Biosimilar Development

Biosimilar development is a highly skilled, multistep process and requires extensive understanding of the reference product.1

Manufacturers of biosimilars execute two paths—first to understand the reference product and second for the creation of the biosimilar.1

Understanding a Reference Product

To understand how a reference product works to treat patients, scientists acquire the reference product and use sophisticated analytical tests to characterize the medicine, identifying its critical quality attributes that provide the function that allows the medicine to treat patients. Additionally, they review the literature published in peer–reviewed medical journals on both the diseases and the reference product, while also leveraging company‐based therapeutic area expertise, if available.2

Creating a biosimilar

Creating a biosimilar requires skilled scientists to conduct steps in a laboratory that require a high level of precision. Sophisticated analytical tools and methods are used to compare the biosimilar to the reference product on the very fine details of the molecule. In most cases, a robust analytical data package is insufficient for approval without non–clinical and clinical data. The analytical data with the non–clinical and clinical data together comprise the “totality of evidence” for which the level of similarity can be assessed.3-5

Step 1: Transfect living cells with DNA, meaning to insert the genetic “instructions” for each new clone (version of the cell) to produce the amino acid sequence of the biologic. 

Step 2: Once several  versions of the candidate biologic are created, each by a different clone, scientists evaluate them to identify and select the clone that is most similar to the reference product.

Step 3: The manufacturing process is then developed, and later fine–tuned, to enhance the level of similarity between the biosimilar and the reference product. This process will be the platform for creating an adequate quantity of the biosimilar to supply patients with medicine.

Step 4: Following development of the manufacturing process, non-clinical and clinical testing can occur. Clinical testing often involves two stages:

-A first stage in healthy volunteers or patients to test that the body processes the biologic in the same way  as the reference product (ie, pharmacokinetics and pharmacodynamics)

-A second stage in a broader set of patients to test that the biosimilar works with a similar level of  efficacy, safety, and immunogenicity as the reference product

Biosimilar Development Process


  1. Kozlowski S. US FDA Perspectives on Biosimilar Biological Products. Presented at 2014 Biotechnology Technology Summit; June 13, 2014; Rockville, MD.
  2. Nowicki M. Basic facts about biosimilars. Kidney Blood Press Res. 2007;30:267-272.
  3. Alten R, Cronstein BN. Clinical trial development for biosimilars. Semin Arthritis Rheum. 2015;44:S2-S8.
  4. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies. Drugs. 2011;71:1527-1536.
  5. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. Accessed November 23, 2016.
  6. Conner J, Wuchterl D, Lopez M, et al. The biomanufacturing of biotechnology products. In: Shimasaki C, ed. Biotechnology Entrepreneurship: Starting, Managing, and Leading Biotech Companies. Waltham, MA: Academic Press; 2014:351-385.