Intended for healthcare professionals


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

BMJ 2017; 357 doi: (Published 27 April 2017) Cite this as: BMJ 2017;357:j1707
  1. Nicole Casadevall, professor of haematology1,
  2. Oliver Flossmann, consultant nephrologist2,
  3. David Hunt, honorary consultant neurologist and Wellcome Trust intermediate clinical fellow3
  1. 1Hôpital Sainte-Antoine, Paris, France
  2. 2Royal Berkshire Hospital, Reading, UK
  3. 3Anne Rowling Clinic, Centre for Clinical Brain Sciences, University of Edinburgh, UK
  1. Correspondence to: D Hunt david.hunt{at}
  • Accepted 26 March 2017

Changes to the manufacturing of biological agents can lead to drugs with different components from the original medicine tested in clinical trials, challenging assumptions about safety, say David Hunt and colleagues

Biological drugs, such as recombinant proteins and monoclonal antibodies, have revolutionised the treatment of many diseases.12 By definition, these agents are complex molecules produced in living cells, requiring multistep manufacturing processes such as cell culture, purification, stabilisation, and packaging.3 Biological drugs (or “biologicals”) differ from small molecule drugs in that they are highly sensitive to changes in manufacturing. As a result, the safety profile of established biologicals can alter over time, posing a major challenge to the safety frameworks for such drugs.

Biologicals change over time

Changes to the manufacturing of biologicals are surprisingly common, although healthcare professionals and patients are often unaware of them. For example, infliximab has undergone more than 35 alterations in its clinical lifetime of nearly 20 years.4 Most of these changes will have been relatively minor, and the manufacturer will have demonstrated to the regulator that the biological was unchanged at a physicochemical level.3 But not all changes are trivial, and some are introduced with the explicit intention of improving clinical parameters. Even if clinical trials are required after substantial alterations, they are typically short and rarely powered to detect adverse events that are uncommon or rare and serious.

“Biological evolution” describes how sequential manufacturing changes can cause the properties of a biological to diverge from the original (fig 1).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? Whether an object retains it …

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