Summary of the content of the stability test of the CTD data of the raw materials and preparations

The purpose of stability test is to investigate the law of raw material drug changes over time under the influence of temperature, humidity, and light, to provide scientific basis for the production, packaging, storage, and transportation conditions of the drug, and to establish the validity period of the drug through the test.

The basic requirements for stability testing are

(1) Stability test includes influencing factor test, accelerated test and long-term test. The influencing factor test was carried out with 1 batch of bulk drugs or 1 batch of pharmaceutical preparations. The accelerated test and long-term test require 3 batches of test products.

(2) The test product of the raw material drug should be produced on a certain scale, and the quantity of the test product should be equivalent to the batch required by the formulation stability test. The synthesis process route, method, and steps of the raw material drug should be consistent with mass production.

The test product of the pharmaceutical preparation should be the product of the scale-up test, and its prescription and production process should be consistent with the mass production. For pharmaceutical preparations such as tablets and capsules, the scale of each batch of scale-up test should be at least 10,000 tablets and at least 10,000 capsules. For large-volume packaged preparations such as intravenous infusions, the number of scale-ups in each batch should be at least 10 times the total required for each test.

The required quantity of special varieties and special dosage forms shall be determined separately according to the situation.

(3) The quality standards of the test products should be consistent with those used in pre-clinical research, clinical trials and mass production.

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

(5) To study drug stability, it is necessary to adopt specific, accurate, precise, and sensitive drug analysis methods and related substances (including degradation products and other products generated by changes) inspection methods, and verify the methods 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 promise that after obtaining approval, when transferring from scale-up tests to scale production, accelerated tests are still required for the three batches of products that initially passed the production verification. And long-term stability test.

The summary of the stability test content is divided into two parts, the first part is the bulk drug, and the second part is the pharmaceutical preparation.

1. raw materials

The following tests should be carried out for the API:

(1) Influencing factor test

This test is conducted under more severe conditions than the accelerated test. Its purpose is to explore the inherent stability of the drug, understand the factors that affect its stability, 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 product can be carried out with 1 batch of raw materials. Place the test product in a suitable open container (such as a weighing bottle or a petri dish) and spread it into a thin layer ≤5mm thick, and spread the loose raw material into a thin layer ≤10mm thick , Carry out the following experiment. When the test results find that the degradation products have obvious changes, the potential hazards should be considered, and the degradation products should be qualitatively or quantitatively analyzed if necessary.

1. High temperature test

Place the test product in a suitable airtight clean container at the opening of 60℃ for 10 days, take samples on the 5th and 10th day, and test 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 under the condition of 40℃. If there is no significant change at 60°C, the 40°C test is no longer performed.

1. High humidity test

The test sample is placed in a closed container with constant humidity and placed at 25°C under a relative humidity of 90%±5% for 10 days. Samples are taken on the 5th and 10th days. The test is carried out according to the requirements of the key stability inspection items, and it is accurate at the same time. Weigh the weight of the test product before and after the test to investigate the moisture absorption and deliquescence performance of the test product. If the weight gain by moisture absorption is more than 5%, the test shall be carried out in the same way under the condition of relative humidity of 75%±5%; if the weight gain by moisture absorption is less than 5%, and other inspection items meet the requirements, the test will not be carried out.

Constant humidity conditions can be achieved by placing saturated salt solution in the lower part of a closed container such as a desiccator. 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°C).

1. Strong light exposure test

Place the test sample opening in a light box equipped with a fluorescent lamp or other suitable lighting device, and place it for 10 days under the condition of an illuminance of 4500lx±500lx, take samples on the 5th and 10th days, and test according to the key stability inspection items , Pay special attention to the changes in the appearance of the test product.

Regarding the lighting device, it is recommended to use the “adjustable lighting box” of the styling equipment, or use a light cabinet, and install several fluorescent lamps in the box to achieve the specified illuminance. The height of the test sample table in the box can be adjusted. The top of the box is equipped with an exhaust fan to remove the heat generated by the light source. The box is equipped with an illuminance meter to monitor the illuminance in the box at any time. The light box should not be interfered 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 when necessary according to the nature of the drug to explore the effects of pH, oxygen and other conditions on the stability of the drug, and to study the analysis methods of decomposition products. Innovative drugs should carry out the necessary analysis of the nature of the decomposition products.

(2) Accelerated test

This test is carried out under accelerated conditions. Its 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 preparation design, packaging, transportation, and storage.

The test products require 3 batches, packaged according to the market, and placed for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The equipment used should be able to control the temperature ±2°C, the relative humidity ±5%, and be able to monitor the real temperature and humidity. Samples were taken at the end of the first month, two months, three months, and six months of the test period, and the tests were conducted according to the key stability inspection items.

Under the above conditions, if the test product fails to meet the established quality standards within 6 months, it should be under intermediate conditions, that is, at a temperature of 30℃±2℃ and a relative humidity of 60%±5% (Na2CrO4 can be used) Saturated solution, 30℃, relative humidity 64.8%) for accelerated test, the time is still 6 months. For accelerated test, it is recommended to use water-proof electric heating constant temperature incubator (20～60℃). A desiccator with a saturated salt solution with a certain relative humidity is placed in the box. 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. A constant humidity and thermostat 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 this drug can be carried out under the conditions of temperature 25℃±2℃ and relative humidity 60%±10%. For 6 months.

(3) Long-term test

The long-term test is carried out under conditions close to the actual storage of the drug, and its purpose is to provide a basis for formulating the validity period of the drug.

The test product requires 3 batches, commercially available packaging, placed for 12 months at a temperature of 25℃±2℃ and a relative humidity of 60%±10%, or at a temperature of 30℃±2℃ and a relative humidity of 65%±15 It is considered from the difference between the climate in southern and northern my country for 12 months under the condition of %%. As for the choice of the above two conditions, it is up to the researcher to decide. Sampling is performed every 3 months, and tests are carried out according to the key stability inspection items at 0, 3, 6, 9 and 12 months. It is still necessary to continue the inspection after 12 months, and to continue the inspection at 18 months, 24 months, and 36 months respectively, and take samples for testing. Compare the results with month 0 to determine the expiration date of the drug.

Due to the dispersiveness of the measured data, statistical analysis should generally be carried out at the 95% credibility limit to arrive at 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 shows that the measurement results change very 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 ℃ ± 2 ℃ for 12 months, and the test shall be carried out according to the above-mentioned time requirements. After 12 months, it is still necessary to continue the investigation according to the regulations and formulate it under low temperature storage conditions Validity period.

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

Table International Climate Zones

① Record the temperature.

②MKT is the average kinetic temperature.

The temperate zone includes the United Kingdom, Northern Europe, and Russia; the subtropical zone includes the United States, Japan, and Western Europe (Portugal-Greece); the dry tropical zone includes Iran, Iraq, and Sudan; and the temperate zone includes Brazil, Ghana, Indonesia, Nicaragua, and the Philippines.

Generally speaking, China is in the subtropical zone. Therefore, the long-term test must adopt a temperature of 25℃±2℃ and a relative humidity of 60%±10%, or a temperature of 30℃±2℃ and a relative humidity of 65%±15%. The European Commission for International Coordination (ICH) adopts the same conditions.

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

2. Pharmaceutical preparations

To study the stability of pharmaceutical preparations, you should first consult the relevant information on the stability of the raw material, especially to understand the influence of temperature, humidity, and light on the stability of the raw material. In the process of prescription screening and process design, refer to the raw material according to the nature of the main drug and auxiliary materials. The test method of the drug, the necessary stability influencing factors test, and the packaging conditions are examined at the same time. On this basis, the following tests are carried out.

(1) Influencing factor test

The purpose of this test for pharmaceutical preparations is to investigate the rationality of the preparation prescription 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 a vial, the cap cannot be opened to maintain the integrity of the tight seal), and the outer packaging is removed. High temperature test, high humidity test and strong light irradiation test are carried out in a suitable open container. The test conditions, methods, and sampling time are the same as those of the API. The key investigation items are shown in the attached table.

(2) Accelerated test

This test is carried out under accelerated conditions. 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 prescription design, process improvement, quality research, packaging improvement, transportation and storage. data.

The test products require 3 batches, packaged according to the market, and placed for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The equipment used should be able to control the temperature ±2°C, the relative humidity ±5%, and be able to monitor the real temperature and humidity. Samples were taken at the end of the first month, two months, three months, and six months of the test period, and the tests were conducted according to the key stability inspection items. Under the above conditions, if the test product fails to meet the established quality standards within 6 months, the accelerated test should be carried out under intermediate conditions (ie temperature 30℃±2℃, relative humidity 60%±5%) , The time is still 6 months.

Solutions, suspensions, emulsions, injections and other aqueous medium formulations do not require relative humidity. The equipment used in the test is the same as that of the bulk drug.

Pharmaceutical preparations that are particularly sensitive to temperature can only be stored and used in the refrigerator (4～8°C). The accelerated test of such pharmaceutical preparations can be performed at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 10%. It takes 6 months to proceed.

Emulsions, suspensions, ointments, creams, pastes, gels, eye ointments, suppositories, aerosols, effervescent tablets and effervescent granules should be directly used at a temperature of 30℃±2℃ and a relative humidity of 60%± The test is carried out under the condition of 5%, and the other requirements are the same as above.

For pharmaceutical preparations packaged in semi-permeable containers, such as low-density polyethylene infusion bags, plastic ampoules, ophthalmic preparation containers, etc., the temperature should be 40 ℃ ± 2 ℃, relative humidity 20% ± 2% conditions ( Available CH3COOK·1.5H2O saturated solution) for testing.

(3) Long-term test

The long-term test is carried out under conditions close to the actual storage of the drug, and its purpose is to provide a basis for formulating the validity period of the drug.

The test product requires 3 batches, commercially available packaging, stored for 12 months at a temperature of 25℃±2℃ and a relative humidity of 60%±10%, or at a temperature of 30℃±2℃ and a relative humidity of 65%±15 It is considered from the difference between the climate in southern and northern my country for 12 months under the condition of %%. As for the choice of the above two conditions, it is up to the researcher to decide. Sampling is carried out every 3 months, at 0 months, 3 months, 6 months, 9 months, and 12 months respectively, according to the key stability inspection items for testing. After 12 months, it is still necessary to continue the inspection, taking samples at 18 months, 24 months, and 36 months for testing. Compare the results with month 0 to determine the expiry date of the drug.

Due to the dispersiveness of the measured data, statistical analysis should generally be carried out at the 95% credibility limit to arrive at 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. The data indicates that the drug is very stable, and no statistical analysis is made.

For drugs that are particularly sensitive to temperature, the long-term test can be placed at a temperature of 6 ℃ ± 2 ℃ for 12 months, and the test shall be carried out according to the above-mentioned time requirements. After 12 months, it is still necessary to continue the inspection according to the regulations and formulate it under low temperature storage conditions. Validity period.

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

In addition, some pharmaceutical preparations should also be investigated for stability during formulation and use.

1. Key Stability Inspection Projects

See the attached table for the key investigation items of APIs and main dosage forms. The investigation items and dosage forms not listed in the table can be formulated according to the characteristics of the dosage form and variety.