The FDA recently released draft guidance offering recommendations for holders of biologics license applications (BLAs) on the minor changes that should be documented in an annual report. As the number of chemistry, manufacturing and controls (CMC) postapproval manufacture supplements continue to increase, the FDA decided to publish this guidance.
Guidance
This guidance provides recommendations to holders of biologics license applications (BLAs) for specified products regarding the types of changes to an approved BLA to be documented in an annual report under 21 CFR 601.12. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that FDA generally consider to have a minimal potential to have an adverse effect on product quality.
Under FDA regulations, postapproval changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on product quality must be documented by applicants in an annual report.
Recommendations for Reporting Certain Changes in an Annual Report
FDA recommends that the changes listed in the Appendix generally should be submitted in an annual report. However, if a BLA holder is planning to make a change that is listed in the Appendix, the BLA holder should evaluate the change in the context of the holder’s particular circumstances to determine whether the proposed change would present a minimal potential to have an adverse effect on product quality and therefore would be appropriately documented in an annual report. 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. If FDA disagrees with the categorization, FDA may notify the applicant of the correct category and request additional information.
To the extent that a recommendation in this guidance to document a single change in an annual report is found to be inconsistent with a previously published FDA guidance, the recommendations in this guidance would apply. For changes not listed in the Appendix, or if multiple related changes being implemented simultaneously increases the potential to have an adverse effect on product quality, applicants should refer to other CDER and CBER guidances to determine the appropriate reporting category for notifying the Agency of the changes.
Contents of Annual Report Notification
To document changes in an annual report, the applicant must include the following information for each change:
- A full description of CMC changes, including:
- The manufacturing sites or areas involved.
- The date the change was made.
- A cross-reference to relevant validation protocols and/or standard operating procedures.
- Relevant data from studies and tests performance to assess the effect of the change on product quality.
- A list of all products involved.
- A statement that the effects of the change have been assessed.
The applicant should describe each change in an annual report in enough detail to allow the Agency to evaluate the change and determine whether the appropriate reporting category has been used. If the submitted change is inappropriate for documentation in an annual report, FDA may notify the applicant of the correct category and may request additional information.
However, inappropriate documentation should be uncommon because applicants should only use this mechanism of reporting a change when they are confident that documentation in an annual report is appropriate.
Examples
Illustrating the guidance, FDA issued the following examples under five categories:
- 1. Components and Composition
1.1. Elimination or reduction of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing losses. Note that this does not apply to loss of potency during storage.
- 2. Manufacturing Sites
2.1. Site change for testing. This includes sites for testing of lower-risk process-related impurities (e.g., host cell proteins, host cell DNA, residual solvents) when the method was successfully validated at the new site and the new site, where applicable, meets relevant CGMP requirements for the type of operation involved (e.g., no outstanding FDA warning letters or “official action indicated” compliance status). This does not include sites for testing for conformance to quality control specifications, including potency, impurities (except those that are lower risk), and safety testing (e.g., sterility and virus testing).
2.2. Site change for labeling or secondary packaging when the new site has a satisfactory CGMP status.
2.3. Change in the location of manufacturing steps within a manufacturing area that is already listed in an approved BLA where those steps are part of a nonsterile drug substance production process and the new location will have no impact or will lower the risk of contamination or cross-contamination (e.g., improved air classification, better process flow, enhanced segregation of pre- and post-viral inactivation steps).
2.4. Modification of a manufacturing facility listed in an approved BLA that does not increase the risk of contamination (e.g., affect sterility assurance) or otherwise present a meaningful risk of affecting product quality.
2.5. Manufacture of an additional drug product (already licensed or an investigational product), in a multiple-product area listed in an approved BLA that is producing other products, if:
2.5.1. Specific identity tests exist to differentiate between all products manufactured at the facility; and
2.5.2. Change-over procedure between manufacturing processes does not require new changes in cleaning procedures; and
2.5.3. The products do not represent an additional level of risk. Additional levels of risk might include, but are not limited to, the manufacture of highly toxic or potent products (e.g., botulinum toxin), highly immunogenic or allergenic products (e.g., penicillin), products that can accelerate degradation of another product (e.g., proteases), products that represent a new or added risk for adventitious agents, or a product for adults added to a line manufacturing pediatric products.
- 3. Manufacturing Process, Batch Size and Equipment
3.1. Changes in mixing times for solution dosage forms.
3.2. Small changes in the size of pooled or separated batches to perform the next step in the manufacturing process if all batches meet the approved in-process control limits and the critical process parameter ranges for the next step remain unaffected.
3.3. Changes to batch sizes that do not involve use of different equipment (e.g., increase in roller bottle number, minor increases in fermenter volume or minor increases in load volumes for chromatography columns).
3.4. Addition of an identical duplicate process chain or unit process in the drug substance and drug product manufacturing process with no change to equipment, process methodology, in-process control limits, process parameter ranges, or product specifications, with the exception of addition of major equipment used in aseptic processing (e.g., new filling line, new lyophilizer).
3.5. Reduction of open-handling steps if there is a reduction in product exposure that represents improvement in the assurance of product protection (e.g., implementation of sterilize-in-place connections to replace aseptic connections, automated weight checks, installation of a barrier to protect product, replacement of a manual stopper recharging step with an automated recharging step).
3.6. For sterile drug products, change from a qualified sterilization chamber (ethylene oxide, autoclave) to another of the same design and operating principle for containers/closures preparation when the new chamber and load configurations are validated to operate within the previously validated parameters. This does not include situations that change the validation parameters.
- 4. Specifications
4.1. Addition of tests and acceptance criteria to specification for approved excipients.
4.2. Change to a drug substance or drug product to comply with an official compendial test, except for changes to assays, impurities, product-related substances, or biological activities or changes described in 21 CFR 601.12(c)(2)(iv).
4.3. Change in the regulatory analytical procedure if the acceptance criteria remain unchanged and the revised method maintains basic test methodology (e.g., change in the flow rate or sample preparation for an HPLC12 method) and provides equivalent or increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it claims to have or is represented to possess.
4.4. Replacement of a nonspecific identity test with a discriminating identity test that includes a change in acceptance criteria (e.g., replacing SDS-PAGE13 with peptide mapping).
4.5. Addition of an in-process test.
4.6 Addition of a test for packaging material to provide increased quality assurance.
4.7 Tightening of an existing acceptance criterion.
- Container Closure System
5.1. Change in the container closure system for the storage of a nonsterile drug substance when the proposed container closure system has no increased risk of leachable substances (based on the extractables and/or leachables profile and whether stability data are consistent with historical trends), and the new container offers equivalent or greater protection properties from air and moisture.
5.2. Use of a contract manufacturing organization for the washing of a drug product stopper, provided the applicant certifies that the organization’s washing process has been validated and its site has been audited by the applicant (or by another party sponsored by the applicant) and found CGMP compliant.
5.3 Changes to a crimp cap (ferrule and cap/overseal), provided that there are no changes to the labeling or the color and that container closure integrity has been demonstrated using a validated test method.”