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PQM 2017.01.17 10:48

Definition and Establishment of the Regulatory Starting Material in the Synthesis of Chemical Pharmaceutical Drug Substances in Europe

Establishment of the regulatory starting material is a hot topic and involves different points of view; especially the two opposite ones from industry and authorities. The starting material has a direct influence on the regulatory requirements and the effort and costs for industry. GMP applies beginning with the starting material, means that more requirements must be met and more documentation work must be conducted. Thus industry intends to define the starting material as late as possible whereas the authority asks for an earlier definition of starting material. This area of conflict already begins in pre-clinical phases of development and continues throughout the whole life cycle of a medicinal product.
Definition of the regulatory starting materials should be based on a broad assessment of the circumstances and the needs to be able to manufacture a suitable drug substance, but also an appropriate medicinal product. A best practice guide is presented in this thesis for the establishment of a regulatory starting material. Different aspects should be considered, like the synthesis of the starting material including the reagents and substances used and the commercial availability. The most important point is the impurity profile of the starting material and the potential carry-over of the impurities towards the intermediates and the drug substance. The later the starting material is defined, the more complex the synthesis of the starting material becomes. The problem is that the information provided to authorities about the starting material is very limited and therefore the assessment of the suitability of the starting material and of the control strategy including its specification is nearly impossible. This contributes also to the conflict mentioned above between industry and authorities.
The data provided concerning the starting material comprise its specification including justifications, the analytical methods used to control it and a flowchart of its manufacturing process. Additionally information about impurities is provided to justify impurity specifications, not only for the starting material itself, but also for the intermediates and the drug substance.
Changes of the starting material must be well reviewed and the potential influences on the drug substance and the medicinal product must be assessed.
All in all no general approaches are available for the definition of a starting material in a dossier. For each synthesis and each final drug substance a case-specific justification and discussion must be provided.
In future it will be crucial to evaluate and assess the starting material defined from the beginning on of the life cycle of the medicinal product.
Recent developments are pointing towards considering a more risk-based approach, for which, however no regulatory practice has been established. The future will show how all parties involved, industry and authorities, will handle this topic.