BioRationality: FDA Clarification Provides New Indications and Process Change for Biosimilars

Post-approval changes are expected and addressed under §601.12 (21 CFR 601.12); there are 3 classes of reporting requirements. First is the annual record reporting for minor modifications that have the minimum potential to affect the product's identity, strength, quality, purity, or potency, which may affect its safety or effectiveness.

The second stage is for moderate changes requiring a CBE-30 supplement submitted at least 30 days before product distribution. A moderate modification may affect the product's identification, strength, quality, purity, or potency, affecting its safety or effectiveness. The FDA notifies acceptance within 30 days or proposes the supplement to expand to the third stage, that is, Prior Approval Supplement (PAS), for significant changes that have the potential to alter the product's identity, strength, quality, purity, or potency, which may affect its safety or effectiveness; this submission requires submitting a comparability protocol for the CMC changes.

If this protocol report is approved, the reporting is lowered to a different category. It is noteworthy that when the FDA uses the term comparability, it is referring to ICHQ5E (ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Applicants), and it is not the same as the analytical assessment that is required for new biosimilar development. In the comparability trial, the comparison is made between the previous and future projected product, not the reference product. Even the most experienced writers frequently misuse this terminology.

While the post-approval modification approvals are well understood, they have not been transparent regarding biosimilars, so the FDA brought a new document to clarify these points in July 2024. First, it requires a thorough study of any changes made to the product, production process, quality controls, equipment, facilities, or responsible personnel in the approved biologics license application (BLA) to determine their impact on the product's identity, strength, quality, purity, or potency, which could potentially impact its safety or effectiveness. It should adhere to the Manufacturing Process Changes (June 2005), comparing before and after manufacturing process adjustments. Data and information should be proportional to the manufacturing modification and its potential to alter product quality, safety, and efficacy to prove comparability.

The quality standards and analysis methods for the comparability exercise should consider the risks of the manufacturing change(s) and give enough information to show that the biosimilar product was comparable before and after manufacturing. As applicable, the supplement should provide product quality data, such as process validation and comparability data. It requires examining the post-change biosimilar product at the appropriate manufacturing stage to detect quality changes. Several phases of production may involve testing the product.

To determine comparability, comparing pre- and post-change data on intermediates most affected by the manufacturing modification in addition to the drug substance and drug product may be appropriate. Many pre-change and post-change materials should be tested side-by-side, including stability data. Comparative stability studies under relevant storage conditions (for example, accelerated testing, stress testing) can find minor differences between materials before and after they change that characterization studies might miss; thus, comparative stability studies are crucial when manufacturing modifications affect protein structure or purity and impurity profiles. The stability study conditions should be chosen based on the relevance of the product and concerns about manufacturing changes.

When these quality changes are validated, comparing their analytical data could support a manufacturing modification. If the performance of an analytical assay has changed since the approval, then bridging data should be provided.

A qualified in-house reference material is used to determine if a post-change product is comparable to the pre-change product. However, if discrepancies are found, the FDA may require using reference products for comparative analytical assessment. What constitutes a discrepancy is not clarified, but it may include significant changes in quality attributes that may be considered relevant based on scientific literature. Still, this argument is not fulfilled unless a comparison with a reference product is made.

A manufacturer may introduce its product into multiproduct manufacturing areas or contract manufacturing facilities, in which case, The Approved Application for Specified Biotechnology and Synthetic Biological Products (July 1997), the CMC Post-approval Manufacturing Changes for Specified Biological Products in Annual Reports (December 2021) apply, and the reporting category should align with the risks associated. Putting a licensed biosimilar into a multiproduct manufacturing area or contract manufacturing facility can be risky. Still, it depends on the product and whether extra controls are added to ensure it is pure and of good quality. Identity testing can identify and manage such hazards. Cross-contamination or product mix-ups may occur in a multiproduct manufacturing area or contract manufacturing facility that produces the reference product and/or another applicant's biosimilar product(s) referencing the same reference product.

A single identity test for each product may not always identify them. To prevent cross-contamination or mix-ups, current good manufacturing practice requirements, including applicable manufacturing and procedural controls (e.g., separate manufacturing areas, control of personnel, process, and material flow, and control of materials, as applicable), must be followed in addition to identity tests for each product.

Changes to the dosage form or strength are not permitted under the 351(k) BLA filing. To suggest a new dosage form or strength to be approved, it must also show that the proposed biosimilar is "highly similar to the reference product notwithstanding minor differences in clinically inactive components" and that "there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product." To support the approval of a supplement for a new dosage form or a new strength, the information submitted in the supplement must be sufficient to demonstrate that the proposed product meets the interchangeability standards described in Section 351(k)(4) of the Public Health Services Act.

Significant modifications, such as the proposal of a new dosage form or strength not licensed under the 351(k) BLA, typically require a PAS that should include: (1) adequate comparability data between a licensed biosimilar (pre-change product) and the proposed new dosage form or strength (post-change product); (2) comparative analytical assessment (CAA) data; and (3) manufacturing data (eg, process validation) to support the proposed post-change product.

A pre- and post-change product differences risk assessment should justify the comparability and CAA data. [Note: CAA refers to comparison with the reference product, and comparability refers to comparison with the pre-change product; it may be appropriate to use the CAA data from the 351(k) to support the proposed dosage form or strength without comparing it to its reference product].

To determine how the changes affect product quality, applicants should consider whether additional CAA studies with the new dosage form or strength are necessary. Applicants should also assess the potential utilization of the proposed product, considering whether the dosage form or strength of the reference product is specific to an indication or a population. Additionally, the FDA may require a pharmacokinetic study to approve the supplement for the recommended dosage form or strength.

When an applicant's supplement proposes a new strength with the same method of administration, dosage form, excipients, patient population, and indication, using the CAA from the 351(k) BLA and a risk-based comparability exercise between the pre-change strength(s) and the projected post-change strength may be suitable.

If an applicant proposes a novel dosage form and strength for a different patient population or indication than the 351(k) BLA, the applicant should not only utilize the CAA data from the 351(k) BLA but also conduct a risk-based targeted comparative analysis (CAA) between the proposed product's new dosage form and strength and its reference product, as well as a risk-based comparability exercise between the pre-change and post-change products.

While the FDA has provided much clarification, and of the most significance is the allowance that a biosimilar product can change its route of administration, such as going from subcutaneous to intravenous, change the formulation, such as going from a citrate buffer to a buffer-free solution, and even introducing a new indication. Reference products have introduced these changes once their patents expire to extend the intellectual property (IP) coverage; a good example is the formulation of Humira in a citrate formulation that was extremely painful, and Abbvie already had a buffer-free formulation, but it was held back until their patent expired while letting the patients suffer for decades. A similar situation arises when the reference products change the concentration to reduce the injection volume.

Biosimilar applicants can change their product to match these changes only if their IP is not hindered. To overcome the IP challenges, the US Senate has passed a new S-150 Bill that will forbid reference products to secure patents for such changes. This bill has yet to go through the House of Representatives, but I anticipate its passage will significantly support the cause of biosimilars.

However, of most tremendous significance is that a biosimilar can secure a new indication that is not included in the reference production without filing it as a new biological drug. Repurposing biological drugs for biosimilars is the most profitable route, making it available at an affordable cost.

I wish to thank the FDA for clarifying these issues and supporting the rationality of biosimilars, which I call BioRationality.