Drift, Evolution, and Divergence in Biologics and Biosimilars Manufacturing

Abstract

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.

Translating European regulatory approval into healthcare uptake for biosimilars: the second translational gap

“…In this discussion and in many other contributions (Berkowitz et al 2012;Lee, Litten, and Grampp 2012;Miletich et al 2011;Ramanan and Grampp 2014;Schiestl 2011), the technological and regulatory capabilities required to develop biosimilars have been regularly highlighted. These challenges were seen as becoming greater with the prospect of the more complex biological medicines which will lose exclusivity over the next decade, the group that Miletich et al (2011) described as 'biosimilars 2.0'.…”

A Primer on Biosimilars: FDA-Approved and those in the Pipeline

“…Like most biologic products discussed in this article, adalimumab is a large glycoprotein and consists of a heterogeneous mixture of structural isoforms [54]. Like Humira, the labeling for Amjevita contains a boxed warning to health care professional and patients about an increased risk of serious infections.…”

Evolution of biological agents: how established drugs can become less safe

“…5 For example, a recombinant protein might undergo sequential alterations to three key components-the active biological substance, the stabiliser, and the packaging-leading to a biological drug where all the main components have been changed. So does the drug retain the safety and efficacy profile of the original?…”

“…[6][7][8][9] These improved parameters can be readily assessed in short trials, comprising a few hundred patients or fewer. [3][4][5][6][7][8][9][10] Such trials can provide reliable safety data about the short term clinical performance of evolved biological drugs but are not usually able to detect changes in long term safety or efficacy. 11 If the biological has diverged from the original in a beneficial "The ship wherein Theseus returned was preserved by the Athenians.…”