The comparability exercises that Amgen performs after completing process changes or manufacturing site changes to show that a comparable product is being produced pre- and post-change is different from a biosimilarity assessment to assess the degree to which a biosimilar is similar to a reference product. Establishing biosimilarity is a much more difficult exercise than establishing comparability. Unlike comparability assessments, biosimilarity assessments require the manufacturer to prove similar quality, safety and efficacy without the reference product’s history or knowledge of the manufacturing process.
At Amgen, our commitment to ensuring a consistent supply of safe and effective biologic medicines requires that we remain abreast of evolving scientific understanding and technological innovations. At times, this may mean that the processes used to manufacture an approved biologic product are changed and depending on the extent of the modification, a comparability exercise may be needed to assess the quality of the product pre- and post-change.
Full characterization of most biologics is challenging because of their molecular complexity and variability. The comparability of the product before and after a manufacturing change, however, should show the product to have highly similar quality attributes. Manufacturing changes should have no negative impact on product quality. These changes are typically incremental, measured and leverage the comprehensive data generated over many years of the biologic product’s life. Most changes can be evaluated by checking the process data and confirming the product quality using comparative analytical testing. Some changes are more complex and require additional testing, up to and including comparative clinical testing.
It is important to recognize that making a manufacturing process change is not the same as developing a biosimilar. In contrast to manufacturing process changes and establishing comparability, developing a biosimilar is far more complex. Part of this complexity lies in the fact that the innovator product information remains proprietary and is not available to the biosimilar manufacturer. Therefore, the manufacturer begins with only the final product and must work backwards – a concept often referred to as the knowledge gap.
Due to this knowledge gap, developing a biosimilar requires reverse engineering to establish an appropriate new cell line and manufacturing process. Because the full range of reference product quality tested in clinical trials is not available, a biosimilar manufacturer must attempt to match product quality within the narrow range of the innovator’s commercial product which is much more difficult to match for biosimilarity than for a comparability assessment of an existing commercial biologic. Therefore, it will require the generation of more evidence to demonstrate biosimilarity than what is needed to show comparability.
Data requirements for comparability exercises for a moderate risk and a high risk manufacturing change by the same manufacturer compared with a biosimilar manufacturing process.
*Manufacturing process changes are governed by the ICH Q5E comparability guidance 11,12.