WHO TRS (Technical Report Series) 970, 2012 Annex 6

WHO TRS (Technical Report Series) 970, 2012 Annex 6

Recommendations for quality requirements when artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients

1. Introduction:

The harmonized good manufacturing practices (GMP) (1,2) describe requirements for the production of active pharmaceutical ingredients (APIs). The applicability of these requirements begins with a defined starting material as follows: 

“An API starting material is a raw material, intermediate, or an API that is used in the production 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 normally have defined chemical properties and structure.”

The focus of GMP for APIs is for field inspector use, rather than in applications for marketing authorization. It defines what may be considered as a starting material and provides guidance on where GMP is applied. The GMP guidelines do not apply to steps taken prior to the first introduction of the defined starting material. The manufacturer should designate and document the rationale for the point at which production of the API begins. For a synthesis process, this is known as the point at which the starting materials are entered into processes.

From a regulatory standpoint, the use of API starting materials marks the beginning of the detailed description of the process. The applicant for marketing authorization should propose and justify which substance should be considered as the API starting material, e.g. incorporated as a significant structural fragment into the structure of the active substance.

In practice the designation of a starting material may be difficult. The number of steps separating the starting material from the final API is an issue to be decided on a case-by-case basis, subject to the manufacturer’s proposal and assessors’ evaluation. Since a designated starting material may be obtained from multiple sources, it is necessary to have well-defined quality requirements to ensure that the APIs produced meet specifications. Establishing these requirements may involve a compromise between the desire for a pure starting material and the impact of this on cost of API production. Impurities can be  tolerated in the starting material if the API manufacturing process has been shown to efficiently remove them. Redundant purification steps may reduce the yield of the final API and thus further increase its cost. 

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WHO TRS (Technical Report Series) 970, 2012 Annex 6:

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