The basic requirements of the stability test are:
(1) The stability test includes the influence factor test, accelerated test and long-term test. Influence factor test with a batch of raw materials. Accelerated test and long-term test requires three batches of test material.
(2) API test products should be a certain scale of production, the amount of test products equivalent to the preparation of stability tests required for the batch, raw material synthesis process routes, methods, steps should be consistent with the large-scale production. Pharmaceutical preparations for the test should be amplified test products, its prescription and process should be consistent with the large-scale production. Pharmaceutical preparations such as tablets, capsules, the size of each batch of amplification test, tablets should be at least 10,000 tablets, capsules should be at least 10,000 particles. Large volume packaging preparations (such as intravenous infusion, etc.) each batch of large-scale quantities should be at least 10 times the total number of tests required. Special varieties, the number of special dosage forms required, according to the situation to be determined.
(3) The quality standard of the test product should be consistent with the preclinical research and clinical trials and scale production of the test product quality standards used.
(4) The packaging of the test article used in the accelerated test and long-term test shall be consistent with the marketed products.
(5) the study of drug stability, to adopt a proprietary, accurate, precise, sensitive drug analysis methods and related substances (including degradation products and other changes in the products generated by the method, and verification of the method, in order to ensure the reliability of the results of the drug stability. In the stability test, the check of degradation products should be emphasized.
(6) Since the number of scale-up tests is smaller than the number of large-scale production, the filer should commit that when moving from scale-up tests to large-scale production after obtaining approval, accelerated tests and long-term stability tests are still required for the three batches of products initially validated through production for large-scale production. This guideline is divided into two parts, the first part of the API, the second part of the drug preparation.
1. API
The following tests are to be conducted for APIs.
(1) Influence factor test This test is conducted under more intense conditions than the accelerated test. Its purpose is to explore the inherent stability of the drug, to understand the factors affecting its stability and possible degradation pathways and degradation products for the preparation of the production process, packaging, storage conditions and the establishment of analytical methods for degradation products to provide a scientific basis. The test material can be carried out with a batch of API, the test material will be placed in a suitable open container (such as weighing bottles or Petri dishes), spread into a ≤ 5mm thick layer, loose API spread into a ≤ 10mm thick layer, the following test. When the test results found that the degradation products have obvious changes, should be considered potentially harmful, if necessary, the degradation products should be qualitative or quantitative analysis.
①High-temperature test, the test material is placed in a suitable clean container, 60 ℃ temperature for 10 days, on the 5th and 10th day to take samples, according to the stability of the key items to examine the test. If there is a significant change in the test material (such as content below the prescribed limit), then the same method under the conditions of 40 ℃ for the test. If there is no significant change at 60 ℃, no longer 40 ℃ test.
② high humidity test test test material openings placed in a constant humidity closed container, at 25 ℃ were placed in 90% ± 5% relative humidity conditions for 10 days, on the 5th and 10th day to take samples, according to the stability of the project focus on the requirements of the inspection, while accurately weigh the test material before and after the test in order to examine the moisture-absorbing moisture properties of the test material. If the moisture absorption weight gain of 5% or more, then under the condition of 75% ± 5% relative humidity, the same method for the test; if the moisture absorption weight gain of 5% or less, the other items meet the requirements, then no longer carry out this test. Constant humidity conditions can be placed in a closed container such as desiccator lower saturated salt solution, according to the requirements of different relative humidity, you can choose NaCl saturated solution (relative humidity 75% ± 1%, 15.5 ~ 60 ℃), KNO3 saturated solution (relative humidity 92.5%, 25 ℃).
3 strong light irradiation test the test material openings in the light box equipped with fluorescent lamps or other suitable light device, in the illuminance of 4500lx ± 500lx under the conditions of 10 days, on the 5th and 10th day to take samples, according to the stability of the key items to be examined for the test, pay special attention to the appearance of the test material changes.
On the light device, it is recommended to use the stereotypes of equipment "adjustable light box", can also be used in the light cabinet, installed in the box of fluorescent lamps to achieve the prescribed illumination. Box for the test table height can be adjusted, the box above the installation of extractor fans to exclude possible heat, the box is equipped with illuminance meter, can monitor the box at any time the illuminance, the light box should be free from the interference of natural light, and to maintain constant illuminance, while preventing dust from entering the light box.
In addition, according to the nature of the drug, if necessary, can design tests to explore the pH and oxygen and other conditions on the stability of the drug, and study the analysis of decomposition products. Innovative drugs should be analyzed for the nature of decomposition products as necessary.
(2) accelerated experiments this test is carried out under specified conditions. Its purpose is to accelerate the chemical or physical changes in the drug to explore the stability of the drug, for the preparation design, packaging, transportation, storage to provide the necessary information. The test material requires three batches, according to the commercially available packaging, at a temperature of 40 ℃ ± 2 ℃, relative humidity of 75% ± 5% of the conditions placed for 6 months. The equipment used should be able to control the temperature ± 2 ℃, relative humidity ± 5%, and be able to monitor the real temperature and humidity. Samples shall be taken once at the end of the 1st month, 2nd month, 3rd month and 6th month of the test period, and tested according to the stability key investigation items. Under the above conditions, if the test product does not meet the developed quality standards after testing within 6 months, the test should be accelerated under intermediate conditions, i.e., at a temperature of 30 ℃ ± 2 ℃, relative humidity of 65% ± 5% (available Na2CrO4 saturated solution, 30 ℃, relative humidity of 64.8%), and the time is still 6 months. Accelerated test, it is recommended to use a waterproof electric thermostatic incubator (20 ~ 60 ℃). Box placed with a certain relative humidity saturated salt solution desiccator, the device should be able to control the required temperature, and the temperature of all parts of the device should be uniform, and suitable for long-term use. Constant humidity constant temperature box or other suitable equipment can also be used.
The drugs that are particularly sensitive to temperature are expected to be stored only in a refrigerator (4-8 ℃), and the accelerated test of such drugs can be carried out at a temperature of 25 ℃ ± 2 ℃, relative humidity of 60% ± 10% of the conditions, for a period of 6 months.