API starting materials: EMA publishes updated reflection paper

An integral part of an approval dossier's quality documentation for an API is the description of its manufacturing process. The applicant has to define his starting material and justify his selection. From here on in, the starting material and all further synthesis steps to the finished API product are subject to the GMP requirements as stated in Guidelines ICH Q7 and ICH Q7 Q&A document. Determining a chemical substance as "starting material" is a requirement of guideline ICH Q11. The requirements described in chapter 5 are not sufficiently precise, though; they leave much room for interpretation for the assessors as well as the regulatory authorities which lead to questions, additional demands and consequently to delays in marketing authorisations. To remedy the situation, the EMA published a reflection paper in October 2014 with the goal of answering unresolved questions about the selection of starting materials and the justification of that choice (New EMA's Reflection Paper on API Starting Materials).

In July this year, an updated version of the "Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances" was published. The only difference from the previous version is that the last passage of "Explanatory note 2" about describing the manufacturing process of an API has been revised. The changes are as follows:

Reflection paper, version of 2014

  • The starting material itself already is a monographed active substance covered by a CEP. The applicant may reference or include the already existing CEP instead of a justification.
  • The starting material itself is an API in an already approved pharmaceutical product. In that case, the applicant may skip the justification and only has to prove that the marketing authorisation in question is still valid and that the API for this approved product was manufactured in accordance with GMP.

Updated reflection paper, version of 2017

  • The intermediate in the proposed synthesis of the active substance is itself an active substance covered by a monograph of the European Pharmacopoeia (Ph. Eur.) covered by a valid CEP. In that case, the applicant may submit the CEP as an alternative to submitting its process description. All additional chemical transformation steps to the finished API should be documented in module 3, passage 3.2.S.2.2. The manufacturers involved in the process covered by the CEP (contract manufacturers, subcontractors, test laboratories etc.) should be listed in module 3.2.S.2.1 and the QP declaration.
  • The intermediate is itself an active substance in an already authorised medicinal product and documented in an ASMF or in module 3 of the authorisation application. In that case, the applicant may reference these documents. They still have to submit complete information on the manufacturing process, though, either as a part of a new ASMF or in the dossier, module 3, passage 3.2.S.2.

With the revision of "Explanatory note 2" of the reflection paper, the regulations concerning the description of the manufacturing process of an API in the dossier have been refined. It remains to be seen whether this helps in further reducing the processing periods of marketing authorisation applications.

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