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Why Biosimilar Approval Applications Break Down


Investigators found that process complexities have created numerous difficulties for biosimilar developers in regulatory filings, but they anticipate that the success rate will improve with experience and improved guidance.

Developing biosimilars is not an easy process. Exact details of the manufacturing process are typically not available from the reference manufacturer. Further, minute variations in product quality can be magnified as biosimilar production moves through its various stages. For these reasons, biosimilar developers often run into complications when seeking approval from regulatory authorities.

A recent study of failed applications for biosimilar approval points out the various reasons why attempts to get biosimilars approved in the United States and Europe have broken down. “Most regulator rejections can be attributed to gaps in the manufacturer’s understanding of what is expected from a comparability exercise and also Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP) implementation,” the authors said.

In this article, The Center for Biosimilars® discusses findings from the report, and in the coming days, we will post a video interview with lead author Anurag S. Rathore, PhD, about the group’s conclusions and general observations about biosimilar development and regulator review.

Difficult Process to Master

Prior to the arrival of epoetin alfa biosimilars, Amgen had difficulty with variability in outcomes for its originator product. During its first decade, the product was associated with a relatively small number of cases of pure red blood cell aplasia (PRCA), which is associated with oxygen-poor blood concentrations. From 1998 to 2004, however, there was an “epidemic” of PRCA related to this product. This increased immunogenicity was eventually attributed to a formulation change, and preventive measures were successful in reducing the incidence of PRCA to normal levels.

This case illustrates the difficulty of maintaining consistency in product quality even for originator companies, according to the authors.

For the pegfilgrastim biosimilar Fulphila, the journey to acceptance by the European Medicines Agency (EMA) was a bumpy one. As a candidate biosimilar, it did not fit within acceptable ranges for purity and impurity to demonstrate biosimilarity with the reference product, Neulasta.

Another issue with Fulphila centered around poor control for sterility of the finished product, which raised questions about the quality of the manufacturing plant. The product applicant, Mylan, withdrew its application to the EMA, adjusted the manufacturing and control processes, and resubmitted. Approval was granted in 2018.

“For receiving approval for a biosimilar application, it is necessary to demonstrate similarity between the proposed product and the reference molecule with respect to safety, efficacy, and quality. This comparability exercise serves as the basis for approval and hence it is not a surprise this also happens to be the most common reason for denying approval to a biosimilar application,” the authors wrote.

Regulatory guidelines typically recommend that biosimilar equivalence be demonstrated by analytical studies, which establish comparability to the reference product, and preclinical and clinical studies, which demonstrate that safety and efficacy fall within acceptable boundaries.

During process validation, different human insulin products from Marvel LifeSciences have been flagged by the EMA for insufficient data on fermentation, harvesting, and purification processes, for example. Similarly, for the candidate Herzuma biosimilar trastuzumab, the FDA had concerns about the processes for lyophilization, or low-temperature dehydration, and vial filling.

“Manufacturing biosimilars is a complex process involving many steps such as choosing appropriate cell line, cell culture, harvest, purification, formulation, and packaging,” the authors wrote. For this reason, manufacturers need to understand the factors that affect safety and efficacy and establish controls that provide for consistency in product quality, they said.

Common Sticking Points

Regulators have held up applications on the grounds of shelf life and product quality concerns. The FDA raised such concerns over stress studies for trastuzumab biosimilar (Trazimera) and epoetin alfa (Retacrit) biosimilar applications, because the stress studies were not representative of how products would hold up under real-time commercial shipping conditions.

Many biosimilar applications have stalled over regulatory concerns about compliance with GMP. In early 2018, Celltrion Healthcare, for example, was asked to make manufacturing facility improvements in order to move forward with its rituximab (CT-P10) and trastuzumab (CT-P6) applications.

The importance of getting the manufacturing formula right on biosimilar development is highlighted by the growth in the market for biologics and the sheer cost of originator products.

Biotherapeutics represented a $4.4-billion market in 1990 and now represent about $275 billion, an increase of more than 6000%. This class of drugs now represents 25% of the total pharmaceutical market. By comparison, biosimilars account for a very small proportion of these revenues, just 2% to 3% of the US biologicals marketplace, according to the study authors.

“It is now widely accepted that continued adoption of biosimilars will result in significant savings to the cost-bearer, the government, or the patients, or both, and that this will dramatically improve the accessibility toward this effective but unaffordable class of products, not only for those living in emerging economies but also significant portions of those living in developed economies,” the authors wrote.

Still, they predict a rapid increase in the number of biosimilars in coming years due to the pending expiration of patents on originator drugs. As of September 2019, there were 83 biosimilar development programs registered with the FDA for 38 biologic drugs. And biosimilars for at least 23 originator biologics were in late-stage development in the United States, according to the authors.

Regulatory policies are working to shape the development of biosimilars. Regulatory diligence is critical to avoid substandard products and elevated patient risk. The EMA has “shown significant success in maintaining this balance, with the US FDA and others (regulators) gradually progressing toward this goal,” the authors said.

Manufacturers are on the early side of a learning curve, regulators can be expected to clarify and improve guidance, and the rejection ratio will diminish over time, thereby driving down the cost of biosimilar development and improving access and affordability of these agents, the authors said. “Indeed, the coming decade will witness the success of biosimilars.”


Rathore AS, Chhabra H, Bhargava A. Approval of biosimilars: a review of unsuccessful regulatory filings, expert opinion on biological therapy. ‎Expert Opin Biol Ther. Published online July 7, 2020. doi:10.1080/14712598.2020.1793954

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