The European Medicines Agency (EMA) announced it has released a newly-revised guideline on the quality of biosimilar medicines and is soliciting comments. The 31 May 2012 guidance, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues, updates a previous guidance released in 2006.
Biosimilar medicines are ones similar to branded biologics pioneered by previous companies. Due to the inherent complexities of manufacturing biologics, which include biotechnology-derived proteins, biosimilar products almost certainly contain minor differences relative to the originator product.
A company must therefore prove to EMA that its biosimilar product contains a similar active substance and acts in a way that provides a similar safety and efficacy profile as the original product. Unlike generic medicines, which can show bioequivalency through relatively simple comparison testing, biosimilar products must demonstrate similarity through "extensive comparability exercises" which allow for "firm conclusions" to be made regarding its similarity.
These comparability exercises include tests comparing the quality attributes of the two products and the performance and consistency of the manufacturing processes. EMA notes these considerations are "two distinct but complementary aspects."
Sponsors should be prepared to generate a quality target product profile (QTPP) of their product, which includes all publicly available information and all information obtained from characterization and studies conducted on the reference biologic. This document will form the basis for future biosimilar development.
EMA explains in the guidance that the production process does not need to be identical to that of the reference product, but should be as similar as possible as to avoid unnecessary risks and enhance the stability, compatibility and integrity of the product. Molecular variants such as isoforms and process-related impurities should be closely monitored given their potential for patient harm.
Biosimilar stability testing should be conducted in accordance with ICH Q5C and must be supported by data, explains EMA.
The guidance also covers a number of comparability standard requirements for biosimilar products, including the use of multiple batches of biosimilar products to test their similarity relative to the reference biologic. Sponsors should also be prepared to undergo "extensive comparability exercises" to demonstrate similar quality, including side-by-side analyses to determine if any differences exist between the two products.
Any differences discovered between the two products must be justified and investigated for possible safety and efficacy impact, and "significant differences" must be justified to EMA. The agency notes "it may be very challenging to claim similarity to the reference medicinal product" in the case of such differences. Minor differences "may be acceptable" if they are justified and found to have "no relevance for the clinical performance of the product," said EMA.
EMA also explains it wishes to see product comparisons made after the final manufacturing process is set into place, as changes can have a material impact on the quality and composition of a product. While changes to the manufacturing process may occur after biosimilarity is established to EMA, "no regulatory requirement for re-demonstration of biosimilarity" exists after a Marketing Authorisation is granted.
Further analytical consideration must include the physicochemical properties of products, their biological activity, immunochemical properties, impurities and the quantities of a product.
Comments on the guideline are due 30 November, 2012.
EMA - Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1)