Biosimilars had a brief spotlight at BDP Week in two track sessions, Analytical Technologies for Biotherapeutic Development (ATBD) and as a featured presentation in Antibody Development and Production (ADP). The focus of the presentations in the ATBD track was on characterization and comparability of biosimilars while the focus in the ADP track was less on characterization and more on addressing the debate on biosimilarity.
Judy Chou, VP of R&D at Tanvex Biologics, divided her presentation into a discussion on the challenges, approaches, and analyses involved in establishing similarity of a biologic to the predecessor innovative drug product, or biosimilarity. To put the challenge in perspective, Chou made a comparison between gaining approval for a generic drug and gaining approval for a biosimilar. She described the complexity of the approval challenge by depicting a generic as a bicycle and a biosimilar as a jet airplane; though they are both transportation vehicles, a bicycle is not only smaller and lighter, but it has far less complexity with respect to its blueprint on the electrical, mechanical, and structural design of its operation. The approach to determining biosimilarity was likened by Chou to the story of the blind men and an elephant. This parable with origins in India is about how six blind men decide that they are going to take it upon themselves to describe and define an elephant, an animal which has stirred their curiosity based on other accounts. Each blind man analyzes the elephant by touch from a different angle or entry point, and as a result derives a different description of the animal. Chou equates the elephant to the biosimilar, and in her version of the parable she wants to setup the blind men for success by equipping them with tools to overcome their blindness. These tools are physicochemical methods of protein characterization and biological activity assays that are each validated or correlated by a secondary orthogonal method and that are all established early on as standard operating protocols.
Chou stressed the importance of gaining a complete understanding of the biological molecule with respect to hotspots of higher order structural variability and when in the process those hotspots are susceptible to undergoing change. She added that early establishment of standard operating protocols pertaining to process analytical technology for characterization is imperative to success. An emphasis was placed on the implementation of quality by design to guide the establishment of design space boundaries and critical process parameters, and definition of critical quality attributes of the biosimilar. Chou concluded by referring back to the blind men and the elephant, and stated that it is when guided by principles of quality and criticality, equipped with capability for “fingerprint analysis”, and results are integrated to arrive at a “totality of the evidence” that a determination can be made about comparability, similarity and interchangeability.
Steve Flatman, Head of Research and Technology and Biosimilars Development at Lonza Biologics, didn’t rely on analogies to proverbs or cartoon graphics such as bicycles, jets and elephants, but his presentation resonated with Chou’s emphasis on the utilization of fingerprint methods in determining comparability and biosimilarity in that he stated that the goal of the biosimilar applicant is essentially “to manufacture a copy”. The approach to the development of a process to, as stated by Flatman, “ensure manufacturability”, relies on an “excruciatingly thorough literature review” of the molecule, tight controls, and incorporation of quality by design principles. The key success factor to making such a copy, or biosimilar, is testing strategy, which Flatman advised is guided by a clear understanding of requirements and compliance as put forth by the FDA in guidance documents, as well as in market intelligence forecasting. Product assessment should take place at “relevant stages” of the process, such as where the biosimilar is susceptible to losing comparability and biosimilarity, and rely on methods that are rated highly in specificity and sensitivity so that analytical results and differences to the reference product can be constructively evaluated with respect to “meaningfulness”. Some characterizations paramount to comparability and biosimilarity referred to by Flatman included isoform profiles and assessment of heterogeneity by orthogonal methods.
Basant Sharma, VP of API Large Molecule at Janssen R&D, started off giving a similar talk as Chou and Flatman, but then veered onto a different course. He started by saying that “the process defines the product”, and that the process includes production, purification, formulation, and handling and storage. He used epoetin as an example product. He depicted the structure of epoetin and noted that it is a mixture of isoforms in solution and that this is an important aspect when asking, “how similar is a biosimilar”, because a major concern of the FDA is immunogenicity as a function of protein structure. At this point Sharma veered onto a different course by introducing the “4 P’s” that factor into the scientific debate on acceptance of biosimilars.
P-1 is the policy maker who struggles with clearing the hurdle of interchangeability. P-2 is the physician who takes the stance of the residents of Minnesota, which is “show me” interchangeability, for example by conducting head-to-head trials. P-3 is the payor, or health insurance industry, whose focus is on discount prices and pharmacovigilance. Finally, P-4 is the patient who wants better than “marginal benefits”.
In summary, the major common themes amongst the three presentations were utilization of state of the art analytical capability, implementation of a thorough and orthogonal testing strategy especially regarding structure, integration of results to arrive at a “totality of evidence”, and being knowledgeable about the molecule and process in order to ensure manufacturability by applying quality by design and defining critical quality attributes and process parameters.
Today's post comes from Gregory T Mrachko a Protein Chemist and Enzymologist. He specializes in protein purification, enzymology, high throughput assay/screen conceptualization/development/implementation, analytical biochemistry, biocatalysis, liquid column chromatography, and protein analytics. He is a guest blogger at this year's Biopharmaceutical Development and Production Week and can be reached at gmrachko@msn.com.
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