The 2015 edition of the Chinese Pharmacopoeia Chemical Drugs (APIs and Preparations) Stability Research Technical Guidelines

1. Overview

The stability of a drug substance or preparation refers to its ability to maintain physical, chemical, biological and microbiological properties. Stability research is based on the systematic research and understanding of APIs or preparations and their production processes. The quality characteristics of APIs or preparations obtained through design experiments will vary under the influence of various environmental factors (such as temperature, humidity, light exposure, etc.). The law of time changes, and based on this, provide supporting information for the determination of the prescription, technology, packaging, storage conditions and expiration date/re-inspection period of the drug.

Stability research starts at the early stage of drug development and runs through the entire process of drug development. This guideline is a general principle for the stability of APIs and preparations. It is mainly applicable to the marketing applications of new APIs, new formulations, and generic APIs and generic formulations (NDA/ANDA, New Drug Application/Abbreviated New Drug Application) . Other stability studies such as the clinical application (IND, Investigational New Drug Application) and post-marketing change application (Variation Application) of innovative drugs (NCE, New Chemical Entity) should follow the rules of drug development and refer to the quality of innovative drugs in different clinical stages. The specific requirements of the control research and post-marketing change research technical guidelines are carried out.

This guideline is based on current knowledge and considerations, and other methods may be used if proven reasonable.

2. The basic idea of stability research

(1) The content and experimental design of the stability study

Stability research is an important part of the quality control research of raw materials or preparations, which is to reveal the stability characteristics of raw materials and preparations by designing a series of tests. Stability tests usually include influencing factor tests, accelerated tests and long-term tests.

The influencing factor test is mainly to investigate the stability of APIs and preparations to light, humidity, heat, acid, alkali, oxidation, etc., to understand their sensitivity to light, humidity, heat, acid, alkali, oxidation, etc., and the main degradation pathways And degradation products, and based on this, provide a reference for further verifying the specificity of the analytical method used, determining the placement conditions of the accelerated test, and selecting appropriate packaging materials.

The accelerated test is to investigate the stability of the drug substance or preparation under long-term storage temperature and humidity conditions, and provide a basis for the formulation process design and whether it can still maintain stable quality if it deviates from the actual storage conditions. According to the test results, it is determined whether intermediate Stability test under conditions and determine the storage conditions for long-term testing.

The long-term test is to investigate the stability of the API or preparation under the proposed storage conditions, and provide data support for confirming the packaging, storage conditions, and expiration date/retest period.

For the preparations that are used for immediate use, or the preparations that have a certain expiration date after opening the multi-dose package, the compatibility stability test or the stability test after opening should also be carried out according to their specific clinical use.

The stability test design should be carried out around the corresponding test purpose. For example, the light test of the influencing factor test is to investigate the sensitivity of the drug substance or preparation to light. Usually, the sample with the package removed should be used for the test; if the test result shows that it is excessively degraded, the first thing to do is to eliminate the surrounding caused by the light Degradation caused by rising ambient temperature, so parallel samples protected from light can be added as a control to eliminate the influence of other factors other than light exposure on the test results. In addition, samples with inner packaging (if necessary, even inner packaging plus outer packaging) should be used for testing to investigate the protective effect of the packaging on light.

(2) Requirements for stability test samples and considerations for setting up inspection items

The samples for stability test should be representative. The registration stability test of APIs and preparations should usually be carried out with samples of at least pilot scale batches. The synthesis route, prescription and production process should be consistent with the commercialized product or the key process steps of the commercialized product. The quality of the sample should be consistent with the quality of the commercial production product; the packaging container should be the same or similar to the commercial production product.

The influencing factor test usually only needs one batch of samples; if the test result is not clear, two additional batches of samples should be tested. Accelerated tests and long-term tests are usually carried out with 3 batches of samples.

The inspection items of the stability test should be able to reflect the changes in product quality, that is, indicators that are prone to change during the placement process that may affect its quality, safety and/or effectiveness, and should cover physics, chemistry, biology and The characteristics of microbiology. In addition, items such as moisture absorption and weight gain or water loss should be added according to the test conditions such as high humidity or high temperature/low humidity.

The investigation items of APIs usually include: properties (appearance, optical rotation or specific rotation, etc.), pH, solution clarity and color, impurities (process impurities, degradation products, etc.), enantiomers, crystal form, particle size , Loss on drying/moisture, content, etc. In addition, investigation items should be set up according to the specific conditions of the variety; such as the viscosity, molecular weight and molecular weight distribution of the polymer; bacterial endotoxin/pyrogen, sterility, and visible foreign matter of sterile APIs.

The investigation items of the preparation usually include: properties (appearance), impurities (degradation products, etc.), moisture and content, etc. In addition, indicators that can reflect the quality characteristics of the dosage form should be set according to the characteristics of the dosage form; such as the dissolution rate of solid oral preparations, the release rate of sustained and controlled release preparations, enteric-coated preparations, transdermal patches, and the droplets (granules) of inhaled preparations. Distribution, encapsulation rate and leakage rate of liposomes, etc.

In addition, the migration test and adsorption test for the compatibility study of the formulation and the packaging material or container are usually carried out by increasing the corresponding potential target extracts and functionality in the accelerated and/or long-term stability test (note that the drug should be in full contact with the packaging material). Testing indicators such as the content of excipients can be used to obtain the absorption data of the extracts contained in the drug and the packaging materials to the drug components; therefore, the stability test of high-risk preparations (inhalation preparations, injections, eye drops, etc.) should be considered with packaging materials or The compatibility test of the container is designed together. For the specific content and test methods of compatibility studies, please refer to the technical guidelines for the compatibility of medicines with packaging materials or containers.

3. Research on the stability of APIs

(1) Test of influencing factors

The influencing factor test is to give the drug substance more severe test conditions, such as high temperature, high humidity, light, acid, alkali, oxidation, etc., to investigate its degradation under the corresponding conditions to understand the test drug substance’s resistance to light, humidity, and heat. , Acid, alkali, oxidation, etc., possible degradation pathways and degradation products produced, and provide reference information for the selection of packaging materials.

The influencing factor test usually only needs 1 batch of samples, and the test conditions should consider the physical and chemical stability of the drug substance itself. The high temperature test is generally higher than the accelerated test temperature by more than 10°C (such as 50°C, 60°C, etc.), the high humidity test usually uses a relative humidity of 75% or higher (such as 92.5% RH, etc.), and the total illuminance of the light test is not less than 1.2 ×10^6Lux·hr, near ultraviolet energy is not less than 200w·hr/m2. In addition, the drug substance should also be evaluated for its sensitivity to water (hydrolysis) in a solution or suspension state and within a wide range of pH values. If the test result is not clear about the sensitivity of the drug substance to light, humidity, heat, etc., two additional batches of samples should be tested for degradation under corresponding conditions.

Constant humidity conditions can be achieved by using a constant temperature and humidity box or by placing a saturated salt solution in the lower part of a closed container. According to different humidity requirements, choose NaCl saturated solution (15.5℃-60℃, 75%±1%RH) or KNO3 saturated solution (25℃, 92.5%RH).

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 [ISO 10977(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; ultraviolet light in the two band ranges of 320-360nm and 360-400nm should occupy a significant proportion.

Samples of solid APIs should be placed in appropriate open containers and placed in a dispersed manner, with a thickness of no more than 3mm (the thickness of loose APIs can be slightly higher); if necessary, use a transparent cover for protection (such as volatilization, sublimation, etc.). Liquid APIs should be placed in chemically inert transparent containers.

The investigation time point should be set based on the stability of the drug substance itself and the changing trend of the stability under the test conditions of the influencing factors. The high temperature and high humidity test can usually be set to 0 days, 5 days, 10 days, 30 days, etc. If the quality of the sample changes significantly under higher test conditions, the corresponding test conditions can be reduced; for example, the temperature is reduced from 50°C or 60°C to 40°C, and the humidity is reduced from 92.5%RH to 75%RH.

(2) Accelerated test

Accelerated testing and intermediate condition testing when necessary are mainly used to evaluate the impact of short-term deviation from the storage conditions on the label on the quality of the API (such as what may happen during transportation), and for the setting of long-term testing conditions and formulations Process design provides basis and supporting information.

The accelerated test is usually carried out with 3 batches of samples, placed in the same or similar packaging container of the commercial production product, the test condition is 40℃±2℃/75%RH±5%RH, and the inspection time is 6 months. The test includes at least 3 time points (for example, 0, 3, and 6 months), the initial and the last. 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.

If the long-term test is performed under the condition of 25℃±2℃/60%RH±5%RH, when the quality of the accelerated test changes significantly at any time point during the 6 months, the intermediate condition test should be carried out. The intermediate condition is 30℃±2℃/65%RH±5%RH. The recommended inspection time is 12 months. All inspection items should be included. The inspection includes at least the initial and final 4 time points (such as 0, 6, September and December).

If the API exceeds the requirements of the quality standard, it means that the quality has undergone a “significant change”.

If the storage condition of the long-term test is 30℃±2℃/65%RH±5%RH, no intermediate condition test is required.

For APIs intended for refrigerated storage (5°C±3°C), the accelerated test conditions are 25°C±2°C/60%RH±5%RH.

New APIs or generic APIs should include at least 6 months of test data when applying for registration.

In addition, for APIs to be stored in cold storage, if the quality changes significantly within the first 3 months of the accelerated test, the impact of short-term deviation from the storage conditions on the label (such as during transportation or handling) on its quality should be dealt with. Carry out evaluation; if necessary, an additional batch of samples can be tested for less than 3 months, increasing the frequency of sampling and testing; if the quality has changed significantly in the previous 3 months, the test can be terminated.

At present, there are no storage conditions for accelerated testing of cryopreservation (-20°C±5°C) APIs; researchers can take 1 batch of samples at a slightly higher temperature (such as 5°C±3°C or 25°C±2°C) Place the test for an appropriate time to understand the impact of short-term deviation from the storage conditions on the label (such as during transportation or handling) on its quality.

For APIs that are to be stored below -20°C, reference may be made to APIs that are stored frozen (-20°C ± 5°C), and accelerated tests are carried out as appropriate.

(3) Long-term test

The long-term test is to investigate the stability of the API under the planned storage conditions, and provide data support for confirming the packaging, storage conditions and expiry date (re-inspection period).

Long-term tests are usually carried out with 3 batches of samples, placed in the same or similar packaging containers of the commercial production products, and the storage conditions and inspection time should be fully considered during the entire process of storage and use.

The storage conditions for long-term tests are usually 25℃±2℃/60%RH±5%RH or 30℃±2℃/65%RH±5%RH. The time point of inspection should be able to determine the stability of the API; as suggested The validity period (re-inspection period) is more than 12 months, and the testing frequency is generally once every 3 months in the first year, once every 6 months in the second year, and once a year thereafter until the validity period (re-inspection period).

When applying for registration, long-term trials of new APIs should include at least 3 registered batches and 12 months of trial data, and at the same time, a commitment should be made to continue the investigation for sufficient time to cover its validity period (re-inspection period). The long-term test of generic drug substance should include at least 3 registered batches and 6 months of test data, and at the same time, it should be committed to continue the inspection for sufficient time to cover its validity period (re-test period).

The long-term test condition of the raw material drug to be stored in cold storage is 5℃±3℃. For APIs to be stored in cold storage, if the quality of the accelerated test changes significantly between 3 months and 6 months, the validity period (re-test period) should be determined based on the stability data of the actual inspection time under the long-term test conditions.

The long-term test conditions for the crude drug to be cryopreserved are -20℃±5℃. For APIs to be cryopreserved, the validity period (re-inspection period) should be determined based on the stability data of the actual inspection time under long-term test storage conditions.

For APIs that are to be stored below -20°C, the test should be conducted under the planned storage conditions, and the validity period (retest period) should be determined based on the stability data of the actual inspection time under the long-term test storage conditions.

4. Analysis methods and acceptable limits

The analytical methods used in the stability test need to be verified by methodology, and the acceptable limits of each inspection index should meet the requirements of safety, effectiveness, and controllable quality.

The acceptable limits of safety-related quality indicators should be based on toxicological tests or literature, and should be able to meet the requirements of preparation technology and key quality attributes.

5. Analysis and evaluation of results

The ultimate goal of stability research is to pass at least 3 batches of API testing and evaluation of stability data (including physical, chemical, biological, and microbiological test results), and establish that it is suitable for all future conditions in similar environmental conditions. The expiry date (re-inspection period) of all batches of APIs produced and packaged.

If the stability data shows that the degradation of the test drug substance and the variation between batches are very small, it can be clearly seen from the data that the validity period (retest period) applied for is reasonable. At this time, it is usually not necessary to conduct a formal statistical analysis. Just state the reason for omitting statistical analysis. If the stability data shows that the test drug substance has a degradation trend and there is a certain variation between batches, it is recommended to determine its validity period (retest period) through statistical analysis.

Statistical analysis of quantitative indicators that may change over time (usually the content of active ingredients, the level of degradation products, and other related quality attributes, etc.), the specific method is: the 95% one-sided confidence limit of the average curve is compared with the acceptance standard The time point corresponding to the intersection point is regarded as the validity period (re-inspection period). If the analysis results show that the variation between batches is small (the slope and intercept of the regression curve of each batch of samples are statistically tested), that is, the P value is> 0.25 (no significant difference), it is best to combine the data for overall analysis and evaluation . If the variation between batches is large (P value ≤ 0.25), the analysis cannot be combined, and the validity period (re-inspection period) should be determined based on the time of the shortest batch.

Whether the data can be converted into linear regression analysis is determined by the nature of the degradation reaction kinetics. Generally, the degradation reaction kinetics can be expressed as a mathematical or logarithmic first, second or third function relationship. The degree of fit between the data of each batch and combined batch (when appropriate) and the assumed degradation straight line or curve should be tested by statistical methods.

In principle, the validity period (retest period) of the API should be determined based on the stability data of the actual inspection time under long-term test conditions. If it is proved to be reasonable, the validity period (re-inspection period) outside the actual observation time range can be obtained by limited extrapolation based on the measured data obtained under the long-term test conditions during the registration application. The extrapolation should be based on a comprehensive and accurate analysis of the degradation mechanism, including the results of accelerated tests, good fitting of mathematical models, and supporting stability data of the batch size obtained; the assumption of the extrapolation method is based on the belief that “in Outside the observation range, there is also the same degradation relationship as the existing data.”

6. Stability Commitment

When the long-term stability data of the three production batch samples applied for registration have covered the recommended validity period (re-inspection period), it is considered that post-approval stability commitment is not required; however, a commitment should be made if one of the following situations occurs:

1. If the submitted information contains the stability test data of at least 3 production batch samples, but the validity period (re-inspection period) has not yet expired, you should commit to continue the research until the recommended validity period (re-inspection period).

2. If the submitted materials contain less than 3 batches of stability test data of production batch samples, you should promise to continue the research until the recommended validity period (re-inspection period), and at the same time supplement the production scale batches to at least 3 batches, and Perform long-term stability studies until the recommended validity period (re-inspection period).

3. If the submitted materials do not contain the stability test data of the production batch of samples (only the stability test data of the registered batch of samples), you should promise to use the first three batches of production-scale production for long-term stability test until Recommended validity period (re-inspection period).

Generally, the long-term stability test plan of the promised batch should be the same as the plan of the declared batch.

7. Label

The storage conditions of the drug substance should be indicated on the label in accordance with relevant national management regulations; the content of the statement should be based on a comprehensive assessment of the stability information of the drug substance. There should be special instructions for APIs that cannot be frozen. Inaccurate expressions such as “ambient conditions” or “room temperature” should be avoided.

The expiration date (re-inspection date) calculated from the validity period (re-inspection period) derived from the stability study should be indicated on the container label.