Guidance Breakdown: Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products

We dissect the FDA's new draft guidance on postapproval manufacturing changes for biosimilar and interchangeable biosimilar products.

Aug 06, 2024

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The FDA has released a draft guidance addressing manufacturing changes for approved biosimilars and interchangeable biosimilars.

It outlines the information applicants need to provide when reporting changes under § 601.12, categorizing them as major, moderate, or minor based on their potential impact on product safety and effectiveness.

Read the full draft guidance

The FDA details required data, quality control measures, and comparability demonstrations between pre- and post-change processes. It also covers specific scenarios like introducing products into multiproduct facilities and seeking approval for new dosage forms. The agency emphasizes maintaining quality throughout manufacturing stages and storage while also streamlining the reporting process.

We break it down below.

Background

Section 351 of the PHS Act establishes an abbreviated licensure pathway for biosimilars and interchangeable biosimilars. (Biosimilarity means the product is highly similar to the reference product without significant clinical differences. Interchangeability means the product can be expected to produce the same clinical result as the reference product and poses no greater risk when switching.)

The Q&A format of this guidance updates recommendations relevant to the development of biosimilar and interchangeable biosimilar products, focusing on manufacturing changes. The guidance fulfills FDA's commitment under the Biosimilar User Fee Act (BsUFA) to advance biosimilar product development.

Question 1

What is the nature and type of information, for different reporting categories, that FDA recommends to support postapproval manufacturing changes to licensed biosimilar and licensed interchangeable biosimilar products?

Reporting Categories

Applicants must report manufacturing changes to biosimilars or interchangeable biosimilars according to § 601.12. The potential impact on the product’s identity, strength, quality, purity, or potency must be assessed.

The FDA categorizes these changes into three reporting categories:

Prior Approval Supplement (PAS): Required for major changes with a substantial potential to adversely affect the product. They must be approved by the FDA before distribution. Applicants can submit a comparability protocol in a PAS to propose specified types of postapproval CMC changes, which, if approved, may justify a reduced reporting category. This is regulated under § 601.12(b)-(e).
Changes Being Effected in 30 Days (CBE-30) / Changes Being Effected (CBE-0) Supplements:
1. CBE-30: This is required for moderate changes with moderate potential adverse effects. It must be submitted at least 30 days before distribution. If the FDA informs the applicant within 30 days that the change requires prior approval or any required information is missing, distribution cannot proceed until compliance is achieved.
2. CBE-0: For specific validated changes, the product may be distributed upon FDA receipt. Reference § 601.12(c).
Annual Report: Required for minor changes with minimal potential adverse effects. Must be documented in the annual report as stated in § 601.12(d).

Applicants should clearly identify the reporting category in the submission and include a complete list of changes in the cover letter. If the changes impact labeling, the corresponding labeling changes must be included with the CMC supplement.

Relevant guidances for the industry include:

Product Quality Data

Applicants intending to make a manufacturing change should follow the principles outlined in the ICH guidance for industry “Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process” (June 2005). The comparability exercise should evaluate the product before and after the change, with data commensurate with the type and potential impact of the change.

The exercise should include quality attributes and analytical methods addressing the risks of the change. Process validation data should also be included in the supplement.

Data submitted should demonstrate that quality attributes remain comparable pre- and postchange. The product should be evaluated at the most appropriate process step, potentially at multiple stages, including intermediates most affected by the change.

Comparative stability studies are crucial, especially when changes might alter protein structure or impurity profiles. The studies should justify conditions based on relevance to the product and the risks of the change. Historical analytical data from various stages of the product's lifecycle should be included, with scientific justification for any subset used.

Question 2

What reference materials should applicants include in the comparability exercise?

Applicants should include a well-qualified, in-house reference material in the comparability exercise to evaluate whether a postchange biosimilar remains comparable to the prechange product. The in-house reference material serves as an important calibration point for the evaluations conducted in a comparability exercise.

If sufficient data predict no adverse impact on quality, safety, or efficacy, the FDA may consider the data adequate without additional reference materials beyond the in-house reference material. However, demonstrating comparability should assure that a postchange product remains biosimilar to or interchangeable with the reference product. When differences in quality attributes are observed, comparison to the reference product data submitted for licensure should be considered to assess potential impact and acceptability of these differences.

In-house reference materials refer to appropriately characterized materials prepared in-house by the manufacturer from representative lots for the purpose of biological assay and physicochemical testing of subsequent lots.

Question 3

How should proposals to introduce a licensed biosimilar and/or licensed interchangeable biosimilar product into a multiproduct manufacturing area or a multiproduct contract manufacturing facility be reported?

Applicants proposing to introduce a licensed biosimilar or interchangeable biosimilar into a multiproduct manufacturing area or contract manufacturing facility should refer to several key guidances.

These include:

The appropriate postapproval reporting category should be based on the risks associated with product introduction and its impact on the biosimilar's quality attributes.

The risks depend on the type of product and the additional control measures needed to ensure the product meets its intended quality characteristics, including purity. Identity testing is one tool to detect and control these risks.

Introducing a biosimilar into such facilities poses significant risks, such as cross-contamination or product mix-ups. To prevent these risks, applicants must follow cGMP requirements, including manufacturing and procedural controls like separate manufacturing areas, control of personnel, process and material flow, and control of materials. Detailed descriptions of these controls must be provided to the FDA to evaluate their adequacy.

Question 4

What is the nature and type of CMC information that FDA recommends to support the approval of a supplement for a dosage form or a strength that has not previously been licensed under the 351(k) BLA?

When submitting a supplement to a Biologics License Application (BLA) under section 351(k) of the Public Health Service (PHS) Act proposing a new dosage form or strength, applicants must include comprehensive information to demonstrate the new dosage form or strength's comparability to the reference product.

This includes showing that the proposed biosimilar or interchangeable biosimilar product is "highly similar" to the reference product with "no clinically meaningful differences" in terms of safety, purity, and potency. The proposal of a new dosage form or strength not previously licensed is typically considered a major change, and thus generally requires a Prior Approval Supplement (PAS).

Requirements for Supplement Submission:

Comparability Data: Applicants must provide data comparing the prechange product (licensed biosimilar or interchangeable biosimilar) with the postchange product (proposed biosimilar or interchangeable biosimilar with the new dosage form or strength). The extent of data required should be justified based on a risk assessment of the differences between the prechange and postchange products.
Comparative Analytical Assessment (CAA) Data: The supplement should include CAA data to support the proposed new dosage form or strength. In some cases, leveraging previously submitted CAA data in the original 351(k) application may be appropriate, but applicants should assess whether additional CAA studies are needed to address the potential impact of the new dosage form or strength on product quality.
Manufacturing Data: The supplement should include process validation data to support the manufacturing of the postchange product. All relevant manufacturing information for the proposed new dosage form or strength should be included.

In some cases, additional data, such as pharmacokinetic studies, may be necessary to support the supplement's approval. Applicants should consider how the proposed product would be used, including whether the new dosage form or strength is specific to certain indications or populations compared to the reference product.

A couple of examples:

New Strength with Same Route of Administration and Dosage Form: If the supplement proposes a new strength with the same route of administration, dosage form, excipients, patient population, and indication as the licensed product, leveraging previously submitted CAA data along with a risk-based comparability exercise may be reasonable.
New Dosage Form and Strength for Different Population: If the supplement proposes a new dosage form and strength intended for a different patient population or indication, leveraging previous CAA data may still be appropriate, but the applicant should also include a risk-based targeted CAA and comparability exercise between the prechange and postchange products.

The FDA recommends that applicants discuss the adequacy of the analytical and manufacturing data with the appropriate FDA review division before submitting the supplement. Various additional scenarios are possible, and the data and information needed to support each unique scenario may differ.

Our Recommendations

Here’s our roadmap for operationalizing this guidance into your postapproval change program.

Understand the reporting categories for manufacturing changes. Familiarize yourself with the FDA's categorization of manufacturing changes into major, moderate, and minor changes. Determine the potential impact of manufacturing changes on product identity, strength, quality, purity, or potency, as they relate to safety and effectiveness. If a manufacturing change involves a new facility, this is likely a major change requiring a PAS. Conversely, a minor change might involve a slight alteration in the manufacturing process that does not impact the product’s quality.
Submit appropriate supplement documentation. Prepare and submit the correct documentation based on the type of change: PAS for major changes, CBE-30 for moderate changes, and annual report for minor changes. Make sure that each supplement submission includes a complete list of all changes and, if applicable, corresponding labeling changes. If, for example, you’re implementing a new sterilization method, submit a PAS. If you’re slightly modifying an existing method, submit a CBE-30. Minor adjustments like changing a supplier for a non-critical component can be reported in the Annual Report.
Conduct comprehensive comparability exercises. Perform detailed comparability studies to demonstrate that the product remains comparable pre- and post-change. Be sure to include quality attributes and analytical methods that address the risks of the manufacturing change, supported by sufficient data and information. If you were changing a cell line, for example, you need to conduct comparability studies to show that the biosimilar’s quality attributes, such as protein structure and purity, remain unchanged.

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