As an important part of stability research, factor test plays an important role in the process of drug research and development, such as the rationality evaluation of prescription composition, the feasibility judgment of analytical methods in quality research, the selection of packaging materials and the determination of storage conditions.
The Chinese Pharmacopoeia prescribes the test method of high temperature, high humidity and other influencing factors. However, at present, the importance of influencing factor test is not fully understood and even ignored by the researchers. Due to the existence of incorrect and unreasonable understanding, the research and development work is not in place, such as unreasonable prescription composition, unscientific accelerated test and long-term test design, which brings waste and loss of resources to the research and evaluation.
1、 Purpose and category of influencing factor test
The experiment of influencing factors is carried out under severe conditions. The purpose of the experiment is to understand the factors affecting the stability of drugs, the possible degradation pathway and degradation products, and to provide basis for the selection of preparations, the selection of packaging materials and containers, and the determination of storage conditions.
In addition to the usual three tests of high temperature, high humidity and light, if necessary, based on the drug properties, dosage form characteristics, clinical use, etc., the influencing factors test should also be carried out, including freeze-thaw test, compatibility test, low humidity test, and the effects of pH value, oxygen, low temperature and other tests on the drug quality. All kinds of tests of influencing factors are to investigate and discuss the stability of drugs from different angles and levels, so as to ensure the quality stability of drugs on the market.
2、 The function of influencing factor test and the problems of application materials
For the purpose of influencing factors test, the main functions are as follows
To know the inherent stability of drug, we can know the stability information of drug substance to light, heat and humidity by the experiment of influencing factors. For the preparation, the stability of the API preparation can also be understood
In order to provide the basis for the selection of formulation process, the stability of API determines the formulation of the drug to a certain extent, and also determines the formulation composition and production process parameters of the preparation.
Choosing reasonable packaging material and container influence factor test can know the influence degree of the preparation affected by light, heat, humidity, oxygen and other factors, so as to select and determine the packaging and storage conditions according to the stability of the preparation and ensure the stability of the quality of the medicine.
Determine the accelerated test and long-term test conditions. If the test results of the influencing factors show that the sample changes significantly at high temperature of 60 ℃ and 40 ℃, the inspection temperature of the accelerated test should not adopt the normal 40 ℃ condition, but should be properly reduced, and the long-term test temperature should be adjusted accordingly.
To understand the possible degradation pathway and degradation products of drugs during the placing process, and the influencing factor test is to make the drugs degrade under a severe condition such as high temperature, light, etc. to investigate the possible degradation products of drugs, through the qualitative or quantitative analysis of the degradation products, we can understand the degradation pathway of drugs.
The above system analyzes the role of the influencing factors test in the prescription process, quality research, packaging selection at the time of marketing and the determination of storage conditions after marketing. We hope that you can determine the specific tests to be carried out according to the research purpose, comprehensively analyze, comprehensively judge, obtain information, and ensure the quality of drugs.
Analysis of the problems in the test of the influencing factors of preparations
However, key indicators such as specific varieties or dosage forms are often ignored and lost
The setting of test conditions is unreasonable, such as semisolid preparations such as cream. The guiding principle has clearly stated that 30 ℃ should be used for the test, and some researchers still use the conventional 40 ℃ condition, which may cause demulsification of cream and make the test meaningless.
3. In order to reflect and achieve the purpose of the test, appropriate measures should be taken to control the external interference factors.
4. There are many kinds of influencing factor tests. Different tests play an important role in ensuring the quality of drugs. 5. Whether the prescription composition of the declared varieties and the technology of the existing national standard drugs are reasonable and feasible without the influence factor test shall be investigated through the influence factor test. Otherwise, the rationality of the existing national standard drugs' prescription technology will be directly affected without the influence factor test.
3、 Discussion on common problems
1. Consideration of packaging selection of test samples
The test of influencing factors with or without packaging shall be based on the purpose of the test. To test the influencing factors directly without inner packaging is to investigate the inherent stability of drugs, so that suitable packaging materials and storage conditions can be selected, and at the same time, the rationality of prescription technology can be screened; to verify the protection degree of packaging on drugs, to prove the rationality of the selected packaging.
2. Inspection time, sampling point and inspection index of compatibility test
Some preparations, such as small needle and powder needle, need to be used after compatibility with other infusion clinically. Whether the drug precipitates and accumulates after compatibility, and whether the interaction between the main drug and infusion occurs;
In general, the stability of the sample should be inspected within 8 hours in compatibility test. If the sample is unstable within 4 hours, that is, significant changes have taken place, and stable within 2 hours, it must be clearly noted in the instruction manual that the sample should be dripped within 2 hours after compatibility, so as to ensure the stability of the drug and the safety of clinical medication;
The content of some water injection and powder injection is very low. When the compatibility test is carried out, it is diluted to a certain amount of solvent, the content is lower. Therefore, it is recommended to use the instrument with higher detection sensitivity for content determination.
3. Significance of low temperature and freeze-thaw test
In the process of transportation, storage or use, drugs may encounter lower temperature. Once the quality of drugs changes, it will directly affect the safety of clinical medication.
Therefore, low temperature test and freeze-thaw test are to investigate the stability of drugs under low temperature conditions, so as to attract enough attention to the changes of external conditions in the process of transportation, storage and use.
4. Study on Influencing Factors of temperature sensitive drugs
If the drug changes significantly when it is tested at high temperature of 60 ℃ and 40 ℃, the results have shown that the sample is sensitive to temperature, then it is not necessary to continue to reduce the temperature to carry out the influencing factor test, but in the accelerated test, it should be considered that under the condition of 30 ℃ or lower temperature, the long-term test should also choose the lower temperature.
5. Two experimental designs of high temperature and high humidity
Generally, the high temperature includes 60, 40 ℃, and the high humidity includes 75% and 90% of RH. If the high temperature is 60 ℃, the high humidity RH 90% test results show that the sample is stable, then the stability test under low conditions is not necessary;