Quality Documentation of API mix in the Marketing Authorisation Procedure

The manufacture of APIs sometimes requires adding of one or several excipients like for example an antioxidant or an inert matrix for stabilisation purposes. Occasionally, corresponding mixtures can be manufactured to optimize workability for further processing or filling (e.g. improvement of flowability). Yet, within a marketing authorisation procedure, such an API mix can possibly be accepted differently than the pure API.

To clarify the questions around this topic, EMA's QWP has published a document entitled "Quality Working Party questions and answers on API mix". Please find hereinafter a summary of the questions addressed in the document:

What is an API mix?
An API mix is defined as the mixture of an API with one or more excipients. This also applies to APIs in solution (e.g. Benzalkonium chloride solutions). The manufacture of an API mix is considered to be the first step of the manufacture of the finished product.

Under which circumstances can an API mix be submitted in a CTD (part 3.2.S or 2.C.1), in an ASMF or a CEP within an authorisation procedure?
The quality documentation in a CTD, an ASMF or a CEP is accepted when the mixture must be manufactured for stability or safety reasons. The API mix must comply with the requirements of Part II of the EG GMP Guide (sterile preparations must comply with Part I of the Guide). If an API mix is manufactured for workability or other reasons it should be described in section 3.2.P. The submission via an ASMF is not allowed.

Is an API mix acceptable when it is stated in a pharmacopoeial monograph "A suitable antioxidant may be added"?
Basically, yes. It is acceptable. Nevertheless, the choice and the level of the antioxidant has to be justified and the description of a control test is required.

In the context of an authorisation procedure is there a difference for API monographs with or without reference to a potential excipient admixture?
For monographs containing this reference, an ASMF can generally be accepted. For monographs without the reference, an ASMF can only be accepted when the API mix is required for stability or safety reasons.

Which data must be submitted to justify the acceptability of an API mix manufactured for safety or stability reasons when no pharmacopoeial monograph exists?
The authorisation authority expects comparative stability data API mix / pure API under long term conditions (6-month data). The data should demonstrate a clear improvement of stability in presence of the excipient mix. In any case the choice and level of excipient should be justified.

If an ASMF or a CEP for an API mix is accepted: Which data are required and how should they be structured?
The open part of the ASMF should contain all relevant information on the mixing process, qualitative and quantitative composition of the mixture and control strategy. Information regarding the excipients must be submitted in accordance with the requirements of Annex I of Directive  2001/83/EC. The quality of the excipient has to be documented in module 3.2.P.1 (composition of the medicinal product). If a CEP is available for the API mix the following additional data have to be submitted:

• The description of the manufacturing process for the API mix (CTD section 3.2.S.2.2).
• Stability data (if not documented in the CEP)
• Information on the packaging material (if not mentioned on the CEP)

If a new CEP is presented as a variation then these data also have to be included.