Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

Biosimilars are required to be similar or highly similar in structure to their biologic reference product but are neither expected nor required to contain identical active substances. For example, glycosylated biosimilars approved to date demonstrate quantitative and qualitative structural differences from their reference product and exemplify the latitude of variations permitted for biosimilars. Although differences between a candidate biosimilar and its reference product will be evaluated for differential clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource, generic drugs.

SUMMARYBiosimilars are biological products that are highly similar to their biological reference products, notwithstanding minor differences in clinically inactive components. However, unlike generics of small-molecule drugs, biosimilars are not identical to their reference products, since each manufacturer uses unique cell lines and processes, and these lead to slight structural differences between products. Because these structural variations can lead to differences in clinical response, clinical studies demonstrating biosimilarity are required before and robust pharmacovigilance after approval. Although the FDA has not yet issued formal guidance on interchangeable biosimilars, higher standards of similarity will be required in order to achieve an interchangeable designation. In this commentary, we review the differences between generics and biosimilars, describe their respective regulatory approval pathways, discuss interchangeability and substitution, and review substitution of interchangeable biosimilars, focusing on key professional considerations for pharmacists.

The manufacturing of biologic medicines (biologics) requires robust process and facility design, rigorous regulatory compliance, and a well-trained workforce. Because of the complex attributes of biologics and their sensitivity to production and handling conditions, manufacturing of these medicines also requires a high-reliability manufacturing organization. As required by regulators, such an organization must monitor the state-of-control for the manufacturing process. A high-reliability organization also invests in an experienced and fully engaged technical support staff and fosters a management culture that rewards in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures. Such a combination of infrastructure, technology, human capital, management, and a science-based operations culture does not occur without a strong organizational and financial commitment. These attributes of a high-reliability biologics manufacturer are difficult to achieve and may be differentiating factors as the supply of biologics diversifies in future years.

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