起始原料的选择1

Title

Drug Substance Starting Material Selection (002)

MA对化学原料药生产起始物料的选择和论证要求思考 (009)

EUROPEAN MEDICINES AGENCYSCIENCE MEDICINES HEALTH (023)

原料药合成工艺中复杂起始原料的质控要求 (037)

Drug Substance Starting Material Selection

原料药起始物料的选择

The authors review the current regulatory framework for the selection of drug substance starting materials. In addition, a proposal is discussed for a science- and risk-based approach for the submission of starting materials to global regulatory authorities to ensure patient safety while allowing the flexible economic manufacture of drug substances.

作者审核了原料药起始物料现有的法规框架，另外，讨论了基于科学和风险的方法来向全球性管理当局提交起始物料以保证患者的安全并允许原料药灵活经济生产的倡议。

Dec 2, 2008

By: Graham T. Illing, Robert J. Timko, Linda Billett

Pharmaceutical Technology

Volume 32, Issue 12, pp. 52-57

The term starting materialhas been adopted to indicate the point where regulatory change control andcurrent good manufacturing practices (CGMPs) are introduced into the synthesisof a drug substance. A typical example of a drug substance synthesis is shownin Figure 1. This generic scheme depicts four regulatory steps and variousquality control points (specifications).

Figure 1: Schematic of regulatory drug substancesynthesis. Steps 1–4 involve a covalent bond formation. The regulatory stepsare disclosed in the Marketing Authorization Application and require regulatoryapproval for changes. Boxes in red have the greatest regulatory significance.Materials in bold text are usually given a comprehensive and robustspecification. Boxes in orange are synthetic intermediates, which can beisolated or remain in situ but are controlled using a more limitedspecification. (IMAGE SOURCE/GETTY IMAGES)

Using a science- and risk-basedframework, this article reviews the regulatory guidelines in the United States(US Food and Drug Administration), European Union (European Medicines Agency,EMEA), and Japan (Ministry of Health, Labour, and Welfare, MHLW). In addition,the authors address the International Conference on Harmonization (ICH)guidelines that currently impact the selection of starting materials for newdrug substances for global registration. The discussion takes into account therecent guidance changes since the initial publication with the introduction ofICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Managementand the withdrawal of FDA's BACPAC I and drug substance ICH guidances (1–5).

Guidance review

ICH guidances. The definition of a starting material, as presentedin ICH Q7 Good Manufacturing Practice Guide for Active PharmaceuticalIngredients, reflects the diverse source of potential starting materialsand notes that chemical properties and structure are normally defined (6). Thefocus is for field inspector use (CGMP) rather than marketing authorizationapplication (MAA) or new drug application (NDA) review. It defines what may beconsidered a starting material, rather than how to select the startingmaterials for a synthesis from, for example, the raw materials and theintermediates.

A starting material can be defined as a raw material,intermediate, or a drug substance that is used in the production of a drugsubstance and that is incorporated as a significant structural fragment intothe structure of the drug substance. A starting material can be an article ofcommerce, a material purchased from one or more suppliers under contract orcommercial agreement, or produced in-house and is normally of defined chemicalproperties and structure.