CMC: BIO Comments on FDA Draft Guidance CMC Postapproval Manufacturing Changes for Specified Biological Products to be Documented in Annual Reports


Re: Docket No. FDA–2017–D–2802: Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports; Draft Guidance For Industry

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA or Agency) for the opportunity to submit comments on FDA’s Draft Guidance for Industry “Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports” (Draft Guidance).

BIO is the world’s largest trade association representing 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.

  1. General Comments:

BIO appreciates the Agency’s efforts towards a categorization of listed annual reportable changes for biologics based on the associated commensurate risk, along with the annual reportable manufacturing type examples provided in the Draft Guidance.  However, as recognized in the Draft Guidance, “BLA holders may, based on their specific circumstances, determine that a change described in the Appendix would appropriately be submitted as a supplement rather than in an annual report.” As such, to minimize ambiguity in the future among applicants, we would recommend that the Final Guidance include examples of situations where annual reportable listed changes in the Guidance may be better categorized by applicants as a supplement based on certain specific circumstances. This could be in the form of an Annex to the Final Guidance, as a means of underpinning the principles to be considered by applicants in determining the applicable categorization to be used under certain circumstances, along with a better understanding of the Agency’s current thinking on the topic.

Relatedly, it would also be helpful for FDA to acknowledge and confirm that a Sponsor can perform an impact assessment to determine if the proposed change may be reported in an annual report, even if the proposed change is not listed within the guidance. In other words, it would be helpful to provide clarity that the list in the appendix is not all inclusive.

Additionally, it would be helpful for FDA to define when the potential for an adverse effect is determined. Is it the potential at the first thought of the change, after a risk assessment, after generating some data, after validation, or at time of implementation? This is important because as the change is analyzed and data are generated generally the potential for adversely affecting the product decreases.

Finally, it will be important that this Guidance is aligned with the final ICH Q12 guideline once complete. To this end, BIO notes that continuity and consistency of terms across various guidances and guidelines will be necessary to ensure clarity and consistency in expectations for both Sponsors and Regulatory Authorities.

  1. Examples/Situations from Other FDA Guidances:

There are a number of other FDA Guidances that discuss changes to an approved application related to CMC that are either reportable in the annual report and should be reflected in this guidance or that this Draft Guidance should be harmonized with to ensure consistent reporting.

2014 Guidance “CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports[1]

Some of the annual reportable situations listed in this document may also be applicable for biological products. Some parallel examples from the 2014 Guidance to the Draft Guidance include:

  • Section 3.5. – “For sterile drug products, addition of, deletion of, or change in a reprocessing protocol for refiltrations to control bioburden because of filter integrity test failures.”
  • Section 3.7. – “For sterile drug products, changes to the ranges of filtration process parameters (such as flow rate, pressure, time, or volume, but not pore size) that are within currently validated parameters ranges and therefore would not warrant new validation studies for the new ranges.”
  • Section 5.6. – “Change to delete the company trademark or other markings on the crimp cap (ferrule and flip cap/overseal) to comply with the official compendium.”
  • Section 7.3. – “For changes in an application that are fully consistent in scope and requirements with changes previously approved in a grouped supplement (also defined as a Bundled Supplement), the same applicant can make the same change to similar drug products.”

Further, this same Guidance includes “For equipment used in aseptic manufacturing processes (e.g., new filling line, new lyophilizer), replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits.” as a change that can be documented in annual reports. However in the Draft Guidance, line 234 excludes a new filing line or lyophilizer from the example to be reported in an annual report. We believe that the two guidances should be in agreement and that the Draft Guidance should allow a new filling line or lyophilizer to be included in an annual report provided there are no changes in the approved process methodology or in-process control limits.

1997 Guidance “Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products[2]

This Guidance includes “Establishment of a new Working Cell Bank derived from a previously approved Master Cell Bank according to an SOP on file in the approved license application” which should also be included in this guidance when finalized.

Additionally, this Guidance includes two annual reportable changes that are not included in this Draft Guidance. We ask FDA to clarify whether these should now be considered an unreportable change. These include:

  • 4. “Replacement of an in-house reference standard or reference panel (or panel member) according to SOPs and specifications in an approved application”
  • 10. “A change in the stability test protocol to include more stringent parameters (e.g., additional assays or tightened specifications)”

1997 Guidance “Changes to an Approved Application: Biological Products[3]

This Guidance includes relocation of equipment within approved operating room as an annual report. This represents minor risk to product quality for specified biological products and therefore should be listed in the new guidance.

  1. Conclusion:

BIO appreciates this opportunity to comment on the Draft Guidance for Industry “Chemistry, Manufacturing, and Controls Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.


[2] FDA, “Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products”, (July 1997)