Pharmaceutical Technology - May 2019

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Page 42 of 50

Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 43 process is designed to address this residual un- certainty (4). In both the United States and Europe, limited clinical data have been required so as to enable evaluation of safety and efficacy of the bio- similar drug in comparison to the original drug. EMA, for ethical reasons, is exploring ways to re- duce the clinical testing to a minimum to avoid extensive and thereby expensive clinical trials. The success of biosimilars has been somewhat muted, in particular in the United States, though certainly picking up with time. The reasons for this are several including the complexity of bio- pharmaceutical processes and products as well as the inherent heterogeneity of these products, which makes it difficult if not impossible to main- tain identical purity even by the innovator itself. For this reason, both in the US and in Europe, new regulatory pathways have been developed for the assessment of copies of biological medicines after expiration of market exclusivity (1). Europe has been a leader in creating the regulatory framework for approval of biosimilars, and as a result, more than 50 biosimilars of 15 innovator biotherapeu- tics have been approved by the EU as of April 2019 (3). This is a sharp contrast with the US, where only 17 biosimilar products related to nine in- novator biotherapeutics have been approved and only 10 were available on the market at the time of writing (5). In this 42nd article in the Elements of Bio- pharmaceutical Production, the authors pres- ent a perspective on challenges with successful commercialization of biosimilars. Aspects that have been explored include common principles in biosimilar development and assessment, key differences between the US and EU regulations, and the role of pharmacovigilance in biosimilars. Development and characterization of biosimilars The design of a biosimilar is mostly an art of re- versed engineering (6). A biosimilar company may purchase 10–20 different batches of the product they seek to copy and perform an analytical char- acterization exercise. The number of batches used needs to be justified to the regulator. A selection of attributes that are often examined as well as the numerous analytical techniques used in the assess- ment can be found in Kwon et al. (4). The biosimilar manufacturer attempts to de- fine the critical quality attributes (CQA) that are responsible for mode(s) of action on one side but also for side effects (like immunogenicity) on the other. In addition, the variability in the CQA be- tween batches of the reference product is defined, as the biosimilar is required to stay within these boundaries. According to FDA, "although the scope of ICH [International Council for Harmo- nization] Q5E is limited to an assessment of the comparability of a biological product before and after a manufacturing process change made by the same manufacturer, certain general scientific principles described in ICH Q5E are applicable to an assessment of biosimilarity between a pro- posed product and its reference product. How- ever, demonstrating that a proposed product is biosimilar to an FDA-licensed reference product manufactured by a different manufacturer typi- cally will be more complex and will likely require more extensive and comprehensive data than as- sessing the comparability of a product before and after a manufacturing process change made by the product's sponsor. A manufacturer that modi- fies its own manufacturing process has extensive knowledge and information about the product and the existing process, including established

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