FDA Releases Draft Guidance on Postapproval Manufacturing Supplements of Biologics

The guidance describes chemistry, manufacturing, and controls postapproval manufacturing changes considered to have minimal potential to adversely affect quality.

The FDA released a draft guidance last week on postapproval manufacturing changes for biologics.

The guidance provides recommendations to holders of Biologics License Applications (BLAs) on the types of minor changes to be documented in an annual report, according to the FDA. More specifically, it describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes.

“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 (AE) on product quality must be documented by applicants in an annual report,” according to the report.

Postapproval changes are required to be submitted as either major, moderate, or minor. If a change is considered major, an applicant is required to submit and receive FDA approval for a BLA supplement before the product produced with the manufacturing change is distributed.

For moderate changes, applicants must submit a supplement at least 30 days before the product is distributed. In some cases, the product may be distributed immediately upon the agency’s receipt of the supplement.

Applicants must notify the FDA of any minor changes in an annual report, but can proceed with the change otherwise.

Document changes in an annual report must include a full description of the CMC changes, including the manufacturing sites or areas involved, date the change was made, a cross reference to relevant validation protocols and/or standard operating procedures, and relevant data from studies and tests performed to assess the effect of the change on product quality.

The annual report should also contain a list of all products involved and a statement that the effect of the change has been assessed.

The following are examples from the FDA of CMC postapproval manufacturing changes that the agency generally considers having minimal potential to have an AE on product quality:

1.Components and Composition

1.1. An elimination or reduction of an overage from the drug product manufacturing batch formula previously used to compensate for manufacturing losses.

2.Manufacturing Sites

2.1. Site change for testing.

2.2. Site change for labeling or secondary packaging when the new site has a satisfactory CGMP status.

2.3. Change in location of manufacturing steps within a manufacturing area that is already listed in an approved BLA, in which the steps are part of a nonsterile drug substance production process and the new location does not impact or will lower the risk of contamination or cross-contamination.

2.4. Modification of manufacturing facility listed in an approved BLA that does not increase the risk of contamination or otherwise present a meaningful risk of affecting product quality.

2.5. Manufacture of an additional product, in multiple-product areas listed in an approved BLA that is also producing other products if: specific identity tests exist to differentiate between all products manufactured at the facility; change-over procedure between manufacturing processes do not require new changes in cleaning procedures; and the products do not represent an additional level of risk.

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 not involving the use of different equipment.

3.4. Reduction of open-handling steps if there is a reduction in product exposure that represents improvement in the assurance of product protection.

3.5. For key sterile drug products, changes from a qualified sterilization chamber to another of the same design and operating principle for containers/closures preparation when new chamber and load configurations are validated to operate within previously validated parameters.

4.Specifications

4.1. Addition of tests and acceptance criteria to specification for approved excipients.

4.2. Change to a drug substance or product to comply with an official compendial test.

4.3. Change in regulatory analytical procedure if the acceptance criteria remains unchanged and the revised method maintains basic test methodology.

4.4. Replacement of a nonspecific identity test with a discriminating identity test that included a change in acceptance criteria.

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.

5.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, 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.

5.3. Changes to a crimp cap, provided there are no changes to the labeling or the color and the contain closure integrity has been demonstrated using a validated test method.

Click here for more details on the above examples.