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Biological medicines: how does their manufacturing process differ from traditional medicines?

Biological medicines, also referred to simply as biologicals, are a class of medicines whose active substance is made by a living organism. The active substance, usually a protein, is produced by bacteria or yeast, or plant or animal cells in a large-scale cell culture, from which the substance of interest is then purified. This is quite different from small molecule medicines, which are usually made synthetically and are small in size and simple in structure.

The differences in the manufacturing process and the nature of the active substance itself mean that biologicals differ from traditional medicines in many ways.

Control of impurities in biological products is of much greater importance than in chemical drugs

One interesting example is the purity of the active substance. Since biologicals are produced by living organisms, the desired recombinant protein needs to be separated during the manufacturing process from Host Cell Proteins (HCPs)—which are just one type of impurity one needs to consider. HCPs are proteins produced by the host organism that are unrelated to the active substance. The main concern with the HCPs is immunogenicity, although they can also have a negative impact on the efficacy and stability of the active substance and the medicinal product.

Host cell proteins may trigger the body’s immune system

When an HCP has low homology with human proteins, i.e. no similar proteins exist in the human body, there is a high likelihood that the immune system recognises it as foreign and tries to clear it. In this situation, the HCP causes an allergic reaction that could be anything from undetectable to very severe. On the other hand, if an HCP has high homology with a human protein, the likelihood of it being recognised as foreign is lower. However, when the immune system does react to it, there is an increased risk of cross-reactivity. This means that the anti-HCP antibodies produced by the immune system could target human proteins of similar structure and potentially disrupt their normal function. This could lead to various side effects.

Separating the active substance from host cell proteins is challenging

Considering the above, removing HCPs is obviously important. However, it is also challenging. Even the simpler host organisms have thousands of genes that could potentially be expressed along the desired recombinant DNA and could thus be present as a protein in the cell culture. Each of these proteins could also undergo various post-translational modifications, which further increases the potential number of impurities. Because of this diversity, some HCPs will always co-purify with the active substance.

Before a biological medicine receives a Marketing Authorisation (MA) and can be prescribed to patients, the MA Holder will need to demonstrate that their manufacturing process is capable of removing HCPs and other impurities to a degree that ensures the quality, safety and efficacy of the medicinal product.

Contact us if you need expertise in biologicals. We have the regulatory know-how and a team of experts at Biopharma Excellence by PharmaLex with decades of experience at every stage of the biologicals’ regulatory and product development processes.