Studies

    This message was posted by a user wishing to remain anonymous
    Posted 20-Aug-2018 16:26
    This message was posted by a user wishing to remain anonymous

    What are the Expectations from Health Authorities asking for Forced degradation studies @ 3.2.P.8?

    The drug product is a lyophilized powder for solution for injection.

    Drug substance:
    - organic, synthetic, 
    - existing active substance described in Ph. Eur, USP

    proposed Drug product, a generic
    - stable at 25/60 for 12 months.
    - not stable in the intermediate conditions (30/65): an upward trend of specified degradation impurities, and water
    - not stable in the acc. conditions (40/75): the same as above

    The reference medicinal product has the same trend of degradation and water uptake. The data were presented in parallel.

    What should be the meaningful forced degradation conditions to be selected?
    Thank you for reading all that. I should be happy to have your feedback.
     


  • 2.  RE: Forced Degradation Studies

    This message was posted by a user wishing to remain anonymous
    Posted 21-Aug-2018 16:08
    This message was posted by a user wishing to remain anonymous

    ​​The force degradation is useful to predict the stability of the drug by defining the impurity profile and behavior of a drug under various stress conditions. The forced degradation also plays a role in the development of the analytical methods and setting specifications of the stability study for example.
    Note that the force degradation is not a stability study which I think you are referring to.
    Below is the link to an article that will address some of your questions on force degradation:
    FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions
    Pharmtech remove preview
    FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions
    Forced degradation is synonymous with stress testing and purposeful degradation. Purposeful degradation can be a useful tool to predict the stability of a drug substance or a drug product with effects on purity, potency, and safety. It is imperative to know the impurity profile and behavior of a drug substance under various stress conditions.
    View this on Pharmtech >

    Hope this help.
    Original Message


  • 3.  RE: Forced Degradation Studies

    This message was posted by a user wishing to remain anonymous
    Posted 23-Aug-2018 09:05
    This message was posted by a user wishing to remain anonymous

    Thank you for the information.

    Keep on asking myself why this question came for the drug-product in the Stability chapter.
    It should have been more correlated to the Pharmaceutical Development.

    Are there forced degradation studies a specific topic to the finish products lyophilized powders? 

    Original Message


  • 4.  RE: Forced Degradation Studies

    Posted 24-Aug-2018 08:56
    ​The question of where forced degradation studies really "belong" has been around since I first entered Reg Affairs in 2002. ICHM4Q(R2) puts it in S.7 (drug substance stability, since it's usually done on the drug substance), even though the purpose and outcome really is more toward characterization of the molecule than looking at the stability under any sort of realistic conditions.

    But the following text appeared in an FDA guidance on the content of 3.2.P (subsequently withdrawn) under P.8:

     3. Stress Studies

    Any results from drug product stress testing and thermal cycling studies should be

    provided in this section of the application. The design of the stress studies should be

    discussed briefly. The information should be used, as appropriate, to support the

    validation of analytical procedures (P.5.3), the impurities acceptance criteria and/or

    characterization of expected impurities (P.5.1, P.5.5), justification of the drug product

    specification (P.5.6), and stability summary and conclusions (P.8.1).


    Regulators just seem to lump forced degradation studies with other stressed stability studies and ask for it all to be in the stability section. Often we've been able to put that information in S.3.1 (or, in your case, possibly P.2.3) and just be sure to include a cross-reference in P.8 so the reviewer can find the information.

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

    Original Message


  • 5.  RE: Forced Degradation Studies

    Posted 24-Aug-2018 09:02
    ​Minor correction: It's ICHM4Q(R1) (not R2, as I stated in my previous message)

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

    Original Message


  • 6.  RE: Forced Degradation Studies

    Posted 27-Aug-2018 01:16

    Hi all,
    To add to the debate and maybe create a little more confusion around where to locate in CTD !

    In recent NCE submissions for organic, synthetic molecules in solid oral dosage forms i've placed forced deg studies at end of S.3.2 Imps for DS linked to potential deg pathways and in P.5.5 Characterisation of Imps for DP with a x-ref back to S.3.2.  Due to it's artificial, forced nature producing secondary deg products some not even seen in stressed stability (e.g. light, 50C) I prefer to ring fence these data and discussion and keep away from S.7 and P.8 stability data/discussion.

    Certain agencies, Brazil in particular and some of the ASEAN region, are very keen on both DS and DP forced deg data to demonstrate the stability indicating nature of the analytical methods for both DS & DP.  Brazil take it to a whole new level and therefore I have produced an Appendix to P.5.5 to cover their extensive raw data requirements including peak purity demonstration.

    Hope the above helps,
    Regards,
    Roy



    ------------------------------
    Roy Jamieson
    Regulatory CMC Director
    AZ Gothenburg, Sweden
    ------------------------------

    Original Message


  • 7.  RE: Forced Degradation Studies

    Posted 28-Aug-2018 10:14
    ​I actually think that's a really good idea, since they are usually focused on characterization of potential impurities. If I disagree with the location specified in guidelines, I usually put the information where I think it makes the most sense and put a cross-reference in the section specified by the guidance. Usually that works OK, though there have been some exceptions, but we are usually able to deal with those situations in responses to questions.

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

    Original Message


  • 8.  RE: Forced Degradation Studies

    This message was posted by a user wishing to remain anonymous
    Posted 21-Aug-2018 16:08
    This message was posted by a user wishing to remain anonymous

    It may be of help:

    https://dgra.de/media/pdf/studium/masterthesis/master_janzen_h.pdf
    Original Message


  • 9.  RE: Forced Degradation Studies

    Posted 30-Aug-2018 10:10
    Health authority has seen your application and stability data.

    In further evaluation they need to understand or evaluate by which path degradation impurities are increasing.

    The force degradation includes exposure of drug substance and drug product in to various conditions including acidic, basic, oxidation, reduction, thermal, humid and photo stability.




    ------------------------------
    Gaurang Bhavsar, MS, RAC
    Manager, R&D and RA
    Sunrise Pharmaceutical, Inc.
    Rahway, NJ 07065
    USA
    ------------------------------

    Original Message


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