EMA Clarifies How to Include API Mix Data in a Marketing Application

API mixes, which are mixtures of one or more excipients and an active pharmaceutical ingredient, are used to improve the safety, stability or workability of an active ingredient. Some examples of commonly used excipients for these purposes include antioxidants, preservatives and diluents.

EMA says it considers the mixing process "to be the first step of the manufacture of a finished product." As such, sponsors are required to submit information about the mixture just as they would for a standalone API.

However, there are two different ways sponsors can include API mix data in an application: in accordance with the information required in part 3.2.S (Quality Module) of the Common Technical Document (CTD), or by including either an Active Substance Master File (ASMF) or Certification of Suitability (CEP) issued by the European Pharmacopoeia (Ph. Eur.).

EMA says that when an API mix is used for safety or stability reasons, sponsors can use either method. For reasons not related to safety or stability such as handling an API during manufacturing, EMA says sponsors should describe the manufacturing steps taken in 3.2.P of the CTD.

Additionally, sponsors must ensure the API mix complies with the same good manufacturing practice (GMP) guidelines as a standard API.

EMA says it considers cases where the monograph specifically states an API mix is appropriate to be "sufficient and acceptable" to justify an API mix's use, but says sponsors still need to provide "justification on the choice and level" of the excipients used in the mix.

When an existing Ph. Eur. monograph does not exist, EMA says it will still accept an ASMF "only for safety or stability reasons [and] on a case by case basis."

To justify using an API mix for safety or stability reasons, EMA says sponsors should consider the following:

• "In all cases the choice and level of excipient should be justified.
• In case the originator uses no stabiliser, it is expected that the same approach as the originator is taken by any subsequent new product.
• Acceptable stability reasons include both chemical and physical stability.
• Documentation to be provided: A comparison of the stability data of both the stabilised and nonstabilised
• API under (V)ICH long term conditions for up to 6 months (in a refrigerator/freezer/inert atmosphere where relevant). Results with a stabiliser should demonstrate a relevant stability improvement.
• For APIs of an explosive nature the use of an API mix may be justified, and an appropriate explanation is considered sufficient.
• A justification based only on workability reasons, e.g. to ease handling when processed into final dosage form, is not acceptable.
• Toxicological considerations (e.g. very potent drugs) fall under workability reasons and are not accepted as justifications"

In cases where an ASMF/CEP is acceptable, EMA says the dossier "should contain all relevant information on the mixing process, qualitative and quantitative composition of the mixture and control strategy."