国家药品标准物质制备指导原则-en

Guideline for Preparation of NationalPharmaceutical Reference StandardsThis guideline is indicated for normalizing and guiding preparation of national pharmaceutical reference standards and ensuring implementation of national drug standards.I. Establishment of varieties of national pharmaceutical reference standardsVarieties of reference standards to be prepared should be established according to use requirements (varieties, purpose) put forward in setup and revision of national drug standards.II. Selection of candidate materials for reference standards1. For selection of materials, the principles of suitability, representation and availability should be followed, and the quantity needed should be satisfied.2. Properties of materials should comply with the use requirements.3. Quantity value spectra of homogeneity, stability and other relevant properties of material should be suitable for purposes of the corresponding reference standards.III. Preparation of candidate reference standards1. Select rational preparation procedures and crafts according to physicochemical properties of candidate reference standards and prevent contamination and value changes of corresponding properties.2. For candidate reference standards the corresponding property values of which cannot be homogenized easily, not only necessary homogenizing measures should be taken in the process of preparation, but also preliminary homogeneity test should be carried out.3. Where values of corresponding properties of a candidate reference standard show the trend to be unstable, factors affecting its stability should be paid attention to in the process of preparation and necessary measures should be taken to improve its stability, and a suitable environment should be selected for storage.4. When the prepared amount of a candidate reference standard is large, graded subpackaging may be applied for convenient storage.5. Suppliers of candidate reference standards should have favorable experimental conditions and capacity and provide the following data:1) Completed data including test methods, values, number of repeated times of tests, necessary spectra and chromatograms;(2) Storage conditions (temperature, humidity and light irradiation) complying with stability requirements;(3) Hygroscopicity study results or hydroscopicity description of candidate reference standards;(4) Results of accelerated stability study;(5) Specific data about identification and percentages of related substances, relative response factors of principal ingredients in national drug standards;(5) Latest safety data related to health risks.IV. Standardization of candidate national drug reference standardsCandidate reference standards are standardized as per the following requirements. Conditions permitting, comparison with international reference standards or pharmacopoeial reference standards of advanced countries and regions such as Europe and America should be performed: 1. Characterization of chemical structures or components1) As for validation of a compound with known structure, necessary physicochemical parameters and spectral data as well as relevant literatures and comparison data should be provided. Where no literature report is available, complete structure elucidation should be provided.2) For reference standards the structures of which cannot be characterized using contemporary physicochemical methods, suitable methods should be carried out to identify their components. 2. Examination of physicochemical propertiesTest items of physicochemical properties should be established depending on properties of the reference standards and the specific conditions, e.g. description, melting point, specific optical rotation, crystal form, loss on drying and hydroscopicity.3. Test for impurity and related substancesTest items for impurity and related substances should be established according to use requirements of reference standards, e.g. reaction intermediates, byproducts, etc.4. Homogeneity testCandidate reference standards prepared in batches and subpackaged into minimum packaging units must be subjected to homogeneity test. Candidate reference standards of graded subpackaging, homogeneity test must be carried out when they are subpackaged from large packages to minimum packaging units.5. EvaluationEvaluation can be performed after the above requirements are met.The evaluation method should be one proving to be accurate and reliable in both theory and practice. Inherent systematic errors and random errors from the measurement method, the measurement process and the sample treatment process, e.g. contamination and loss of the sample in dissolution and separation operations, should be first investigated; measurement equipment should be calibrated periodically; traceable reference substances should be used; a feasible quality assurance system should be available to ensure traceability of measurement results.1) Principle of evaluationIn the assay of a candidate chemical standard substance/reference substance, the sum of determination results of water, organic solvents, inorganic impurities and organic impurities is 100%.2) Use the following methods for evaluation of candidate reference standards(1) Use a high-accuracy absolute or authoritative measurement method for evaluationIn the measurement, more than two analyzers should carry out the operation independently on different experimental instruments.(2) Use more than two reliable methods of different principles with known accuracy for evaluationPrecision of measurement methods of different principles should be investigated to estimate the systematic errors of the methods, and necessary measures should be taken to validate accuracy of the methods.(3) Multiple laboratories cooperate for evaluationLaboratory participating in collaborative standardization should have necessary conditions and relevant laboratory qualification for evaluating the candidate reference standards. Each laboratory should use the specified measurement method. The number of collaborative laboratories or of independent evaluation groups should comply with statistical requirements.V. Stability testing of candidate pharmaceutical reference standards1. For candidate reference standards, stability testing of corresponding property values should be carried out periodically under the specified storage or use conditions.2. The time intervals of stability testing may be set following the principle of “being close first and then loose”. Monitoring data at multiple time points during the testing period should be provided.(1) When the candidate reference standard has multiple property values, those that are prone to change and representative should be selected for stability testing; (2) measurement methods being not less precise than the evaluation method and being sufficiently sensitive should be used for stability testing; (3) samples for stability testing should be drawn randomly from the sample population, and the number of samples drawn should be sufficiently representative for the population; (4) if measurement results obtained by the temporal sequence wave within the random uncertainty range of the measurement method, the property value is stable over the tested time interval.。