By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA

The FDA recently released this guidance to detail the agency’s recommendations for the design and evaluation of comparative analytical studies to demonstrate 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). Furthermore, the guidance includes recommendations for sponsors concerning scientific and technical information for the chemistry, manufacturing, and controls (CMC) areas of the marketing application for a proposed product submitted under section 351 (k) of the PHS Act. Ultimately, this guidance is part of a series of guidances that FDA is developing to facilitate implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI) Act.

Additional relevant guidances include Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Questions and Answers on Biosimilar Development and the BPCI Act, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, Labeling for Biosimilar Product, and Considerations in Demonstrating Interchangeability With a Reference Product.

The BPCI Act amends the PHS Act and other statues to generate a condensed licensure pathway in section 351 (k) of the PHS Act for biological products shown to be biosimilar to an FDA-licensed reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (ACA) (Public Law 111-148). This guidance is different than this pathway because of its specific focus on therapeutic protein products.

The guidance details factors for consideration when conducting a comparative analytical assessment of biosimilarity. One factor manufacturers should contemplate is the expression system. Essentially, therapeutic protein products can be made from microbial cells, cell lines, or animal or plant tissues. The FDA expects that the proposed product construct has the same primary amino acid sequence as the reference product. However, slight alterations, including N- or C- terminal truncations, can be made as long as they do not alter the protein performance and can be explained by the sponsor. It is suggested by the FDA that minimizing differences between the proposed product and reference product expression systems will increase the probability of generating a biosimilar protein product.

Another factor to consider is the manufacturing process. A cohesive understanding of total procedure of the manufacturing process for the proposed product should be made during product development. Enhanced approaches in pharmaceutical development, quality risk management, and effective quality systems will all help to repeatedly produce a high-quality product. It is important to note that an application for a biological product submitted for licensure under section 351 (k) of the PHS Act may not incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file.

There are several other factors the guidance suggests analyzing: physicochemical properties, functional activities, target binding, impurities, reference product and reference standards, finished drug product, and stability.

In order to develop a successful biosimilar product, there must be a thorough understanding of the reference product. In order to do this, the FDA suggests that sponsors approach the comparative analytical assessment by understanding the physicochemical and biological characteristics of the reference product. It is important to characterize the reference product and review publicly available information to fully understand the product.

Regarding the reference product, it is important to correctly capture the full range of product variability. This can be achieved through attaining multiple reference product lots during the development of the proposed biosimilar in a sufficient quantity that allows for the completion of numerous physiochemical and functional assays. It is recommended that at least 10 reference product lots are included.

For the proposed product, the FDA suggests having at least 6 to 10 lots of the proposed product in the comparative assessment. This quantity will ensue sufficient characterization of the proposed product and comparison to the reference product.

In conclusion, the foundation for an assessment and demonstration of biosimilarity between a proposed product and its reference product includes analytical studies that show these similarities. This means that there needs to be an extensive analysis of the proposed product. Also, a 351 (k) application for a proposed product should include  data  from animal studies and clinical studies. These data can only be excluded from this application if the FDA deems it appropriate.


At HartmannWillner LLC we understand the regulatory requirements for development of biosimilar and interchangeable biological products through the PHS Act §351(k) and Biological License Application (BLA) process. We have assisted with the development of well over 25 biosimilar and interchangeable biological products. Contact us today to learn more about our services and how we can help you.

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at