Online Exclusives

Setting a Precedent for Biosimilars in the U.S.

By Kristin Brooks, Contract Pharma | May 19, 2015

Niall Dinwoodie of Charles River discusses several key industry issues on biosimilars and addresses some of the development and regulatory hurdles that remain

The approval of the first biosimilar in the U.S. will likely serve as a case study for shaping future biosimilar programs until further regulatory guidance is available. However, this can present more questions than answers for some developers, namely, how to proceed with an already complicated development process. We can expect that additional regulatory clarity and approvals will play a significant role in streamlining the biosimilar development process in the long run, but in the near-term several challenges remain.
There is high demand in the industry to gain approval to manufacture biosimilars. Chemistry World recently reported that, as of October 2014, the FDA had received nearly 80 requests from companies for initial meetings to discuss biosimilar development programs for 14 different reference products, and had received 28 IND applications for biosimilar development programs.
Niall Dinwoodie, global coordinator of Analytical Testing, Biologics Testing Solutions, at Charles River Laboratories, recently participated in a Q&A on Eureka, an online community for scientists, on the FDA’s first biosimilar approval addressing several industry issues on biosimilars. He discusses the implications on the development process and what we can anticipate in the near term with respect to strategy and regulatory hurdles.  – Kristin Brooks

Contract Pharma: What sort of activity do you anticipate in the near term now that the first biosimilar product has been approved in the U.S.?

Niall Dinwoodie: Many companies will be studying the information available on the approval of Sandoz’s Neupogen biosimilar, particularly the FDA Briefing Document from the Oncologic Drugs Advisory Committee meeting held January 7, 2015, which contains much detail on the extent of characterization, animal and clinical data generated by Sandoz to support the application. The range of batches of reference product and biosimilar tested in the characterization package is extensive and may give cause to some developers to review the data they have, or were intending to, generate. Those companies that have already begun discussion with the regulators will be unaffected but many may be reconsidering their understanding of the reference product and their own production process, leading to delays or possibly cancellations in the development programs.

CP: What regulatory hurdles still need to be overcome?

ND: The big hurdle is still interchangeability. In the U.S., the FDA is committed to providing guidance on the approaches needed to gain interchangeable status and European national authorities are working to improve access to biosimilars but this still remains the key “unknown” in calculating potential return on investment for biosimilar developers. Naming conventions and post-market surveillance issues are being gradually resolved, which should help with physician acceptance. The FDA has now finalized three of the biosimilars guidance documents, providing more detail and changing emphasis on aspects of the development program

CP: What services areas are currently being outsourced and what areas do you expect to pick up?

ND: All service areas relating to biosimilar development are currently being outsourced; cell line development and characterization, manufacture, product characterization, release and stability testing, animal data and clinical testing and the assays that support both the nonclinical and clinical programs. Some companies are outsourcing the whole package but many, especially the larger players, keep the development and characterization in-house to gain the understanding of the product, such as the relationship between structural variants and efficacy/safety, necessary for discussion with the regulators. We expect this trend to continue as knowledge of the product’s characteristics is key to limiting the animal and clinical testing required and thus reduces the time to market. Outsourcing of manufacture and fill/finish is likely to grow as more biosimilar products are developed and reach the market.  

CP: What are some of the main challenges working with biosimilars?

ND: Obtaining a sufficient pool of reference product batches can be a challenge. For characterization purposes a range of batches is required, from different markets if the intention is for a global submission. These batches must be tested within their shelf-life and ideally, as near to production date as possible to give an indication of the acceptable range for each parameter tested. If there are low numbers of batches produced, this can mean that batches have to be obtained, and tested, over a number of years or held at a storage condition that will prevent deterioration. Understanding the pattern of drug substance to finished product manufacture for the reference product can also be difficult; the biosimilar manufacturer will want to assess reference product made from a wide variety of drug substance batches not multiple product batches from the same drug substance lot.

CP: What factors play a role in streamlining biosimilar development?

ND: Knowledge of the reference product is key to developing a biosimilar and streamlining that development process. A good understanding of the expression system used and how it can affect the quality attributes of the reference product drug substance will help in developing the target quality envelope for the bisomilar. The program for development of the biosimilar product must be well thought out, and discussed with the regulatory authorities, to minimize the extent of testing performed. The use of platform technologies, particularly in expression systems and to an extent, purification and production processes, allow a greater understanding of subsequent biosimilars coming from the same development route.

CP: Do certain products present greater challenges?

ND: The more complex the molecule, the greater the challenges. Monoclonal antibodies, with glycosylation and more complex amino acid sequences, present a greater challenge than a simple non-glycosylated recombinant protein. Blood products are covered by the biosimilar guidelines and present different challenges with comparability of donor pools and residual proteins.

Kristin Brooks has been associate editor at Contract Pharma since 2004.

Related Contract Manufacturing: