Technical Guidelines for the Stability of Biological Products (Trial)

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I. Introduction
Stability research is an important part of the whole drug research and development stage and the support of drug listing and post-marketing research. It is the basis for setting the product's validity period and can be used to judge the rationality of product production process, preparation prescription and packaging material selection. But also the basis for product quality standards. To standardize the stability of biological products research, the development of the technical guidelines.

The technical guidelines apply to the stability of biological products such as liquid, finished or intermediate products such as the design of the results of the analysis. For some special varieties, such as gene therapy and cell therapy products, should also be based on the characteristics of the product to carry out the corresponding research.

The research and evaluation of the stability of biological products should follow the guiding principles and should meet the requirements of the relevant provisions of the national drug administration.

Second, the research content

Prior to carrying out the stability study, a holistic plan or program of stability research needs to be established, including research samples, research conditions, research projects, research time, transport studies, and analysis of research results.

The stability studies of biological products generally include real-time stability studies under actual storage conditions (long-term stability studies), accelerated stability studies and forced conditional studies. Long-term stability studies can be used as the main basis for setting the conditions and validity of the product. Accelerated and forced conditional tests can be used to understand the stability of the product in the short term deviation from the preservation conditions and extreme conditions, and to provide supportive data for the determination of the validity and preservation conditions.

Stability testing methods used in the detection method should be verified, the testing process to be rational design, should try to avoid personnel, methods or time and other factors introduced test error. The method of long-term stability research should be consistent with the method of product release detection. The method of intermediate product or raw liquid and finished product should be accelerated and the method of force test should be reasonable and sensitive according to the purpose of the study and the characteristics of the sample.

The stability study should also take into account the effect of the cumulative storage time on the stability of the final product in the storage of the samples.

(A) sample

Research samples usually include the stock solution, finished product and the product comes with diluent or heavy suspension, due to the continuous operation and need to save a certain time of the intermediate product should also be the corresponding stability study.

  The number of sample batches for stability studies should be at least three batches. Stages of the various stages of the study of the production process and quality should be consistent (that is representative), batch should meet the needs of stability research. Research products should come from different batches of liquid. The stability of the finished product should be the same as the actual storage of packaging containers and closed systems; liquid or intermediate product stability studies can be used with the actual application of the same material or material containers and sealing system.

Stability studies can be based on the representative of the test sample, a reasonable design research program to reduce the frequency of detection of some samples or according to product characteristics (such as specifications) to select part of the representative test items. In principle, the concentration of inconsistent specifications of a variety of products, should be carried out in accordance with the requirements of stability studies.

(B) conditions

The stability study should be based on the purpose of research and product characteristics of the research conditions to explore and optimize. Stability research conditions should take full account of the future storage, transportation and use of the entire process. According to the preliminary research results of various influencing factors (such as temperature, humidity, light, repeated freezing and thawing, vibration, oxidation, acid and alkali and other related conditions), long-term, accelerated and forced conditions test and other stability research program.

1. temperature

The temperature conditions for long-term stability studies should be consistent with the actual storage conditions; the temperature in the forced condition test should be such that the sample can be observed to degrade and exceed the quality standard; the stability conditions for the stability study are generally between long- Between the tests, it is usually possible to reflect the product may be short-term deviation from the actual preservation of the situation.

2. Humidity

If the packaging container and sealing system can be proved to have good sealing performance, the stability study under different humidity conditions can be omitted; otherwise, the relevant research needs to be carried out.

3. Repeated freezing and thawing

For the need to cryopreservation of the liquid, intermediate products, should be verified in the repeated repeated freezing and thawing conditions of product quality changes.

4. other

Lighting, vibration and oxidation conditions should be based on product or sample storage conditions and research purposes to design.

In addition, the liquid preparation in the stability of the study should also take into account the product placement direction, such as orthodox, inverted or horizontal placement.

Simulation of the actual use of the study should consider the use of products, storage methods and conditions, such as the number of injectors and the impact of extraction and so on. For some biological products, such as for multiple use, a single administration of a long time (such as intravenous infusion), need to be prepared before use, the use of special circumstances (such as plateau low pressure, marine high salt spray and other environments ), As well as the presence or absence of a small volume of dosage form such as the use of the product, should carry out the corresponding stability study to assess the actual use of the stability of the product.

    (C) the project

Taking into account the characteristics of biological products, stability research should be used in a variety of physical, chemical and biological test methods, for a number of research projects on a comprehensive analysis and verification of the product. The test items shall include product-sensitive items, such as biological activity, purity and content, that are sensitive to the product and may reflect product quality, safety and / or effectiveness. According to the characteristics of the product dosage form, should consider setting the relevant inspection items, such as injection of sterile powder should be investigated for changes in its moisture content; liquid dosage form should be used to investigate the appropriate changes in volume and so on. At the time of the annual inspection, the product should be tested as soon as possible.

1. Biological activity

Biological activity detection is a key research project in the research of biological product stability. In general, the biological activity is expressed in terms of potency and is the unit of activity obtained by comparison with the reference substance. The reference material used in the study should be a standardized substance. In addition, we need to pay attention to the consistency of the application reference and its own stability. At the same time, according to the characteristics of the product itself to consider in vivo biological activity, in vitro biological activity or other alternative methods of research.

2. purity

A variety of principles should be used to carry out a comprehensive assessment of the purity of the method. The limits of the degradation product should be based on the overall situation of the results of the batch analysis of the samples used in the preclinical and clinical studies. In the long-term stability study, it is suggested that a new degradation product is present or if the content change exceeds the limit, it is recommended to identify it and carry out the evaluation of safety and efficacy. For alternative substances that can not be identified by appropriate methods or samples that can not be tested for purity by conventional analytical methods, alternative test methods should be presented and their rationality should be demonstrated.

3. other

Some other test items are also more important aspects of the research on the stability of biological products and need to be addressed in the stability study. Such as the content, the appearance (color and clarity, the color of the sterile powder for injection, texture and re-dissolved time), visible foreign matter, insoluble particles, pH, moisture content of sterile powder for injection, sterile examination. Additives (such as stabilizers, preservatives) or excipients may also be degraded during the duration of the formulation. If the initial stability test indicates that the reaction or degradation of these substances has an adverse effect on the quality of the drug, To be monitored. The stability study should also take into account that the packaging container and the sealing system may have a potentially adverse effect on the sample and should be addressed in the design process.

(D) time

The general principle of long-term stability study time points is to detect once every three months in the first year, once every six months in the second year, and once a year. If the period of validity (retention period) is one year or less, the long-term stability study should be tested once a month for the first three months and once every three months thereafter. In some special cases, the flexibility to adjust the detection time, for example, based on the preliminary stability of the research results, can be targeted for the product changes in the intense period of time more intensive detection. In principle, long-term stability studies should be done as far as possible. The validity of the product should be based on the results of the long-term stability study. Forced and accelerated stability studies should be observed for product failure.

To report the stability of the clinical trial phase, should be able to explain the initial stability of the product. When reporting production, the stability study should provide effective basis for the storage conditions and the validity period (shelf life).

(5) Research on transport stability

Biological products usually require cold chain preservation and transportation, the product (including liquid and finished product) of the transport process should be the corresponding stability simulation verification study. (Temperature, humidity, vibration, etc.), product packaging (packaging, packaging, etc.), product placement and monitor conditions (temperature monitoring), temperature control, The number of devices, location, etc.) and so on. Stability Study design should simulate the worst conditions during transport, such as transport distance, vibration frequency and amplitude and desoldering chain. Through validation studies, it should be confirmed that the product in the transport process under the conditions of the preservation of the product can maintain the stability of the product and assess the product in a short out of the proposed conditions for the preservation of the impact of product quality. For the need for cold chain transport products, products from the cold chain temperature, the number of times, the total time to develop the appropriate requirements.

(6) Analysis of the results

A reasonable method of determining the results and acceptable acceptance criteria should be established in the stability study. Different test indicators in the study should be analyzed separately; at the same time, should also be a comprehensive assessment of the stability of the product.

At the same time to carry out the study of different batches of stability research results should have a good consistency, it is recommended to use statistical methods to determine the consistency between the batches. The same batch of products, at different time points to collect the stability of the data should be trend analysis to determine the degradation of the situation. The acceptance criteria should be formulated or modified with reference to the detection values ​​of the clinical study samples, taking into account the variability of the methodology, which can not be lower than the quality standard of the product.

Through the analysis of the stability of the research results and comprehensive assessment, clear product sensitivity conditions, degradation pathways, degradation rate and other information, to develop product preservation conditions and validity (shelf life).

Third, marked

According to the results of the stability study, the product specification or label in the product clearly the storage conditions and validity. Products that can not be frozen are described separately. If the product requires dark, moisture or to avoid freezing and thawing, etc., it is recommended in the packaging of various types of containers and instructions in the instructions. For multi-dose specifications of the product, should be marked after the longest use of the period and placement conditions. For freeze-dried products, the stability of the lyophilized product should be clarified, including the storage conditions after dissolution and the longest shelf life.

Fourth, the term explained

Degradation product: the product in the storage process changes over time with the material. This change may occur during product production or during storage, such as deamidation, oxidation, polymerization, protein hydrolysis, and the like.

Intermediate product: the formation of the process, for the next process of the material used, not including the liquid.

Validity: The maximum expiration date (number of days, months or years) for which the product is available for normal use. The validity period is determined based on the shelf life obtained by the stability study during the product development process.

Shelf Life: The time at which the stock solution and intermediate product can be stored under suitable storage conditions.

Long-term stability studies: Stability studies carried out under actual storage conditions were used to develop the shelf life of the product and the shelf life of the stock solution.

Accelerated Stability Study: Stability Study Above the Actual Storage Temperature. Usually refers to 37 ° C or room temperature.

Forced conditions test: the impact of more intense conditions for the stability of the study, such as high temperature, light, vibration, repeated freezing and thawing, oxidation and so on.