Drugmakers Critique FDA Draft Guidance on Postapproval Changes for Drug Substances

Regulatory NewsRegulatory News | 03 December 2018 |  By 

More than a dozen drugmakers have offered comments on the US Food and Drug Administration’s (FDA) draft guidance on postapproval changes for drug substances, with some offering changes and others calling for the document to better reflect guidance from the International Council for Harmonisation (ICH).

The draft guidance covers facility, scale and equipment changes associated with all steps of drug substance manufacturing; specification changes to starting materials, raw materials, intermediates and the unfinished and final drug substance; synthetic manufacturing process changes; changes in the source of drug substance; and changes to container closure system of the drug substance.

In comments filed late last month, Sanofi noted that the guidance refers to various ICH guidance documents (e.g., referring to Q7, Q8(R2), Q9, Q10, Q11, and M7), but, “It does not seem to incorporate many of the approaches and concepts for simplification of post-approval changes that have been included in ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Lifecycle Management.”

It is also unclear whether FDA plans to update this guidance once Q12 is finalized. Therefore, Sanofir requests that FDA clarify its views on this in the final version of the guidance, “to help ensure that FDA’s requirements and expectations are harmonized with those set forward in ICH Q12, once that guideline becomes effective.”

Eli Lilly also took issue with the guidance, noting that it is “often more conservative and more prescriptive” than current guidance, “particularly in an environment when ICH Q12 is recognizing that too many changes require regulatory reporting and often at too high a reporting level, stifling innovation and creating potential global supply challenges.”

AbbVie, meanwhile, is seeking additional clarification to define the linkage and relationship between this guidance and other FDA guidance documents on post-approval changes, “e.g., Changes to an Approved NDA or ANDA; Guidance for Industry (issued April 2004) and CMC Postapproval Manufacturing Changes to be Documented in Annual Reports; Guidance for Industry (issued March 2014).”

Three Batches

Throughout the guidance, there is what AstraZeneca calls, a “default requirement” to manufacture three pilot and/or commercial batches of drug substance and provide batch analysis to support impacted changes.

AstraZeneca calls such a requirement “onerous and not risk-based” and suggests that “at a minimum two batches at least at pilot scale, where applicable i.e., case-by-case. As per ICH Q9, the company should conduct a risk assessment and provide a justification for number of batches required. It is perceived that this is in line with current FDA thinking on risk-and science-based approach to manufacturing of drug product.”

Gilead similarly questions this “arbitrary number of batches,” saying that in many cases this “would not reflect the true process variation either before or after a change. Instead of including such an inflexible requirement the focus of the guidance should be on how to select which materials should be compared based on the nature of the change (i.e. do you compare intermediate data, drug substance data, drug product data, or some combination of the three) and how to evaluate the appropriate amount of data for comparison.”

Boehringer Ingelheim also notes that in keeping with ICH Q9, the risk assessment process should be used to determine the number of batches to demonstrate equivalence pre- and post-change. Additionally, data beyond three pre-change batches may be identified as appropriate for comparison.

Vertex, meanwhile, raised concerns on the guidance’s “lack of acknowledgement or accommodations for enhanced approaches to development, such as Quality by Design (QbD), continuous manufacturing (CM), real time release testing (RTRT), or continuous process verification.”



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