Relevant regulations III: Article 1   In order to ensure the quality of national drug reference materials and standardize the development of drug reference materials, this technical specification is formulated according to the national measures for the administration of drug reference materials.
Article 2   This technical specification is applicable to the National Institute for food and drug control (nifdc) (hereinafter referred to as the Chinese Academy of inspection) for the research, preparation, calibration, review and supply of national drug reference materials.
Article 3   National drug reference materials refer to the substances that are used for physical and chemical tests and biological method tests in drug quality standards, and have certain characteristics to calibrate equipment, evaluate measurement methods, or characterize or assign values to the tested drugs.
（1） National drug reference materials for physical and chemical testing refer to the reference materials used for physical and chemical testing in drug quality standards, which have certain characteristics and are used to identify, inspect, determine the content and calibrate equipment. According to their uses, they are divided into the following four categories:
  1. chemical reference material for content determination: refers to the reference material with a certain quantity value used to determine the content of specific components in drugs.
2. chemical reference materials for identification or impurity inspection: refers to reference materials with specific chemical properties used to identify or determine certain specific components of drugs.
3. reference drug / reference extract: refers to the reference substance used to identify a certain kind of component or component in traditional Chinese medicine or traditional Chinese patent medicine.
4. reference substance for calibration instrument / system suitability test: refers to the reference substance with specific chemical properties used for calibration of testing instrument or system suitability test.
（2） National drug reference materials for biological detection refer to biological standards or biological reference materials used for the determination of potency, activity and content of biological products or their characteristics identification and inspection, which can be divided into biological standards and biological reference materials.
1. biological standard refers to the standard substance calibrated with international biological standard or developed by China (where there is no international biological standard) for quantitative determination of the potency or toxicity of a product. Its biological activity is expressed in international unit (IU) or unit (U).
2. biological reference materials refer to biological reagents, biomaterials or specific antiserum calibrated with international biological reference materials or developed by China (where there is no international biological reference materials) for qualitative identification of microorganisms (or their products) or disease diagnosis; Or refers to the reference substance used for quantitative detection of the biological potency of some products, such as the reference substance used for the determination of measles live vaccine titer or toxoid flocculent unit. Its potency is expressed in specific active units, not in international units (IU). Article 4   When establishing a new national drug reference material, the development department shall submit the development application, and the reference material management office is responsible for evaluating the necessity of development. The newly added reference materials shall follow the principles of applicability, representativeness and accessibility. The development department can prepare and calibrate them only after the development application is approved.
Article 5   Except for special cases, the characteristics of the raw materials of national pharmaceutical reference materials for physical and chemical testing shall be consistent with the use requirements of reference materials. The uniformity, stability and characteristic value range of raw materials shall be suitable for the use of the reference materials. Each batch of raw materials shall have sufficient quantity to meet the supply needs.
The raw materials of national drug reference materials for biological detection shall be subject to confirmatory verification by the laboratory, and shall be of the same quality with the test sample, free of interfering impurities, with sufficient stability, high specificity and sufficient quantity.
Article 6   The raw materials of national drug reference materials are collected mainly through the following three ways:
（1） For the newly added drug reference materials, when applying for the production of new drugs, the applicant shall report the raw materials (materials) of the reference materials for inspection of the variety to the reference materials management office of our hospital, and submit the relevant research materials.
（2） To purchase or commission the preparation of raw materials through domestic or foreign enterprises or institutions with production capacity, the supplier shall provide the following relevant technical data:
1. inspection report of raw materials (materials) (including test methods, test values, test repetition times, spectra, chromatograms and other relevant data)
2. experimental data or research data of raw material (material) stability
3. research results or description of moisture entrainment of raw materials (materials)
4. safety data related to raw materials (materials)
（3） For special reference materials, the Chinese Academy of inspection shall prepare or collect raw materials (materials) by itself.
Article 7   For the varieties with insufficient supply of raw materials (materials) or difficult to obtain, the development department shall explain the reasons and submit them to the reference material management office, which shall summarize them and submit them to relevant units.
Article 8   Candidate raw materials (materials) shall be tested according to relevant quality standards and using a variety of analysis methods before sub packaging. Sub packaging can be carried out only after they meet the requirements.
（1） The following tests shall be carried out before the sub packaging of national drug reference materials for physical and chemical testing:
1. chemical structure confirmation or component confirmation. The compounds with known structures shall be consistent with the values or spectra of authoritative literature. If there is no authoritative literature, the structures shall be confirmed by means of elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry, etc. For reference materials that are not monomeric compounds, are not related to chemical structure or cannot be determined by accurate physical and chemical measurement methods, appropriate methods shall be selected to confirm their components or characteristics.
2. physical and chemical property inspection. The physical and chemical property test items shall be determined according to the characteristics and specific conditions of the reference materials, such as properties, melting point, specific rotation, crystal form, drying loss, wettability, residue on ignition, ash, heavy metals, etc.
3. purity and impurity inspection. The pure test items shall be determined according to the use requirements of reference materials. Chromatographic separation techniques (liquid chromatography, gas chromatography, capillary electrophoresis, thin layer chromatography, etc.) can be used to separate and determine reaction intermediates, by-products, degradation products or residual solvents.
（2） The following items shall be tested before the sub packaging of national drug reference materials for biological testing:
1. confirmation of biological characteristics. The raw materials of biological reference materials shall follow the principle of homogeneity with the test samples. The bacteria and virus species involved in production shall comply with the "Regulations on the management of bacteria and virus species used in the production of biological products". If conditions permit, they shall be traced to the international biological reference materials. Adopt corresponding biological, immunological or chemical technologies for confirmatory detection, such as biological method identification, antigenicity analysis, immunogenicity analysis, biochemical analysis, gene sequencing, peptide map, potency (potency) test, etc. To confirm that it meets the conditions for preparing biological reference materials for the intended use.
2. physical and chemical property inspection. The physical and chemical property test items shall be determined according to the characteristics and specific conditions of biological reference materials, such as pH value, isoelectric point, molecular weight, mobility determination, bacterial morphology, bacterial endotoxin, sterility, etc.
3. inspection of purity and content of related substances. The purity and inspection items of related substances shall be determined according to the use requirements of biological reference materials. Such as content determination, bovine serum albumin residue, exogenous DNA residue, host protein residue, residual antibiotic activity, etc; Purity check of principal components of different test methods.
Article 9   The laboratory shall submit the raw materials (materials) that meet the requirements to the reference material preparation room, fill in the sub packaging report and sub packaging card, and the sub packaging conditions of drug reference materials must meet the requirements of their relevant characteristics. For the varieties that need to be separated and packaged by units outside the hospital, the reference material management office and the preparation room shall organize corresponding review and approval.
Article 10   The packaging containers of national pharmaceutical reference materials for physical and chemical testing must ensure the stability of the contents. Glass (plastic) ampoules are mainly used for oxidizing and liquid raw materials. Conventional varieties can be packed in vials. For varieties prone to oxidation or deliquescence, the humidity of the sub packaging room must be controlled and the sub packaging shall be carried out in a nitrogen (argon) atmosphere.
The actual loading capacity of the smallest packaging unit of reference materials for physical and chemical testing and the marked loading capacity shall meet the specified tolerance requirements. The loading capacity of solid raw materials is generally ± 10% of the marked capacity.
Article 11   The preparation, subpackaging, freeze-drying and sealing of national pharmaceutical reference materials for biological detection shall be prepared and diluted according to the requirements of varieties. If protective agents and other substances are required, such substances shall have no effect on the activity, stability and test operation process of reference materials, and shall not volatilize when dry.
The sub packaging accuracy of national drug reference materials for biological detection shall be within 1%. Those requiring drying preservation shall be freeze-dried and melt sealed immediately after repacking. The moisture content of freeze-dried products shall not be higher than 3.0%. The consistency of potency and stability among ampoules must be paid close attention to during the whole sub packaging, freeze-drying and sealing process.
Article 12   In principle, uniformity inspection shall be conducted for pharmaceutical reference materials prepared in batches and sub packaged into the smallest packaging unit. Article 13   The method for determining the value of national drug reference materials should be proved to be accurate and reliable in theory and practice. The inherent systematic and random errors of the measurement method, sample processing and measurement process, such as the contamination and loss of the measured samples in the process of dissolution and separation, shall be studied first. The measuring instruments shall be calibrated regularly, the traceable reference materials shall be selected, and a feasible quality assurance system shall be established to ensure the traceability of the measurement results.
Article 14   In principle, the principle of mass balance is adopted for the determination of national drug reference materials for physical and chemical testing, that is, the sum of the contents of main components, moisture, organic solvents, inorganic impurities and organic impurities of a chemical reference material shall be 100.0%. If necessary, the uncertainty of the fixed value can be evaluated.
Article 15   For the determination of the quality value of national drug standards for physical and chemical testing, the following methods can be used to determine the characteristic quantity value, taking into account the relevant drug standards and expected uses:
（1） Use the absolute or authoritative measurement method with high accuracy to set the value. The systematic error of absolute (or authoritative) measurement method can be estimated, and the level of relative random error can be ignored. During measurement, two or more analysts are required to operate independently and use different experimental devices as much as possible.
（2） Use two or more reliable methods with known accuracy based on different principles to determine the value. Study the precision of measurement methods with different principles, estimate the systematic error of the method, and take necessary means to verify the accuracy of the method.
（3） Collaborative calibration by multiple laboratories. The laboratories participating in the collaborative calibration shall have the necessary conditions for testing drug reference materials, and each laboratory shall adopt a unified measurement method. The number of cooperative laboratories or the number of independent calibration groups shall meet the requirements of statistics. The laboratory responsible for calibration must carry out quality control on other participating laboratories and formulate clear guiding principles.
Article 16   The value of national drug reference materials for biological detection shall first determine whether there is an international standard or reference material. If so, it shall be used as the standard to calibrate the national drug reference materials for biological detection to be prepared; If not, the scheme and method for determining the value of the reference material shall be formulated according to Chinese Pharmacopoeia, national drug standards or other validated methods.
Article 17     The method for determining the value of national drug reference materials for biological detection is as follows:
（1） Collaborative calibration. The development or calibration of new reference materials generally requires the cooperation of three experienced laboratories. The participating units shall adopt a unified design scheme, a unified method and a unified record format, and the calibration results must be statistically processed (the calibration results must obtain at least 5 independent valid results).
（2） Determination of activity value (potency unit or toxicity unit). Collect the calibration results of each cooperative unit, sort out statistics, and generally express them with the mean value of the results of each cooperative unit.
Article 18   The batch change preparation of national pharmaceutical reference materials shall ensure the consistency and stability of the characteristics of raw materials (materials). Article 19   The development report of national drug reference materials shall include the following contents: summary report of drug reference materials, original experimental records, original records of collaborative calibration provided by the cooperative unit, relevant preparation materials, draft of labels and instructions for use, and relevant technical documents.  
Article 20   The national drug reference materials shall determine the variety number and batch number. One reference material corresponds to one number. When the production or use of the reference material is stopped, the number can not be used for other reference materials, and the original number can still be used when the production and use of the reference material are resumed. One time preparation of reference materials (the same batch of raw materials, the same batch of refining, and the same batch of calibration) is regarded as one batch number.
The batch number of national pharmaceutical reference materials to be changed, the varieties to be discontinued or withdrawn shall be announced to the public in a timely manner. After replacing a new batch, according to the variety monitoring, a buffer period of 3-6 months is generally set for the previous batch.
Article 21   The national drug reference materials shall be attached with labels or instructions, indicating the reference material number, batch number, name, preparation date, purpose, use method, preparation unit, quantity, storage conditions, loading capacity, precautions during use, etc.
If beyond the specified use, the user shall be responsible for the applicability of reference materials.
Article 22   The national drug standard substance Committee reviews the drug standard substance report from the aspects of development plan, raw material selection, preparation method, calibration method, calibration result, data statistical analysis, accuracy and stability of the fixed value, and makes a conclusion whether it can be used as the national drug standard substance. The packaging, supply and use of certified reference materials can only be carried out after the approval of the competent leader of the Institute. Article 23   Each stage of the packaging process of national pharmaceutical reference materials shall have clear provisions and control procedures.
Article 24   The storage conditions of national drug reference materials shall meet the requirements of the reference materials and be conducive to the stability of characteristics and characteristic quantities. Generally, it shall be stored in a dry, cool and clean environment. If there are special storage requirements, special storage measures shall be taken, which shall be indicated in the label and operation manual.
Article 25   The national drug reference materials shall be subject to regular stability monitoring.
（1） The stability verification principles of national drug reference materials for physical and chemical testing are as follows:
1. the time interval of stability test can be arranged according to the principle of "dense before sparse". There should be monitoring data at multiple time intervals during use.
2. when the drug reference material has multiple characteristic quantities, the variable and representative undetermined characteristic quantities shall be selected for monitoring.
3. select a measurement method that is not lower than the precision of the fixed value method and has sufficient sensitivity for stability test, and pay attention to the consistency of operation and experimental conditions.
4. the samples used to investigate the stability shall be randomly selected from the samples sub packed into the smallest packaging unit, and the number of samples selected shall be representative of the overall sample.
5. if the measurement results in time sequence fluctuate within the random uncertainty range of the measurement method, the characteristic value is stable within the time interval of the test. The test interval can be used as the validity period of drug reference materials. During the distribution of drug reference materials, the stability data shall be continuously accumulated to extend the validity period.
6. during stability monitoring, when new impurities or purity changes damage the consistency of this batch of reference materials, the batch of reference materials shall be publicized immediately and the use of this batch of reference materials shall be stopped.
（2） For the stability study of national drug reference materials for biological detection, accelerated destruction test shall be carried out. According to the nature of the product, the biological activity shall be measured at different temperatures (generally -20 ℃, 4 ℃, 25 ℃, 37 ℃) and different times to evaluate its stability.
Article 26   According to the practice of international drug reference materials management, at present, the national drug reference materials do not have a "validity period", and the Chinese Academy of inspection and quarantine monitors the drug reference materials.