Addressing Protein Aggregation
The formation of protein aggregates in biopharmaceuticals can be difficult to predict and control. Here’s how we can improve patient safety through primary packaging materials and bedside filtration.
Benjamin Patrick Werner and Gerhard Winter |
Biopharmaceuticals possess the capability to treat severe illnesses and can generally be considered as relatively safe, but despite stable formulations resulting in high product quality, the formation of protein aggregates can occur for a number of reasons, including chemical or physical degradation, such as oxidation or denaturation (1). Aggregates can be small and soluble or grow into larger particles. Other factors that contribute to particle generation include light, shearing, shaking or temperature (2)(3)(4). The majority of protein drug products will encounter most of the above mentioned factors at some point during their production cycle and shelf life – and the risk associated with these protein aggregates is that they can endanger drug safety and efficacy (5)(6). Immune reactions caused by non-native protein species have been known about since the 1950s (7). Despite many improvements in the generation of recombinant proteins, such as fully humanized proteins or sequence modifications, it is still rather common to detect the formation of anti-drug antibodies in the blood of patients treated with protein drug products because of protein aggregation (8)(9).
In the majority of cases, anti-drug antibodies only have minor clinical relevance, but severe events – anaphylaxis, serum sickness or life-threatening cases like the neutralization of an endogenous protein – can occur (5)(10). Furthermore, beside proteinaceous particles, a protein drug product can contain other particles, such as silicone oil, glass microflakes, rubber, plastic or metal (11)(12)(13). Combined particles, such as non-proteinaceous particles covered with native or non-native protein species, can also be formed. Some of these combinations, like protein adsorbed to silicone oil, are known to trigger an immune response (14). However, with the immunogenic potential of each of the possible particle subgroups, one could theoretically encounter in a protein drug product that is not yet known, and unlikely to be clarified in the near future.
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