Reworked sections of the six-year old European Medicines Agency (EMA) guidelines clarify the level of flexibility biosimilar manufacturers have when choosing formulations and closures for their drugs.
“The formulation of the biosimilar does not need to be identical. If a different formulation and/or container/closure system to the reference medicinal product is selected its potential impact on the safety and efficacy should be appropriately justified”, the EMA wrote in draft biosimilar guidelines.
An earlier version of the EMA guidelines, which came into effect six-years ago this week, lacked such an explicit statement of support for biosimilar closure and formulation flexibility. The new wording is more in line with draft US Food and Drug Administration (FDA) biosimilar guidance from February.
Innovator companies spoke out against flexibility in the FDA draft, with some saying variations from reference products create safety risks, and have until November 30 to send comments to the EMA.
The EMA tries to forestall negative comments by noting the risk of using different methods. “The use of novel expression systems should be carefully considered, as they may introduce additional risk, such as atypical glycosylation pattern or even a different impurity profile”, the EMA wrote.
Identification of critical quality attributes (CQA) and the detailing, preferably early in development, of the quality target product profile (QTPP) are part of EMA advice on mitigating potential safety risks.
CQA and QTPP are new additions to the biosimilars quality guidelines and their inclusion reflects the changes in manufacturing methods and terms since the original document was drafted by the EMA.
“The QTPP should be detailed at an early stage of development and forms the basis for the development of the biosimilar product and its manufacturing process. It is important to identify CQAs that may impact the safety and efficacy of the product”, the EMA wrote.
The revised draft also features a major overhaul, four-times the length of the original, of advice for manufacturers of biosimilars that want to conduct comparability exercises with reference products.
“An extensive comparability exercise will be required to demonstrate that the biosimilar has a highly similar quality profile when compared to the reference medicinal product. This should include comprehensive side-by-side analyses of the proposed biosimilar and reference medicinal product.”
Minor differences are acceptable, if justified, and particularly if the quality attributes have minimal impact on safety or efficacy. Other, more major differences may require a new approach though.
“If significant quality differences at the level of the active substance and/or the finished product are confirmed it may be very challenging to claim similarity to the reference medicinal product, and thus, a full Marketing Authorisation Application may be more appropriate”, the EMA wrote.