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June 1, 2022
Stability refers to the ability of a drug to maintain physical, chemical, biological and microbiological properties. The purpose of stability test is to investigate the rule of bulk drug or drug preparation changing with time under the influence of temperature, humidity and light, to provide scientific basis for the production, packaging, storage and transportation conditions of drugs, and to establish the validity period of drugs through the test.
01 Influence factor test
Generally including high temperature, high humidity, strong light irradiation test, generally put the API test materials in an appropriate open container (such as weighing bottle or petri dish), spread into a thin layer ≤5mm thick, loose API spread into a thin layer ≤10mm thick for the test. For oral solid preparation products, the smallest preparation unit is generally used to remove the inner packaging and disperse into a single layer under suitable conditions. If the test results are not clear, two more lots of samples should be tested.
1.1 High temperature test
The samples were opened and placed in a suitable clean container at 60℃ for 10 days. Samples were taken on the 5th and 10th day to detect relevant indexes. If the test product changes significantly, the test is carried out at 40℃ with the same method. If there is no significant change at 60℃, the 40℃ test is not necessary.
1.2 High humidity test
The samples were placed in a humid airtight container at 25℃ for 10 days at 75%±5% and 90%±5% relative humidity, respectively, and sampled on the 5th and 10th day. Test items should include moisture absorption and weight gain. Liquid preparations are not subject to this test. Hygroscopic conditions can be achieved by using a constant temperature and humidity chamber or by placing a saturated salt solution under a closed container. According to different humidity requirements, choose saturated solution of sodium chloride (15.5-60℃, relative humidity 75%±1%) or saturated solution of potassium nitrate (25℃, RH92.5%).
1.3 Light test
The test samples were opened in a light box or other appropriate light container and placed for 10 days under the condition of 4500Lx±500Lx (total illumination is 1.2 million Lxh). Samples were taken for detection on the 5th and 10th day, and ultraviolet light should be used when conditions are available.
02 Acceleration experiment
The accelerated test is mainly used to evaluate the influence of short-term storage conditions on the quality of API, which aims to explore the stability of drugs by accelerating the chemical and physical changes of drugs, and provide necessary data for preparation design, packaging, transportation and storage. Three batches of the test products are required to be placed in the same or similar packaging containers of commercially produced products at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. The equipment should be able to control temperature ±2℃, relative humidity ±5℃, and can monitor the real temperature and humidity. Samples were taken at the end of the first, second, third and sixth months of the test period, and key items were investigated according to the stability. Under the above conditions, if the test product does not meet the established quality standards within 6 months, the accelerated test should be carried out under intermediate conditions, namely, temperature 30±2℃, relative humidity 65±5% (Na2CrO4 saturated solution, 30℃, relative humidity 64.8%), the time is still 6 months. For accelerated test, it is recommended to adopt water-proof electric thermostatic incubator (20~60℃). A drying oven with a certain relative humidity saturated salt solution is placed in the box, and the equipment should be able to control the required temperature, and the temperature of each part of the equipment should be uniform, and suitable for long-term use. Also can use constant humidity thermostat or other suitable equipment. Temperature-sensitive drugs are expected to be stored only in refrigerators (4-8 ℃), and accelerated tests of these drugs can be conducted at 25±2℃ and 60±10% relative humidity for 6 months.
03 Long-term Experiment
Long-term tests are carried out in close proximity to the actual storage conditions of the drug, and their purpose is to provide a basis for determining the expiry date of the drug. Three batches of the tested products were placed in the same or similar packaging containers of commercial products at a temperature of 25℃±2℃ and a relative humidity of 60%±10% for 12 months, or at a temperature of 30℃±2℃ and a relative humidity of 65%±5% for 12 months, considering the climate differences between northern and southern China. It is up to the researchers to decide which of the two conditions to choose. Samples were taken every 3 months, and samples were taken at 0, 3, 6, 9 and 12 months respectively. After 12 months, further investigation was required, and samples were taken for testing at 18, 24 and 36 months. Results were compared to 0 months to determine the expiration date of the drug. Due to the dispersion of experimental data, statistical analysis should generally be carried out according to the 95% confidence limit to obtain a reasonable validity period. If the difference between the three batches of statistical analysis results is small, the average value is taken as the validity period; if the difference is large, the shortest one is taken as the validity period. If the data showed that the changes in the test results were small, indicating that the drug was very stable, no statistical analysis was made. For drugs that are particularly sensitive to temperature, long-term test can be placed at a temperature of 6℃±2℃ for 12 months and tested according to the above time requirements. After 12 months, it is still necessary to continue investigation according to the provisions and formulate the period of validity under the condition of low temperature storage. A temperature of 25±2℃ and a relative humidity of 60±10% for long-term tests or a temperature of 30±2℃ and a relative humidity of 65±5% are determined according to the international climate zone.
A simple comparison of the three stabilizations
Influence factor test
|10 days||To clarify the possible degradation pathways of drugs and provide reference information for the selection of packaging materials||Relative to the most violent|
|6 months||To clarify the degradation of drugs deviating from normal storage conditions, and to clarify the long-term retention test conditions||More violent|
The longest time,
throughout the research work
|Confirm the results of influence factor test and accelerated test, determine the changes in drug stability, and determine the expiration date of the drug||Simulate storage conditions of marketed drugs|