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Definition of Impurity Reference Substance and Requirements of Standard Substance

Date: 2020-04-29
浏览次数: 77

Reference (standard) is a kind of physical control for the implementation of drug quality standards. It is an important carrier of the reported quantity value, a special measuring tool for checking the quality of drugs, a reference for determining the quality of drugs, a material comparison for determining the quality of drugs, and a material standard for checking the calibration of instruments and methods. As far as the national drug standard is concerned, it is a kind of drug measurement and quality standard substance published by the state. Pharmaceutical reference materials must have the conditions of uniform raw materials, stable performance and accurate measurement value, in order to play a role of unified measurement value. In drug research and development, reference material (standard material) involves such important links as quantity value traceability, product quality, impurity control, etc. its preparation and calibration are closely related to preclinical basic research such as drug quality research, stability research and dose determination in pharmacology and toxicology research. Therefore, the preparation and calibration of drug standard is an important part of drug technology evaluation. In general, the following principles can be referred to for the use of reference materials in drug development:


1、 All standard reference materials (standards) shall be issued by China Inspection Institute. If the method of use is the same, the current batch number reference (standard) provided by the Chinese Academy of inspection shall be used, and its label and description shall be provided. The batch number shall not use reference materials from other sources; the method of use is different from that in the manual, for example, qualitative reference is used for quantitative, titer determination standard is used for physical and chemical determination, ultraviolet method or volumetric method is used for chromatographic determination, etc The appropriate and verified method shall be used for recalibration, and the calibration method and data shall be provided; the chromatographic content shall be determined by ultraviolet method or volumetric method for reference materials, and the reference materials shall be determined by qualitative and quantitative methods on time, which can be used directly without recalibration.

2、 When there is no reference (standard) in the Inspection Institute, the following reference materials can be used for standard formulation and other preliminary basic research work:

 1). For the reference (standard) published by the foreign drug administration or Pharmacopoeia Committee or the working reference (standard) of the foreign pharmaceutical enterprise, but the color photo of the package label and the copy of the instruction manual shall provide the batch number, validity period, use method and other information to ensure the traceability of the quantity value.

 2). The applicant demarcates or entrusts the Provincial Research Institute to complete the calibration of the reference (standard), and provides relevant research materials and relevant materials at the time of application, generally including the following contents:

① Principal component control substance - research data of preparation process, structure and content, as well as general name, chemical name, layout, molecular formula, molecular weight, content of various impurities (water, residual solvent, inorganic salt, etc.), main component content (different analysis techniques), purpose, storage conditions and other information of determination data.

② Impurity reference material - research data of preparation process, structure (UV, IR, NMR, MS, XRD analysis or providing reference spectrum) and content (different analysis technologies), as well as chemical name, layout, molecular formula, molecular weight, use, storage conditions, etc.

③ Mixed reference (positioning) - the preparation process, structure (UV, IR, NMR, MS, XRD analysis or reference diagram) and purity research data of each component, as well as the chemical name, layout, molecular formula, molecular weight, content (if necessary), specific qualitative methods and restrictions.

At the same time, the applicant shall contact with the Chinese Academy of inspection in time for the calibration of reference materials (standards), so that the legal reference materials can be obtained in time after the products are put on the market.

 3). If in the current situation, the reference materials used in the quality standards are usually not provided by the Chinese Academy of inspection, it is recommended that the applicant clarify the availability of the reference materials and the corresponding measures after the products are listed in the application materials.

 4). For each known impurity involved in the quality standard, its general name (or chemical name), chemical layout formula, molecular formula, molecular weight and other relevant information shall be defined in the quality standard, so as to accurately quote and control each specific known impurity.

 5). Generally speaking, in order to ensure the accurate use and control of reference materials, it is necessary to provide the quality standards of reference materials (standards) and specify specific control items, such as the specific rotation of non enantiomer impurities.

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