Approval of regulatory starting materials

There are significant interpretational differences between the European Medicines Agency (EMA) and US Food and Drug Administration (FDA)’s guidance on active pharmaceutical ingredient (API) starting materials. In this article, Dave Elder explores the ambiguity in guidance from both agencies and addresses why industry struggles to identify and justify starting materials that are likely to garner regulatory approval in both these territories.

ONE OF the biggest challenges faced during API development is the “designation and justification” of the API registered starting materials (RSMs); ie, those stages in the API synthesis where current good manufacturing practice (cGMP) philosophies and practices are first introduced.1 Indeed, the FDA’s cautionary statement from the first guidance in 1987 still holds true: “What constitutes the ‘starting material’ may not always be obvious.”2

ICH Q73 defined an RSM as: “A raw material, intermediate or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or produced in-house. API starting materials are normally of defined chemical properties and structure.” However, the guidance failed to provide insight into the “designation and justification” of the API RSM.1

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