The purpose of the stability test is to investigate the time-varying rule of the raw material drug or preparation under the influence of temperature, humidity and light, to provide a scientific basis for the production, packaging, storage and transportation conditions of the drug, and to establish the validity period of the drug.

The basic requirements for stability testing are:

(1) The stability test includes influence factor test, accelerated test and long-term test. The influence factor test is carried out with 1 batch of API or 1 batch of preparation; if the test results are not clear, 2 additional batches of samples should be tested. Biologics should be used directly in 3 batches. Accelerated and long-term tests are required to be carried out with 3 batches of test articles.

(2) The raw material drug test product should be produced on a certain scale. The amount of the test product is equivalent to the batch required for the preparation stability test, and the synthetic process route, method and steps of the raw material drug should be consistent with the mass production. The drug preparation test product should be the product of the scale-up test, and its prescription and process should be consistent with the large-scale production. For pharmaceutical preparations such as tablets and capsules, the scale of each scale-up test should generally be at least 100,000 tablets and at least 100,000 capsules. For preparations packaged in large volumes, such as intravenous infusions, the scale-up of each batch should be at least 10 times the total required for each trial. The quantity required for special varieties and special dosage forms shall be determined according to the situation.

(3) The quality standard of the test product should be consistent with the quality standard of the test product used in preclinical research, clinical trials and large-scale production.

(4) The packaging of the test product used in the accelerated test and long-term test should be consistent with the marketed product.

(5) To study drug stability, specific, accurate, precise and sensitive drug analysis methods and related substances (including degradation products and products generated by other changes) should be used, and the methods should be verified to ensure Reliability of drug stability test results. In the stability test, attention should be paid to the inspection of degradation products.

(6) Since the number of scale-up tests is smaller than that of scale production, the applicant should undertake that after obtaining approval, when transferring from scale-up tests to scale production, accelerated tests are still required for the three batches of scale-produced products that have initially passed production verification. and long-term stability tests.

(7) For pharmaceutical preparations packaged in non-permeable containers, the moisture sensitivity or possible solvent loss of the drug may not be considered, and the stability study may be carried out under any humidity.

"Significant change" in the quality of the preparation is usually defined as: ① the content differs by 5% from the initial value; or the potency does not meet the requirements when measured by biological or immunological methods; ② any degradation product exceeds the standard limit requirements; ③ appearance, physical constants, functional tests (such as color, phase separation, redispersibility, cohesion, hardness, dosage per press, etc.) do not meet the standard requirements. However, changes in some physical properties (such as: softening of suppositories, melting of creams, etc.) may occur under accelerated test conditions; ④ For some dosage forms, the pH value is not compliant; ⑤ The dissolution rate of 12 dosage units is inconsistent Comply with the requirements of the standard.

This guideline is divided into two parts, the first part is the drug substance and the second part is the pharmaceutical preparation.

1. Raw materials

The drug substance is subjected to the following tests.

(1) Influencing factor test

This test is carried out under more severe conditions than the accelerated test. The purpose is to explore the inherent stability of the drug, understand the factors affecting its stability and possible degradation pathways and degradation products, and provide a scientific basis for the preparation production process, packaging, storage conditions and establishment of degradation product analysis methods. The test sample can be carried out with one batch of APIs. Place the test sample in a suitable open container (such as a weighing bottle or a petri dish), spread it into a thin layer of ≤5mm thick, and spread the loose API into a thin layer of ≤10mm thick. layer, and the following tests were carried out. When the test results find that the degradation products have obvious changes, their potential hazards should be considered, and if necessary, qualitative or quantitative analysis of the degradation products should be carried out.

(1) The high temperature test sample is placed in a suitable clean container, and placed at a temperature of 60°C for 10 days. Samples are taken on the 5th and 10th days, and the tests are carried out according to the key stability inspection items. If the content of the test product is lower than the specified limit, the test shall be carried out in the same way at 40°C. If 60°C: no significant change, no more 40°C test.

(2) High-humidity test The sample to be tested is placed in a constant-humidity airtight container at 25℃ for 10 days under the condition of relative humidity of 90%±5%. Sampling is carried out on the 5th and 10th days, and the focus is on stability. The project requires testing, and at the same time, the weight of the test sample before and after the test is accurately weighed to examine the moisture absorption and deliquescence performance of the test sample. If the hygroscopic weight gain is more than 5%, the test should be carried out in the same way under the condition of relative humidity of 75%±5%; if the hygroscopic weight gain is less than 5%, and other inspection items meet the requirements, this test will not be carried out. Under constant humidity conditions, a saturated salt solution can be placed at the bottom of a closed container such as a desiccator. According to the requirements of different relative humidity, NaCl saturated solution (relative humidity 75%±1%, 15.5~60℃), KNO3 saturated solution (relative humidity 92.5 %, 25℃).

(3) In the strong light irradiation test, the opening of the sample to be tested is placed in a light box equipped with fluorescent lamps or other suitable lighting devices. Under near-ultraviolet lamp and under the condition of illuminance of 4500Lx ± 500Lx for 10 days, take samples on the 5th and 10th days, and carry out the test according to the key stability inspection items, especially pay attention to the appearance change of the test sample.

Regarding the lighting device, it is recommended to use a stereotyped device "adjustable light box", or a light cabinet, and install the corresponding number of fluorescent lamps in the box to achieve the specified illuminance. The height of the test table in the box can be adjusted. An exhaust fan is installed above the box to remove possible heat. The box is equipped with an illuminometer, which can monitor the illuminance in the box at any time. The light box should not be disturbed by natural light and keep the illuminance constant. At the same time, prevent dust from entering the light box.

In addition, experiments can be designed if necessary according to the properties of the drug: when the API is in solution or suspension, or in a wide pH range to explore pH and oxygen and other conditions, the effect on drug stability should be investigated, and the decomposition should be studied. Methods of analysis of the product. For innovative drugs, the necessary analysis of the properties of the decomposition products should be carried out. For raw materials stored in cryopreservation, changes in product quality under repeated freezing and thawing conditions should be verified. Certain degradation products have been shown not to be formed under accelerated or long-term storage conditions, and no special inspection is necessary.

(2) Accelerated test

This test is carried out under accelerated conditions. The purpose is to explore the stability of the drug by accelerating the chemical or physical changes of the drug, and to provide necessary information for the design, packaging, transportation and storage of the drug. The test product requires 3 batches, packaged according to the market, and placed for 6 months under the conditions of temperature of 40℃±2℃ and relative humidity of 75%±5%. The equipment used should be able to control the temperature ±2°C, relative humidity ±5%, and monitor the real temperature and humidity. At the end of the first month, 2 months, 3 months, and 6 months of the test period, samples were taken respectively, and the inspection items were tested according to the stability. Under the above conditions, if the test product does not meet the established quality standards after testing within 6 months, it should be tested under the intermediate conditions, that is, the temperature is 30 °C ± 2 °C and the relative humidity is 65% ± 5% (Na2CrO4 can be used). Saturated solution, 30℃, 64.8% relative humidity) for accelerated test, the time should be at least 12 months, all inspection items should be included, and the test should include at least 4 time points (such as 0, 6, 9, and 12 months) . Accelerated test, it is recommended to use a water-proof electric heating constant temperature incubator (20 ~ 60 ℃). A dryer with a certain relative humidity saturated salt solution is placed in the box. The equipment should be able to control the required temperature, and the temperature of each part in the equipment should be uniform and suitable for long-term use. A constant humidity incubator or other suitable equipment can also be used.

Drugs that are particularly sensitive to temperature can only be stored in the refrigerator (4~8℃). The accelerated test of such drugs can be carried out under the conditions of temperature 25℃±2℃ and relative humidity 60%±10%. for 6 months.

For drugs to be stored frozen, a batch of samples should be tested for an appropriate time at a temperature (eg 5°C ± 3°C or 25°C ± 2°C) to understand short-term deviations from label storage conditions (eg, during transportation or handling) effects on drugs.

(3) Long-term test

Long-term testing is carried out under conditions close to the actual storage conditions of the drug, and its purpose is to provide a basis for formulating the expiration date of the drug. 3 batches of test products, commercially available packaging, placed for 12 months at a temperature of 25°C±2°C and a relative humidity of 60%±10%, or at a temperature of 30°C±2°C and a relative humidity of 65%±5% It was stored for 12 months under different conditions, which was considered from the difference of climate between southern and northern my country. As for the choice of the above two conditions, the researchers decided. Samples are taken every 3 months, and samples are taken at 0 months, 3 months, 6 months, 9 months, and 12 months, respectively, for testing according to the key stability inspection items. After 12 months, it is still necessary to continue the inspection. At 18 months, 24 months, and 36 months, samples are taken for testing. Compare the results with 0 months to determine the drug's expiration date. 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 will be taken as the validity period; if the difference is large, the shortest one will be taken as the validity period. If the data show that the assay results vary little, indicating that the drug is very stable, no statistical analysis is performed.

For drugs that are particularly sensitive to temperature, the long-term test can be placed at a temperature of 6 °C ± 2 °C for 12 months, and the test shall be carried out according to the above time requirements. validity period.

For the drugs to be frozen, the long-term test can be placed at a temperature of -20℃±5℃ for at least 12 months.

The temperature used in the long-term test is 25°C±2°C and the relative humidity is 60%±10%, or the temperature is 30°C±2°C and the relative humidity is 65%±5%, which is formulated according to the international climate zone. International climate zones are shown in the table below.

The temperate zone mainly includes the United Kingdom, Northern Europe, Canada, and Russia; the subtropical zone includes the United States, Japan, and Western Europe (Portugal-Greece); the dry tropics include Iran, Iraq, and Sudan; the wet tropics include Brazil, Ghana, Indonesia, Nicaragua, and the Philippines. China is generally subtropical, and some areas are humid tropics, so the long-term test uses a temperature of 25°C±2°C and a relative humidity of 60%±10%, or a temperature of 30°C±2°C and a relative humidity of 65%±5%. It is basically the same as the conditions adopted by the International Coordination Committee (ICH) of the United States, Japan and Europe.

The packaging used for accelerated testing and long-term testing of APIs should be simulated small barrels, but the materials and packaging conditions used should be consistent with the large barrels.

2. Pharmaceutical preparations

For the stability research of pharmaceutical preparations, first of all, you should consult the relevant information on the stability of raw materials, especially to understand the influence of temperature, humidity and light on the stability of raw materials, and in the process of formula screening and process design, according to the properties of main drugs and auxiliary materials, refer to raw materials For drug test methods, influence factor tests, accelerated tests and long-term tests can be carried out. If certain conditions are met, the bracket method and matrix method can be used to simplify the test plan.

(1) Influencing factor test

The purpose of this test for pharmaceutical preparations is to investigate the rationality of the formulation and the production process and packaging conditions. The test product is carried out in one batch. The test product such as tablets, capsules, and injections (if the sterile powder for injection is in vials, the caps of the bottles cannot be opened to maintain the integrity of the seal), remove the outer packaging, and place them in In a suitable open container, carry out high temperature test, high humidity test and strong light irradiation test. The test conditions, methods and sampling time are the same as those of the API. The key inspection items are shown in the attached table.

For intermediate products or pharmaceutical preparations that need to be cryopreserved, the changes in product quality under repeated freezing and thawing conditions should be verified.

(2) Accelerated test

This test is carried out under accelerated conditions, and its purpose is to explore the stability of pharmaceutical preparations by accelerating the chemical or physical changes of pharmaceutical preparations, and to provide necessary information for formulation design, process improvement, quality research, packaging improvement, transportation, and storage. . The test product requires 3 batches, packaged according to the market, and placed for 6 months under the conditions of temperature 40℃±2℃ and relative humidity 75%±5%. The equipment used should be able to control temperature ±2°C, relative humidity ±5%, and monitor real temperature and humidity. Samples were taken at the end of the first month, 2 months, 3 months and 6 months of the test period, and the inspection items were tested 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 the intermediate conditions, that is, the temperature is 30℃±2℃ and the relative humidity is 65%±5%. , the time period is at least 12 months, all inspection items should be included, and the inspection should include at least 4 time points (such as 0, 6, 9, and 12 months) at the beginning and the end.

Formulations containing aqueous media such as solutions, suspensions, emulsions, and injections may not require relative humidity. The equipment used in the test is the same as that of the drug substance.

Drug preparations that are particularly sensitive to temperature can only be stored and used in a refrigerator (4~8℃). The accelerated test of such drug preparations can be performed under the conditions of temperature of 25℃±2℃ and relative humidity of 60% ±10%. carried out for 6 months.

For preparations intended for refrigerated storage, a batch of samples should be tested at a temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate period of time to understand short-term deviations from label storage conditions (e.g., during transportation or handling). effects on formulations.

Emulsions, suspensions, ointments, creams, pastes, gels, eye ointments, suppositories, aerosols, effervescent tablets and effervescent granules should be directly used at a temperature of 30°C±2°C and a relative humidity of 65%± 5% conditions for testing, other requirements are the same as above.

For pharmaceutical preparations packaged in semi-permeable containers, such as infusion bags made of low-density polyethylene, plastic ampoules, ophthalmic preparation containers, etc., the temperature should be 40℃±2℃ and relative humidity 25%±5%. (Can use CH3COOK•1.5 H2O saturated solution) to test.

(3) Long-term test

The long-term test is carried out under the actual storage conditions close to the drug, and its purpose is to provide a basis for formulating the validity period of the drug. 3 batches of the test product, commercially available packaging, placed for 12 months at a temperature of 25°C±2°C and a relative humidity of 60%±10%, or at a temperature of 30°C±2°C and a relative humidity of 65%±5%. It was stored for 12 months under different conditions, which was considered from the difference of climate between southern and northern my country. As for the choice of the above two conditions, the researchers decided. Sampling every 3 months, at 0 months, 3Monthly, 6-month, 9-month, 12-month sampling, and test according to the key stability inspection items. After 12 months, it is still necessary to continue the inspection, and samples are taken for testing at 18 months, 24 months, and 36 months. Compare the results to 0 months to determine the drug's expiration date. Due to the dispersion of the measured 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 is the validity period. The data indicate a very stable drug, and no statistical analysis was performed.

For drugs that are particularly sensitive to temperature, the long-term test can be placed at a temperature of 6°C ± 2°C for 12 months, and the test shall be carried out according to the above time requirements. validity period.

For preparations to be frozen and stored, the long-term test can be placed at a temperature of -20°C ± 5°C for at least 12 months, and the shelf life should be determined according to the actual time data under the long-term test storage conditions.

For pharmaceutical preparations packaged in semi-permeable containers, the test should be carried out at a temperature of 25°C ± 2°C and a relative humidity of 40% ± 5%, or 30°C ± 2°C and a relative humidity of 35% ± 5%. Which one of the above two conditions to choose is determined by the researcher.

For biological products, the transportation route, vehicle, distance, time, conditions (temperature, humidity, vibration, etc.), product packaging (outer packaging, inner packaging, etc.), product placement and temperature monitoring (number of monitors) should be fully considered , location, etc.) on product quality.

In addition, some pharmaceutical preparations should also be investigated for the stability of the preparation and use during the extemporaneous use. For example, corresponding stability studies should be carried out for preparations that are formulated or diluted and used in special environments (such as high altitude low pressure, high ocean salt spray, etc.) Preparation, storage conditions and shelf life after preparation or dilution.

Stability key inspection project

The key inspection items of raw materials and main dosage forms are shown in the attached table. The inspection items and dosage forms not listed in the table can be formulated according to the characteristics of the dosage forms and varieties. For sustained and controlled release preparations, enteric-coated preparations, etc., the release rate should be investigated, and the particle size, or the encapsulation rate, or the leakage rate, etc., should be examined for microparticle preparations.