Adverse immunostimulation caused by impurities: The dark side of biopharmaceuticals

Abstract

Drug safety is an important issue, especially in the experimental phases of development. Adverse immunostimulation (AI) is sometimes encountered following treatment with biopharmaceuticals, which can be life‐threatening if it results in a severe systemic inflammatory reaction. Biopharmaceuticals that unexpectedly induce an inflammatory response still enter the clinic, even while meeting all regulatory requirements. Impurities (of microbial origin) in biopharmaceuticals are an often‐overlooked cause of AI. This demonstrates that the current guidelines for quality control and safety pharmacology testing are not flawless. Here, based on two case examples, several shortcomings of the guidelines are discussed. The most important of these are the lack of sensitivity for impurities, lack of testing for pyrogens other than endotoxin, and the use of insensitive animal species and biomarkers in preclinical investigations. Moreover, testing for the immunotoxicity of biopharmaceuticals is explicitly not recommended by the international guidelines. Publication of cases of AI is pivotal, both to increase awareness and to facilitate scientific discussions on how to prevent AI in the future.

Influence of Fucoidan Extracts from Different Fucus Species on Adult Stem Cells and Molecular Mediators in In Vitro Models for Bone Formation and Vascularization

“…Therefore, we further analyzed the endotoxin content of the tested fucoidan extracts. Since endotoxins may cause inflammatory and immunological reactions [ 32 , 33 ], parentally applied medical products or materials getting in contact with blood must be endotoxin-free. Especially endothelial cells react highly sensitively toward endotoxins, with release of inflammatory molecules, changes in barrier, and increased angiogenic activity [ 34 , 35 ].…”

“High‐risk” host cell proteins (HCPs): A multi‐company collaborative view

“…These problematic HCPs can be considered high‐risk and can include those that are immunogenic, biologically active, or enzymatically active with the potential to degrade either product molecules or excipients used in the product formulation, and may be difficult to purify (Bee et al, 2015; Chiu et al, 2017; Vanderlaan et al, 2018). Although there are only very few cases known with direct impact of HCPs on patient's safety, the biopharmaceutical industry is concerned about these high‐risk HCPs, as shown through several recent publications (Cheung et al, 2016; Jawa et al, 2016; Reijers et al, 2019; Wang et al, 2009). The BioPhorum Development Group (BPDG) HCP Workstream initiated a collaboration among its 26‐company team with the goal of industry alignment around high‐risk HCPs.…”

Holistic Analytical Characterization and Risk Assessment of Residual Host Cell Protein Impurities in an Active Pharmaceutical Ingredient (API) Synthesized by Biocatalysts

“…Since most of biologics are produced using non-human cell lines, immunogenicity is one of the major concerns caused by residual HCP impurities in biological products if not adequately removed. Immunogenicity can lead to various degrees of adverse effects in patients ranging from more severe cytokine storm, chronic inflammation, hypersensitivity to mild injection site reactions (Reijers et al, 2019). Although the majority of commercialized biologics have proven to be safe with the presence of only trace amount of residual HCPs, there are a few cases where the presence of high level of immunogenic HCPs delayed product development and approval (Vanderlaan et al, 2018).…”