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46 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m Biosimilars biosimilars currently approved in the US have this designation. Challenges in development and commercialization of biosimilars The two major concerns with respect to approval and use of biosimilars are the efficacy and safety of the biosimilars in comparison to the original drug. The foundation for establishing this is to demon- strate product comparability (9). Quality of biotherapeutic products is known to be significantly impacted by the manufacturing process used to produce them as signified by the oft mentioned adage "The Process Defines the Product" (10). A biosimilar manufacturer has to demonstrate their capability to control the process so as to manufacture product of consistent qual- ity (11) and follow it up by a thorough comparison between the biosimilar and the innovator's product based on extensive analytical examination, stabil- ity studies, non-clinical studies (such as receptor- binding studies and cell-based assays), and clinical studies (for pharmacokinetic, pharmacodynamic, and immunogenic behavior) as mentioned previ- ously. In most likelihood, the biosimilar product may differ from the innovator's product in a sub- section of the quality attributes, although it is not allowed to impact on clinical efficacy and safety (12,13,14). A key aspect that needs to be understood as well is the relationship between the product and the clinic. Biotech products tend to be complex and subject to potential modifications. For this reason, all these qualities are scrutinized with advanced analytical techniques. Role of pharmacovigilance in commercialization of biosimilars The complexity of biologic molecules and the as- sociated manufacturing processes mean that these products have the potential for immunologic reac- tions, which could result in a decrease in efficacy (neutralizing antibodies) or adverse reactions (an- tidrug antibodies). Regulatory pathways employed by EMA and FDA place greater emphasis on find- ings from analytical assessments and reduce the need for comparative clinical trial data. While this is efficient in bringing biosimilar products to market, it also means that there is limited clini- cal exposure to the product at the time of market entry. Therefore, it is important that an effective and well-designed post-marketing pharmaco- vigilance program is in place to detect potential product-related problems that would likely not be observed during the biosimilar development. The example of pure red cell aplasia that occurred with the use of a particular epoetin alfa product in Eu- rope (Eprex, Johnson & Johnson) in the late 1990s and early 2000s demonstrated that small manu- facturing changes have the potential to cause clinically significant immunogenic responses (15). While the potential for immunogenic reac- tions is possible given that there will inherently be small structural differences between the reference product and the biosimilar due to the complexity of the molecules and manufacturing processes, in practice there have not been any significant issues related to immunogenicity reported throughout the experience with biosimilars in Europe (over a decade) or the US. Approaches to post-marketing pharmacovigi- lance are often categorized as passive sur veil- lance or active sur veillance methods. Passive