By Nitisha Pyndiah, PhD

Regulatory agencies such as FDA and EMA require that biosimilars be highly similar and have no clinically meaningful differences with a reference product. In February 2018, EMA published in AAPS PharmSciTech, trends in deficiencies identified during the evaluation of the quality part of applications for marketing authorizations. Several of these deficiencies have also been observed in the US.

Here I propose to discuss common deficiencies that I found in biosimilar applications and use the list of common quality deficiencies in EMA marketing submission as a basis. By doing so, I wish to help biosimilar developers address or avoid deficiencies prior to submission to allow their product to reach market faster!

Part 1: What are the major deficiencies identified regarding the Drug Substance?

Biocomparability: Issues due to lack of supporting data when comparing reference product to proposed biosimilar. Differences in glycosylation not well elucidated, insufficient data regarding differences in potency assay results.

Analytical methods validation: All validation characteristics recommended for the type of test should be done. All validation data should be submitted to the regulatory body. I have often seen that there was insufficient validation of the analytical method used.

Reference standards or materials: Issues with calibration and qualification, lack of information about in-house reference material and how they were established.

Stability: Inadequate or insufficient stability data to support the proposed shelf life. No appropriate stability results using the proposed container closure system.

Processes: The manufacturing process and process controls should be described thoroughly.

Specifications: The lack of justification regarding the specification of DS. Specifications unmet due to insufficient validation of the analytical method used.

Drug substance comparability: Comparability of similar manufacturing processes not adequately shown.

Sourcing of reference product: To obtain licensure a sponsor has to demonstrate that the proposed product is biosimilar to a reference product that has been previously licensed by FDA or establish an acceptable bridge between the non-US reference product the US-licensed reference product and the biosimilar.

I have often seen sponsors using a non-US product prior to using a US-licensed reference product and carrying out bridging studies. Inconsistencies in the sourcing of the reference product for the comparability program for quality, safety and efficacy studies have been seen.

Characterization: A common deficiency is the inadequate elucidation of structure and characteristics of the DS, I have observed that the elucidation of the structure was often incomplete. Orthogonal physicochemical methods are important in confirming the structure and characteristics of the drug substance. FDA strongly recommends using multi-parameter approaches that are extremely sensitive in identifying analytical differences.

Mainly, I have often seen that glycosylation was not well characterized; differences in post translational modifications (PTM) between the reference product and the biosimilar may lead to immunogenicity (i.e detrimental immune response in the patients commonly measured using anti-drug antibodies). The most common PTM is glycosylation and should be well characterized to also ensure that not clinically meaningful differences are observed between a biosimilar and a reference product. The drug substance is produced in nonhuman tissues, therefore it is important to ensure that nonhuman glycosylation that could potentially induce a detrimental immune response are not present.

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