FDA: Chemistry, Manufacturing, and Controls (CMC) Reporting

Re: Docket No. FDA-2010-D-0283: Draft Guidance for Industry on Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes Reportable in Annual Reports; Availability

Dear Sir/Madam:

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance for Industry on Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes Reportable in Annual Reports.” BIO welcomes FDA’s initiative to apply scientific and risk based principles to reclassify changes as annual reportable. We encourage the Agency to consolidate existing Chemistry, Manufacturing, and Controls (CMC) reporting guidances, clarify how CMC reporting for biologics will be addressed under future guidance, and help reduce the potential for unintended consequences that may inadvertently increase the regulatory reporting burden.

BIO represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.


1. Consolidation of Guidance Documents Can Minimize Inconsistencies

There are multiple final FDA guidances that provide recommendations for how the Agency wishes to be notified of post approval CMC changes. Further, some of the changes described in the current Draft Guidance are already included in the existing “Changes to an Approved NDA or ANDA" guidance. Yet, on the other hand, some of the annual reportable changes described in the "Changes to an Approved NDA or ANDA" guidance are not contained in the current Draft Guidance, such as a move to a different manufacturing site for secondary packaging or labeling. The reasons for this inconsistency are unclear, as are the reasons for having multiple guidances on these topics. To avoid the confusion likely to stem from the availability of multiple guidances that cover the same topics, we recommend that these guidances, including the various "Changes to an Approved NDA or ANDA" and Scale-Up and Post-Approval Changes (SUPAC) guidances, be consolidated as appropriate and as soon as possible. If FDA does consolidate the guidances, please consider the format adopted by Health Canada in its guidance entitled, “Post-Notice of Compliance Changes: Quality Document.” This guidance, in addition to consolidation of advice on post-approval manufacturing changes into a single document, clearly demonstrates how understanding CMC manufacturing changes and supporting data can result in regulatory relief.

2. Reporting Requirements for Biologics Should Be Clarified

We also note that the scope of the guidance as written covers New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs), but does not discuss biologics regulated under Biologic Licensing Applications (BLAs). We encourage the Agency to extend its work and identify low risk changes to biologics governed under a BLA that are suitable for reporting in an annual report. In fact, many of the principles and changes suggested under the guidance are broadly applicable to biologic products (1.1, 1.3, 2.1-2.3, 3.2-3.8, 4.1-4.5, 4.10, 4.11, 5.2, 5.4, 5.5, 6.1, and 6.2). For example, the risk profiles of the proposed changes are identical and not related to the registration process. As products registered under all of the listed processes have similar (and often identical) annual reporting requirements, the changes listed may be applicable to these additional products.

BIO requests that FDA clarify the status of reporting requirements for biologic products. This could be accomplished by explicitly stating in the “Introduction” to the Draft Guidance that:

1. Biologics subject to Sec. 351 of the Public Health Services Act are not covered under the scope of this guidance and continue to be subject to reporting requirement under 21 CFR 601.12 and existing applicable guidance; and

2. Risk-based principles to reduce the reporting burden for biologics will be addressed in a forthcoming CBER/CDER guidance or revisions to existing guidance.

3. Some Provisions May Have the Unintended Effect of Increasing the Regulatory Burden

The Draft Guidance recommends that CMC annual reportable changes be supported by (among other things) “cross references to validation protocols and standard operating procedures and policies” (line 131). These documents are frequently updated and revised. Currently, except for certain specific categories of products (i.e., natural products, recombinant DNA-derived proteins/polypeptides, complexes or conjugates of a drug substance with a monoclonal antibody), GMP/Compliance regulations require this information to be kept on file and presented to FDA upon request (for example, during an inspection). We are concerned that this general recommendation has the potential to increase industry's regulatory reporting burden. We recommend modifying the recommendation to include a reference to reflect the regulatory requirement as stated at 21 CFR 314.70(d)(3)(v).


BIO appreciates this opportunity to comment on “Draft Guidance for Industry on Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes Reportable in Annual Reports.” We have provided more specific comments in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.


Andrew J. Emmett
Managing Director, Science and Regulatory Affairs
Biotechnology Industry Organization (BIO)