Biologic Drugs

What are biologics? Biological medicines (or biologics) are large and often complex proteins. Based on their molecular mass, biologics can be 200 to 1000 times larger than conventional chemical drugs. Conventional drugs are manufactured by chemical synthesis, which can be strictly controlled. In contrast, biologics are proteins produced in living cells, where they undergo post-translational modifications, such as glycosylation, which is the process of attaching sugar molecules to the protein. These post-translational modifications can produce a variety of different versions with different glycan composition but identical amino acid sequence. In addition, small changes in growth conditions can alter cell behavior and affect the glycosylation profile. Thus, a biologic product may contain several different versions of the same molecule, even though the amino acid sequence of the protein remains the same. Minor variability is therefore inherent to all biologics. It is present within and between batches of the same biologic, and no batch of any biologic is identical to the previous one. Regulatory authorities such as the EMA or the FDA require that manufacturers of biologics control this inherent variability, keeping it within prespecified limits. In addition, companies producing biologics may alter the manufacturing process several times during the lifetime of a product. Some alterations, such as a change in filter supplier, may be considered to have a low risk of affecting the final product. Other changes, such as the use of a different cell line, are considered high risk. Therefore, most if not all biologics will undergo a number of manufacturing changes after initial authorization. Here, the number of low-, moderate-, and high-risk manufacturing changes are shown for 29 monoclonal antibodies marketed in the EU. A total of 404 changes were reported, with the vast majority of changes being low or moderate risk. And while high-risk changes could affect post-translational modifications, the amino acid sequence of the active substance is always identical to the original version. All changes were individually approved by EMA, signifying that they did not impact the overall clinical efficacy and safety of the biologic medicine. Regulatory authorities require companies to demonstrate comparability and show that changes in manufacturing do not affect the quality, safety, and efficacy of the product. Higher risk changes require greater amounts of supporting data to demonstrate comparability. However, this evidence provided to the regulatory authorities is not usually published as peer-reviewed data in the public domain. Here is a comparison of different marketed batches of etanercept made by its parent manufacturers before and after manufacturing changes. The graphs show changes in the relative amount of acidic and basic variants, and differences in the presence of glycan isoforms. Despite the differences, these batches remained on the market without changes to the label. Health authorities found the changes acceptable as they were not predicted to affect the clinical profile. What are biosimilars? According to the World Health Organization, a biosimilar is a biotherapeutic product, which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product. However, due to the inherent complexity and variability of all biologics, no biosimilar can ever be identical to its originator, and it will also have a degree of natural variability, just like the comparison between two batches of biologics. A biosimilar is required to have an identical amino acid sequence as its originator, and the biological activity shall remain the same. Minor variability, such as post-translation glycosylation, may be allowed, provided that this can be shown to have no impact on efficacy and safety, comparable to what may occur between different batches of the same biologics. In summary, biologics are complex biotechnologically engineered proteins produced in living cells and therefore have an inherent degree of minor variability. Minor variability may be allowed as long as the manufacturing company can provide sufficient scientific evidence demonstrating that these differences can be controlled and do not affect the quality, safety, and efficacy of the medicine. A biosimilar is required to have an identical amino acid sequence as its originator, and the biological activity shall remain the same with an unchanged clinical efficacy and safety profile. Biosimilars are developed in order to meet the stringent regulatory pathways in highly regulated markets, and once approved they are expected to have the same efficacy and safety as their reference biologic.