Manufacturing process
The manufacturing process of the biosimilar should be developed based on a comprehensive understanding of the RP gained through detailed characterization studies of a sufficient number of RP batches.
It is understood that a manufacturer developing a biosimilar will not normally have access to confidential details of the RP manufacturing process – thus, the process will differ from the licensed process for the RP. In order to produce a high-quality product as similar as possible to the RP, the biosimilar manufacturer should assemble all available knowledge on the RP regarding the type of host cell, product formulation and the container closure system used for marketing. Although the biosimilar does not need to be expressed in the same type of host cell as that used for the RP, it is recommended that a similar host cell type is used (for example, Escherichia coli, Chinese hamster ovary cells, etc.). This will reduce the potential for critical changes in the quality attributes of the protein, or in post-translational modifications, product-related impurities or the process-related impurity profile, that could potentially affect clinical outcomes and immunogenicity. If a different host cell is used (for example to avoid unwanted and potentially immunogenic glycan structures present in the RP) then changes introduced in terms of product-related substances, as well as product- and process-related impurities, need to be carefully considered.
The manufacturing process used can significantly affect the structure of the drug substance and thereby impact upon the potency of the product. For example, in the case of mAbs, when deciding upon the expression system to employ, manufacturers should be guided by the potential for both enzymatic and non-enzymatic modifications, such as incomplete disulfide bond formation, formation of aggregates, glycosylation, N-terminal pyroglutamine cyclization, C-terminal lysine processing, deamidation, isomerization and oxidation, modification of the N-terminal amino acids by maleuric acid, and amidation of the C-terminal
amino acid.
The manufacturer must demonstrate the consistency and robustness of the manufacturing process by implementing state-of-the-art quality control and assurance
procedures, in-process controls and process validation. The biosimilar manufacturing process should meet the same standards required for originator products, including manufacture under current good manufacturing practices (15, 16).
As for any biological product, if process changes are introduced during the development of a biosimilar then the impact of the changes should be assessed through a comparability exercise (9, 17). Although many of the same principles are followed, the assessment of manufacturing process changes should be addressed separately from the comparability exercise performed to demonstrate biosimilarity with the RP (see section 7.4 below). It is, however, strongly recommended that the pivotal data used to demonstrate biosimilarity are generated using biosimilar batches manufactured using the commercial manufacturing process and therefore representing the quality profile of the batches to be commercialized.
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