Gen Schere 1

Gen Schere 1

 

In order to establish biosimilarity to the innovator biopharmaceutical (reference product) it is necessary for the product to be highly comparable to the reference product from the region in which approval is ultimately sought.

A stepwise approach is recommended by firstly establishing that the CMC aspects are highly comparable to the reference product. For example:

  • The amino acid sequence of the biosimilar would be expected to be identical to that of the reference product.
  • The higher order structure such as the secondary, tertiary and quaternary structures should be highly similar but not necessarily identical.
  • Post-translational modifications (i.e. charge variants N or C terminal truncation, degradants and impurities) should be similar to the reference product but are not expected to be identical.
  • Functional activities, including specific activity and receptor mediated activity, should be highly similar to the reference product; any differences in post-translational modifications or higher order structure can have significant impact on biological activity.

These properties should be tested using state-of-the-art orthogonal methods to provide the highest level of assurance as to the accuracy of the results.

At least three batches should be included in the comparability exercise, however a larger number of batches may need to be included if there is large variability. If the variability in results for the biosimilar are too great, it may be advisable to modify the method of manufacture prior to conducting extensive comparability exercises.

Additionally comparable accelerated and stress stability, under multiple stress conditions, should be conducted as further evidence to support the similarity of the biosimilar to the reference product.

Ultimately the regulator will consider the totality of evidence to determine the similarity of the biosimilar to the reference product. The more extensive the comparability exercise is in establishing similarity to the reference product the more likely it is to be able to justify conducting reduced nonclinical and/or clinical studies.