Relevant explanations on the stability research of pharmaceutical preparations

The stability study of the formulation should be designed based on the understanding of the characteristics of the drug substance and the test results obtained from the stability study of the drug substance and the clinical prescription study, and the possible changes during the storage process and the investigation of the stability test should be explained. Project setting considerations. Stability studies should investigate items that are prone to change during storage and may affect the quality, safety and/or effectiveness of the preparation; the content should cover physical, chemical, biological, and microbiological characteristics, and the content of stabilizers (such as , Antioxidants, antibacterial agents) and functional testing of preparations (eg, dosing system), etc.

(1) Requirements for batches of formulation stability samples

Check batch requirements for formulation stability samples. Where conditions permit, different batches of APIs should be used to produce different batches of preparations.

Smaller batch samples with representative key production steps must be used

(2) Light stability test

Any light source with an output similar to the D65/ID65 emission standard can be used, such as an artificial daylight fluorescent lamp, xenon lamp or metal halide lamp with visible-ultraviolet output. D65 is an internationally recognized outdoor daylight standard [ISO10977(1993)]. ID65 is equivalent to the indoor indirect daylight standard; the emitted light below 320nm should be filtered out. The sample can also be exposed to both a cool white fluorescent lamp and a near-ultraviolet lamp at the same time. Cool white fluorescent lamps should have similar output power as specified in ISO10977 (1993). The near-ultraviolet fluorescent lamp should have a spectral range of 320~400nm, and have a maximum emission energy at 350~370nm; the ultraviolet light in the two band ranges of 320~360nm and 360~400nm should occupy a significant proportion.

At least one sample of the registered batch should be used for testing. If the test results show that the sample is stable or unstable to light, one batch of samples can be used for the test; if the research results of one batch of samples cannot confirm that it is stable or unstable to light, two additional batches should be tested The samples are tested.

Some preparations have been proven that their inner packaging is completely protected from light, such as aluminum tubes or aluminum cans. Generally, direct exposure tests of the preparations are only required. Some preparations, such as infusions, skin creams, etc., should also be tested for light stability during use. Researchers can consider the design and conduct light stability tests according to the way the preparation is used.

(3) Long-term and accelerated stability test

Generally, the thermal stability of the formulation should be evaluated under certain storage conditions (within an appropriate range). If necessary, investigate the sensitivity of the formulation to humidity or potential solvent loss. The selection of storage conditions and the length of the study time should fully consider the entire process of storage, transportation and use of the preparation.

When necessary, stability studies should be carried out on the preparations used after preparation or dilution to provide a basis for the preparation, storage conditions and use period after preparation or dilution on the instructions/labels. At the beginning and end of the long-term test, the application for registration of the batch should be prepared and diluted for the recommended use period stability test, and this test shall be part of the formal stability test. The storage conditions for long-term and accelerated tests are shown in Table 4.

In addition, it needs to be stated that “significant changes” in the quality of preparations are defined as:

1. The content is different from the initial value by 5%, or the titer does not meet the requirements when measured by biological or immunological methods.

2. Any degradation product exceeds the limit specified in the validity period standard.

3. Appearance, physical properties, and functional tests (such as: color, phase separation, redispersibility, precipitation or aggregation, hardness, dose per press) do not meet the requirements of the expiration date standard. Some changes in physical properties (such as softening of suppositories, melting of creams) may occur under accelerated test conditions;

In addition, for certain dosage forms, “significant changes” also include:

1. The pH value does not meet the requirements;

2. The dissolution rate of 12 dosage units does not meet the requirements.

: The recommended inspection time for the intermediate test is 12 months, which should include all inspection items, and the inspection includes at least the initial and final 4 time points (such as 0, 6, 9 and 12 months); for example, the storage conditions for the long-term test are 30±2°C/65%±5%RH, no intermediate condition test is required.

: According to research and development experience, it is expected that the accelerated test results may be close to the limit of significant change, and the test time point should be considered in the test design, such as 1.5 months, or January and February.

In addition, for preparations that are prone to phase separation, viscosity reduction, precipitation or aggregation, low temperature or freeze-thaw tests should also be considered. The specific methods are as follows:

1) For medicines whose temperature change range is above the freezing point

The thermal cycle test should include three cycles. Each cycle of the low temperature test is to be placed at 2-8°C for 2 days, and then placed at 40°C for 2 days, and then sampled for testing.

2) For drugs that may be exposed to below freezing point

The thermal cycle test should include three cycles. Each cycle of the freeze-thaw test is to be placed at -20～-10°C for 2 days, and then placed at 40°C for 2 days, and then sampled for testing.

3) For inhaled aerosol

The recommended thermal cycling experiment includes three to four six-hour cycles in a day, with a temperature below freezing and 40°C (75~85%RH). The experiment needs to continue for six weeks.

4) For cryopreserved drugs

The stability of the drug in accelerating melting in a microwave oven or hot water bath should be investigated, unless such operation is specifically prohibited in the instructions. If verified, other methods can also be used for investigation.

(4) Stability test of preparations packaged in non-permeable or semi-permeable containers

For pharmaceutical preparations packaged in non-permeable containers, the sensitivity of the drug to humidity or possible solvent loss may not be considered; because the non-permeable container has a permanent barrier to moisture and solvent passage. Therefore, the stability study of the formulation packaged in an impermeable container can be carried out under any humidity.

For aqueous formulations packaged in semi-permeable containers, in addition to assessing the physical, chemical, biological and microbiological stability of the formulation, the potential for water loss should also be assessed. The water loss test is to place the preparation samples under the low relative humidity conditions listed in the following table to prove that they can be placed in a low relative humidity environment.

Table 5 Storage conditions for stability test of non-permeable or semi-permeable container packaging

: The long-term test is carried out under the conditions of 25°C±2°C/40%RH±5%RH or 30°C±2°C/35%RH±5%RH, at the discretion of the investigator.

: If the long-term test condition is 30°C±2°C/35%RH±5%RH, no intermediate condition test is required. If the long-term test is carried out under the conditions of 25°C±2°C/40%RH±5%RH, and there is a significant change in quality at any point during the 6-month period under accelerated storage conditions, except for water loss, it should be Conduct intermediate condition tests to evaluate the effect of 30°C temperature on quality.

For preparations packaged in semi-permeable containers and placed at 40°C and no more than 25% RH for 3 months, the water loss is 5% different from the initial value, which is considered to be a significant change. But for small-volume (≤1mL) or single-dose packaged preparations, it is acceptable to store 5% or more of water loss at 40°C and no more than 25%RH for 3 months.

Another method can also be used to conduct the water loss study under the reference relative humidity conditions recommended in Table 6 (including long-term tests and accelerated tests). That is, the stability test is carried out under high humidity conditions, and then the water loss rate at the reference relative humidity is calculated by calculation. For the preparations packed in a specific packaging container, size, and volume, the method for calculating the water loss rate at the reference relative humidity: the water loss rate measured at the same temperature and the measured relative humidity is the same as that in the table below. Multiply the ratio of the water loss rate. The premise is that it should be able to prove that the relative humidity measured in the storage process is linear with the water loss rate. For example, to calculate the water loss rate at a temperature of 40°C and no more than 25%RH is to multiply the water loss rate measured at 75%RH by 3 (the corresponding water loss rate ratio).

Table 6 Water loss rate under relative humidity conditions under the same conditions

(5) Stability test of refrigerated and frozen preparations

If the preparations to be refrigerated are packaged in semi-permeable containers, they should also undergo a low-humidity test under appropriate temperature conditions to assess their loss of water. The storage conditions for the stability of refrigerated preparations are shown in Table 7. For preparations to be stored in cold storage, if the quality changes significantly within the first 3 months of the accelerated test, short-term deviations from the storage conditions on the label (such as during transportation or During the handling process) evaluate the impact on its quality; if necessary, test a batch of preparation samples for less than 3 months and increase the frequency of sampling and testing; if the quality has changed significantly in the previous 3 months, it can be The trial is terminated, and it is not necessary to continue until 6 months.

Table 7 Storage conditions for the stability of refrigerated preparations

: For the preparations to be stored in cold storage, if the quality of the accelerated test changes significantly between 3 months and 6 months, the validity period should be determined based on the stability data of the actual inspection time under long-term storage conditions.

The storage conditions of the frozen preparation stability test are shown in Table 8. For preparations to be stored frozen, the validity period should be determined based on the actual test time under long-term storage conditions. Although the accelerated test conditions for the preparations to be frozen for storage are not specified, a batch of samples should be tested at a slightly higher temperature (for example: 5°C±3°C or 25°C±2°C) for an appropriate time. Understand the impact of short-term deviation from the storage conditions on the instructions/labels on the quality of the preparation.

Table 8 Storage conditions of frozen preparation stability test