1. StandardReference substance and standard substance are two different concepts, which have been clearly defined in Chinese Pharmacopoeia:The reference substance refers to the reference substance used for identification, inspection, content determination and calibration of the performance of the verification instrument, while the reference substance refers to the reference substance used for biological verification, antibiotics or biological drugs content or potency determination, expressed in potency unit (U).Internationally, the English names of reference materials and standard samples are "reference materials", and iso/remco is responsible for this work. "Reference materials ",It mainly refers to the reference materials used for the determination of content or potency in bioassays, antibiotics or biopharmaceuticals, and is mostly expressed in the unit of potency (U). In drug inspection, it is a comparison to determine the quality of drugs and an essential tool to control the quality of drugs.The two concepts are often confused in the literature. It is believed that the reference substance is the standard substance, which is just one substance and two references. The reason for the error may be that some drugs have both reference substance and standard substance. ; When phenacetin is used as a melting point calibration substance, the melting point standard is used. When determining the content, the reference substance is used. Even if it is a standard and reference substance of the same substance, their specifications, calibration methods and uses may be different.2. Reference substanceLike standard products, it refers to reference materials used in national drug standards for identification, inspection, content determination, impurities and related substances inspection. It is an integral part of national drug standards.Mixed use of reference and standard?It is a major problem in drug inspection that the reference or standard is used for content determination that is not its calibration method.Although the contents of the same batch of reference materials with different calibration methods have a good correlation, they are not exactly the same, and sometimes they differ greatly. For example, the cefuroxime proxetil reference substance provided by Glaxo company in the UK is calibrated to 96.9% by HPLC for content determination; The UV was 98.8% for dissolution determination. Although Chinese Pharmacopoeia clearly stipulates that the reference substance issued by the Ministry of health is only used for the analysis method specified in the text, because:(1) The operation instructions of reference substances provided by the Ministry of health are not exhaustive, and most of them have no quality requirements and calibration methods for reference substances;(2) Lack of awareness of the correct use of reference or standard;(3) It is extremely difficult to find the corresponding reference substance in daily scientific research;(4) There is also the problem of mixing the reference substances in the text of Chinese Pharmacopoeia. For example, the standard or reference substance used for content determination is often used for dissolution inspection, and the content determination method is different from the dissolution analysis method, so it is very easy to cause mixing.3. Management system of standard, reference and standard solutionObjective: to establish its preparation, storage and use management system to ensure the accuracy of detection data.Scope of application: it is applicable to the standardized management of the laboratory.Responsibilities: the purchase, storage, preparation, storage and users of standard and reference materials are responsible, and the QC person in charge is responsible.Content:Designate a special person to purchase from National Institutes for food and drug control (nifdc), which will be managed by a special person. After receiving the reference substance and standard substance, the administrator should first fill in the reference substance purchase and use registration account, which includes: name, batch number, quantity, purchase date, storage conditions, container number, use time, user, reviewer, purpose, etc.The reference and standard should be stored according to the storage conditions on their instructions, and those that need to be dried should be put into the dryer,Those stored in a cool place should be stored in a cool place. Those stored in a cold place should be placed in the refrigerator freezer and kept at a temperature of 2 ~ 8 ℃. Those stored below -20 ℃ should be stored in the refrigerator freezer.All reference substances can only be distributed and used by the reference substance administratorUse registration shall be carried out when receiving, and the bottle opener shall fill in the bottle opening label for the reference substance after bottle opening,The contents include: product name, batch number, bottle opening date, expiration date, and bottle opener. After the reference substance is opened, it should be inspected before the next use. It can be used only if it is not obviously degraded.4. Standard TitrantThe person in charge of drug inspection shall prepare and calibrate the titrant, and repeat the standard after 3 months on a regular basis, and fill in the titrant preparation account and titrant calibration and re standard record. The record shall be the original data. If turbidity, sedimentation, discoloration and other abnormalities are found during storage, they should be handled in time. The use of titrant should be distributed by a specially assigned person. The receiver should fill in the titrant use account and indicate the purpose.5. Preparation quality requirements:The standard solution that does not need calibration can be prepared with analytically pure substances. After preparation, the standard solution preparation account should be filled in. The water used for preparation should be purified water that meets the requirements of the Pharmacopoeia. Reference materials must be used to calibrate the standard titrant. In order to prevent moisture absorption after storage, it should be dried to constant weight before calibration.6. Calibration and re calibration of titrant:The preparation and calibration of titrant shall be carried out according to the Pharmacopoeia. Generally, it is calibrated by one person and re calibrated by the second person. Parallel calibration shall be carried out for at least three times, and the relative deviation of the results shall not exceed 0.1%.The relative deviation of the calibration and re calibration results shall not exceed 0.15%, otherwise the re calibration. If the calibration and re calibration errors meet the requirements, the arithmetic mean of the two shall be taken as the titration result.The titrant and the prepared standard solution that are qualified for re labeling must be labeled with the product name, concentration, preparation date, calibration date, temperature, calibrator, re labeling person, expiration date, etc. Titrant should be re labeled regularly, and its service life is generally 3 months.It shall not be used beyond the time limit. The titrant and standard solution shall be stored according to the requirements of Chinese Pharmacopoeia. The titrant and standard solution that are easy to change in light shall be stored in brown bottles. The bottle mouth shall be bound with plastic film to prevent moisture and pollution, and shall be kept by a specially assigned person. The standard solution and titrant beyond the service life shall not be distributed by the keeper and used by the user.7. Tips for keeping standards:The preservation method is freeze-drying method: freeze-drying has no obvious effect on its concentration and immune activity, and is the most commonly used preservation method at present. Freeze dried products can remain stable for a long time at low temperature!When applying freeze-dried products, the accuracy of re solution volume is very important!Recommendations:Adding a certain amount of preservative to the standard can reduce the impact on bacterial pollution. Sealed vacuum storage or filling with inert gas can also increase the stability.So far, the most commonly used method is to add a small amount of preservatives (such as 0.1% sodium azide or 0.1% thimerosal) to it, freeze dry it, seal it, and store it at low temperature.Caution: once redissolved, it should be stored at low temperature and should not be repeatedly frozen! The validity period is significantly shortened after re dissolution, generally no more than 4 weeks, and some substances may be shorter.
