Health Reform WK-EDGE Therapeutic protein biosimilarity studies depend on understanding the reference product
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Thursday, May 23, 2019

Therapeutic protein biosimilarity studies depend on understanding the reference product

By Elena Eyber, J.D.

The FDA offered recommendations on the design and evaluation of comparative analytical studies intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product.

Factors to consider in a comparative analytical assessment to support biosimilarity include expression system, functional activities, and target binding. An FDA guidance offered considerations for the design and evaluation of comparative analytical studies intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product licensed under section 351(a) of the Public Health Service Act (PHS Act). Additionally, this guidance is intended to provide recommendations to sponsors on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) portion of a marketing application for a proposed product (Notice, 84 FR 23569, May 22, 2019).

The BPCI Act. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amends the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (ACA) (P.L. 111-148)). Although the 351(k) pathway applies generally to biological products, this guidance focuses on therapeutic protein products and provides an overview of recommendations for the comparative analytical assessment and other important scientific considerations to support a demonstration of biosimilarity between a proposed therapeutic protein product and the reference product. This guidance is one in a series of guidances that FDA is developing to facilitate implementation of the BPCI Act.

Factors for consideration in performing the comparative analytical assessment. When performing the comparative analytical assessment to support a demonstration of biosimilarity, manufacturers should consider a number of factors, including expression system, manufacturing process, physicochemical properties, functional activities, target binding, impurities, reference product and reference standards, finished drug product, and stability.

Comparative analytical assessment. The FDA recommends that sponsors approach the comparative analytical assessment by first understanding the physicochemical and biological characteristics of the reference product. Protein products are complex molecules that have a certain degree of inherent lot-to-lot variability in terms of quality characteristics. The observed lot-to-lot variability may derive from manufacturing conditions and from analytical assay variability. Factors that contribute to lot-to-lot variability in the manufacture of a protein product include the source of certain raw materials and different manufacturing sites. Therefore, it is important to adequately characterize the lot-to-lot variability of the reference product and the proposed biosimilar product.

In the comparative analytical assessment, risk ranking and data analysis are used to evaluate a large number of attributes, often using multiple orthogonal assays. FDA evaluates the totality of the analytical data. If the results of a particular assay do not meet pre-specified criteria, this alone does not preclude a demonstration of high similarity. If differences between products are observed as part of the comparative analytical assessment, the sponsor may provide additional scientific information and a justification for why these differences do not preclude a demonstration that the products are highly similar. In certain situations, changes to the manufacturing process of the biosimilar product may be needed to resolve differences observed in the comparative analytical assessment. Data should be provided demonstrating that the observed differences were resolved by any manufacturing changes, and that other quality attributes were not substantially affected. If other attributes were affected by the manufacturing change, data should be provided to demonstrate that the impact of the change has been evaluated and addressed.

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