EMEA's Quality Working Party (QWP) recently included several new questions and answers regarding the harmonisation of several chapters of the European Pharmacopoeia into its Q&A page. Two of these questions concern registration-relevant problems.
When creating a dossier for a marketing authorisation for a medicinal product, the quality of the active pharmaceutical ingredient used has to be verified. If the application is for a marketing authorisation within the EC, this is done within the framework of the Active Substance Master File (ASMF) procedure. The regulatory basis for this procedure is 2001/83/EC.
The first question regards the ASMF procedure, saying:
(Within the framework of an application for a marketing authorisation) Can a mixture of an active substance with an excipient be submitted through an Active Substance Master File (ASMF) procedure?
First and foremost the answer to this is: No.
The QWP gives the following reason:
Mixing an active ingredient with an excipient is considered as the first step in manufacturing a medicinal product. Such a mixture does no longer fall within the definition of an 'active ingredient'.
But as always, there is no rule without an exception. There are active ingredients which are unstable in pure form (e.g. sensitive to oxidation) and which can only be handled and stored comfortably when mixed with an excipient. The QWP's answer provides for this exception, e.g. in the case of herbal dry extracts if it is not possible to produce a solid extract in pure form.
The second question refers to Class 2 residual solvents in active ingredients and medicinal products:
Is there a need to take the actual batch results into consideration when specifying Class 2 residual solvents for active substances or medicinal products?
Here, the answer is also: No.
According to the QWP it is sufficient to restrict the specifications to the limit (in ppm) laid down in the "Note for Guidance on Impurities: Residual Solvents"
(http://www.emea.europa.eu/pdfs/human/ich/028395en.pdf) and the "Annexes to Specifications for class 1 and class 2 residual solvents in active substances"
(http://www.emea.europa.eu/pdfs/human/qwp/045003en.pdf). Alternatively, this limit can also be calculated on the basis of the "permitted daily
exposure". The corresponding formulas are likewise given in the "Note for Guidance on Impurities: Residual Solvents".
The QWP explains its answer by reminding of the fact that the limits mentioned in the guidances are based on safety assessment and that it is therefore not necessary to restrict them further due to actual batch results.
The Questions and Answers document by EMEA's Quality Working Party can be found here: