CMC Draft Guidance to Better Define Changes That Must Be Reported to FDA – Clear as Mud

Industry has been dealing with deciding which post-approval changes need to be reported to FDA, based on a series of Guidance documents (i.e., SUPAC-IR, the three Changes to Approved Application documents, CMC Post-Approval Changes to be Documented in Annual Reports) and, of course, the regulations at 21 CFR 314.70 and 601.12.  Industry does not always get either the filing type or the need to file the change correct and, sometimes, due to an overabundance of caution, makes supplemental submissions when they may be able to either report the changes in an Annual Report or may not need to report the change at all, but manage it under their Pharmaceutical Quality System (PQS).  FDA hopes that this new draft Guidance “Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products – Guidance for Industry” will eliminate some of the unnecessary supplemental submissions and better clarify for the industry what types of changes must be submitted.

Well, I have read this document over three times already, and I think I am more confused than I was before I read it the first time.  If I may paraphrase my view of the documents, FDA expects that certain sections of the CTD format may better define what sections of the application will constitute changes that impact the “established conditions” (EC) for which notice must be made to the FDA in a supplement or other manner.  But the FDA will decide if the firms’ evaluation is correct (which is done now) and will, when reviewing the original application, let firms know if their view of the EC are consistent with FDA’s view.  If there are changes in what constitutes the ECs, then the firm must identify these and let FDA now.  FDA says this will help with compliance inspections, but only if the field agrees with the EC as designated in the application.  Getting the drift? Everything appears to depend on interpretation, and that interpretation may be challenged by the reviewers or the investigators.  Now, doesn’t that sound like what firms go through now?  Well, let me step off of my soapbox long enough to give you some of the details of the draft Guidance and to let you have a chance to read it yourself (here).

FDA defines Established Conditions as:

as the description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in an application, that assure process performance and quality of an approved product. Changes to the established conditions must be reported to FDA (21 CFR 314.70 and 601.12).

The Agency is using the term ECs instead of what were previously termed “regulatory commitments” since the latter term may have multiple meanings.  FDA also notes (and provides in the draft document) a list of the CTD sections it believes to generally contain ECs.  I don’t believe the list will not surprise anyone.

FDA notes that “[C]urrently there are elements of an overall control strategy that may not be included in a submission and may be managed solely under the PQS. This guidance is not expanding the definition of control strategy, with respect to submission expectations. The intent of this guidance is to clarify which elements of the control strategy that are submitted in an application may be considered established conditions.”

FDA considers control strategies may be ECs and outlines control strategy elements that should be considered as including, but not limited to:

    • DS/DP (including in-process materials) manufacturing and testing facilities.
    • Source of, and specifications for, starting materials for biological products.
    • Process, including in-process tests and sequence of operations, equipment; and process parameters and their ranges.
    • Specifications, including the tests, analytical procedures and acceptance criteria; including specifications for the DS, other components, in-process materials, and the DP
    • Container closure system, components, and specifications.
    • Maintenance strategy for chemometric and/or multivariate models (e.g., for models that may have a high impact on product quality).


As noted above, the CTD chart is very comprehensive and will not be discussed further here, but it behooves firms to take note of its content and the direction of this draft Guidance document.  Now while it might just be cynical old me that is having a hard time seeing the real benefit of this draft Guidance and am struggling to see the added value it provides, maybe your view will be different.  Please share your take on this draft Guidance with me at  For any assistance in deciding on when to submit and what type of supplement to submit please contact Joan Janulis at