New FDA Draft Guidance Reduces Reporting Burden for CMC Postapproval Changes

A new draft guidance from FDA specifies 40 types of low-risk manufacturing changes that will now qualify for annual report filing and represents a significant step in the agency’s effort to reduce the number of supplements that have to funnel through the Center for Drug Evaluation and Research (CDER) clearance process.

Following a discussion of the agency’s basic approach to regulating manufacturing changes and its goal to reduce the filing burden, the draft “guidance for industry” on “CMC Postapproval Manufacturing Changes Reportable in Annual Reports” provides the list of changes qualifying for annual reporting in an appendix.

The 40 types of changes are divided into six categories: • components and composition • manufacturing sites • manufacturing process • specifications • container/closure system, and • miscellaneous changes.  Examples from the list of qualifying changes include:  a new supplier of inactive ingredients; addition of barriers in a filling or compounding area; certain minor manufacturing process changes made under conditions as prescribed; some changes to a drug substance or drug product to comply with the official compendia; some changes in container/closure systems for nonsterile drug substances; and reduction of expiration dating for a drug product for reasons other than stability failures.

The guidance is applicable to both new and abbreviated new drug applications (NDAs/ANDAs).  A background section describes the categories of changes in FDA’s three-tiered classification system (major, moderate, and minor) and the regulatory filing requirements for each.

A “discussion” section notes that the number of CMC manufacturing supplements for NDAs and ANDAs has continued to increase over the last several years. FDA explains that, in connection with its Pharmaceutical Product Quality Initiative and risk-based approach to CMC review, it has evaluated the types of changes that have been submitted as supplements and determined that many of these “present very low risk to the quality of the product and do not need to be submitted in supplements.”

The guidance clarifies that the list of changes provided is to be used in the context of specific products and circumstances to determine whether the proposed change has the potential to adversely impact that product.  Based on that analysis the “NDA or ANDA holder may decide that a change described in Appendix A would more appropriately be submitted as a supplement rather than in an annual report. We, therefore, consider this guidance to provide recommendations” as opposed to requirements for annual reporting.

The guidance includes a description of the requirements for an annual report and the governing regulations.

FDA is asking that public comments and suggestions regarding its new draft guidance be submitted within 90 days of its June 25 publication date in the Federal Register. For questions regarding the document contact CDER Office of Pharmaceutical Sciences Associate Director for Policy Jon Clark at 301-796-2400.

Manufacturing Change Flexibility Drawing Attention in EU as Well as US

Reduction of the reporting burden for postapproval manufacturing changes has been a target for some time in both the US and the EU, with each moving in the same direction, but at different paces.

The effort is intimately linked to the fostering of the QbD/ICH Q8-10 paradigm and the concerted push by regulators in the ICH regions to encourage the flow of changes that are needed throughout the product lifecycle to support a continuous improvement framework.  Industry and regulators have been debating how to reduce the constraints created by their marketing applications on the one side and the GMP process validation and change control requirements on the other as part of the effort to unleash the power of science and technology to improve products and processes. (IPQ, May 2010, pp. 24-25).

Speaking at an IFPAC workshop in February, Center for Drug Evaluation and Research (CDER) Office of New Drug Quality Assessment (ONDQA) Director Moheb Nasr previewed the now-released guidance and shared his vision for the future.

Nasr suggested that “sometime in the future rather than having three categories of supplements, you may have only two – changes that are low risk that could be reported in annual reports and the high risk changes that will still need to be submitted to the agency for approval.” Manufacturers who have a good understanding of their products and processes and a robust quality system “may not need to have this CBE 0 category, and some of these changes would be moved to annual report,” the ONDQA director said.

In Europe, the encumbrances of its multi-state system have resulted in its lagging behind the US in instituting more progressive policies.  However, the EU has been actively working to update its rules and guidance in this area, and in January released a pair of guidances spelling out revised variation filing expectations and procedures.

At the February IFPAC workshop, EMA Scientific Administrator Evdokia Korakianiti stressed the importance that the improved flexibility in the revisions provide.  “Postapproval regulatory flexibility was not possible until the end of 2009,” she stated.  “We are quite happy to say that now this has been taken care of.”


CMC Postapproval Manufacturing Changes Reportable in Annual Reports

EC Post-authorization Procedural Advice: Human Medicinal Products

EC Q/A List for Submission of Variations