As the number of chemistry, manufacturing and controls (CMC) postapproval manufacturing supplements continues to increase, the US Food and Drug Administration (FDA) on Tuesday released draft guidance offering recommendations for holders of biologics license applications (BLAs) on the types of minor changes to be documented in an annual report.
"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," the agency says (italics are FDA's).
If a manufacturing change is considered "major," an applicant must submit and receive FDA approval of a BLA supplement (also known as a prior approval supplement) before the product produced with the manufacturing change is distributed.
If a change is considered "moderate," an applicant must submit a supplement at least 30 days before the product is distributed (known as a CBE-30 supplement) or in some cases, the product may be distributed immediately upon FDA's receipt of the supplement (known as a CBE-0 supplement).
And if changes are considered "minor," an applicant just has to notify FDA of the change in an annual report. However, FDA adds, "For any change, applicants must assess the effects of the change on product quality through appropriate studies."
For additional background information on reporting categories for BLAs, FDA suggests a guidance known as, "Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products."
As far as which changes generally should be documented in an annual report, as FDA considers they have a minimal potential to have an adverse effect on quality, the guidance offers the following examples:
"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.
4.1. 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.
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 (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."
CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports: Guidance for Industry