Technical Guidelines for Stability Research of Biological Products (Trial)

Technical Guidelines for Stability Research of Biological Products (Trial)
1、 Preface
The stability study is an important content that runs through the entire drug research and development stage and supports the drug marketing and post marketing research. It is the basis for setting the product validity period, can be used to judge the rationality of product production process, preparation prescription, packaging material selection, and is also the basis for formulating product quality standards. This technical guideline is formulated to standardize the stability study of biological products.
This technical guideline is applicable to the stability research design and result analysis of the original solution, finished product or intermediate product of biological products. For some special varieties, such as gene therapy and cell therapy products, corresponding research should also be carried out according to the characteristics of the products.
The study and evaluation of the stability of biological products shall follow these guiding principles and comply with the requirements of the relevant provisions of the national drug administration.
2、 Research content
Before carrying out stability research, it is necessary to establish an overall plan or scheme for stability research, including research samples, research conditions, research projects, research time, transportation research, analysis of research results, etc.
The stability study of biological products generally includes real-time stability study under actual storage conditions (long-term stability study), accelerated stability study and forced condition test study. The long-term stability study can be used as the main basis for setting the storage conditions and validity period of products. Accelerated and forced condition tests can be used to understand the stability of the product in case of short-term deviation from storage conditions and extreme conditions, and provide supporting data for determining the validity period and storage conditions.
The detection method used in the stability study shall be verified, the detection process shall be reasonably designed, and the test error introduced by personnel, method or time shall be avoided as far as possible. The method used for long-term stability study shall be consistent with the method used for product release testing; Reasonable and sensitive methods shall be adopted for the detection of intermediate products or stock solution and finished products under accelerated and forced conditions according to the research purpose and sample characteristics.
The influence of the accumulated storage time of samples in each link on the stability of the final product should also be considered in the stability study design.
（1） Sample
The research samples usually include stock solution, finished product and diluent or heavy suspension of the product. The corresponding stability study should also be carried out for intermediate products that cannot be continuously operated and need to be kept for a certain time.
The number of sample batches for stability studies should be at least three. The production process and quality of stability study samples in each stage shall be consistent (i.e. representative), and the batch size shall at least meet the needs of stability study. The finished products for research shall come from different batches of stock solution. The finished product stability study shall adopt the same packaging container and closed system as the actual storage; Containers and sealing systems with the same material or material as the actual application can be used for the stability study of stock solution or intermediate products.
In the stability study, a reasonable research scheme can be designed according to the representativeness of the test samples to reduce the frequency of testing some samples or select some representative test items according to the product characteristics (such as specifications). In principle, stability studies should be carried out for products of different specifications with different concentrations according to requirements.
（2） Conditions
The stability research should explore and optimize the research conditions according to the research purpose and product characteristics. The stability study conditions shall fully consider the whole process of storage, transportation and use in the future. 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), the long-term, accelerated and forced condition tests and other stability research schemes are formulated.
1. Temperature
The temperature conditions for long-term stability study should be consistent with the actual storage conditions; The temperature in the forced condition test shall be such that the sample can be observed to degrade and exceed the quality standard; The temperature conditions for accelerated stability study are generally between long-term and forced condition tests, which can generally reflect the situation that the product may deviate from the actual storage conditions in a short term.
2. Humidity
If it can be proved that the packaging container and sealing system have good sealing performance, the stability study under different humidity conditions can be omitted; Otherwise, relevant research is required.
3. Repeated freezing and thawing
For the stock solution and intermediate products to be frozen and preserved, the change of product quality under repeated freezing and thawing conditions shall be verified.
4. Others
The study of light, vibration, oxidation and other conditions shall be designed according to the storage conditions and research purposes of the product or sample.
In addition, the placement direction of the product should also be considered in the stability study of liquid preparations, such as upright, inverted or horizontal placement.
The research of simulating actual use should consider the way and conditions of product use and storage, such as the impact of multiple insertion and extraction of syringes. For some biological products, such as those used for multiple uses, long single administration time (such as intravenous drip), those that need to be prepared before use, those used in special environments (such as plateau low pressure, marine high salt fog and other environments), and those with special use conditions such as small volume agents that exist in the preparation or dilution process, corresponding stability studies should be carried out to evaluate the stability of the products in actual use.
（3） Project
Considering the characteristics of biological products, a variety of physical, chemical and biological test methods should be used in the stability study, and the products should be comprehensively analyzed and verified for multiple research projects. The test items shall include those that are sensitive to the product and may reflect the product quality, safety and/or effectiveness, such as biological activity, purity and content. According to the characteristics of the product formulation, relevant investigation items should be considered. For example, the change of water content of sterile powder for injection should be investigated; For liquid dosage form, appropriate methods shall be adopted to investigate the change of its dosage. At the time point of annual inspection, the products shall be comprehensively inspected as far as possible.
1. Biological activity
Biological activity detection is a key research project in the stability research of biological products. In general, biological activity is expressed by potency, which is the active unit obtained by comparison with reference substance. The reference materials used in the study should be standardized substances. In addition, it is also necessary to pay attention to the consistency of the application reference and its own stability. At the same time, research on biological activity in vivo, biological activity in vitro or other alternative methods can be considered according to the characteristics of the product itself.
2. Purity
A variety of purity testing methods should be used for comprehensive evaluation. The limit of degradation products shall be determined according to the overall analysis results of each batch of samples used in preclinical studies and clinical studies. In the long-term stability study, when new degradation products are found or the content changes exceed the limit, it is recommended to identify them and evaluate their safety and effectiveness. For substances that cannot be identified by appropriate methods or samples whose purity cannot be detected by conventional analytical methods, alternative test methods shall be proposed and their rationality shall be proved.
3. Others
Other detection items are also important aspects in the stability study of biological products, which should be paid attention to in the stability study. For example, content, appearance (color and clarity, color, texture and re dissolution time of sterile powder for injection), visible foreign matters, insoluble particles, pH value, moisture content of sterile powder for injection, sterility test, etc. Additives (such as stabilizers, preservatives) or excipients may also degrade within the validity period of the preparation. If there is evidence in the preliminary stability test that the reaction or degradation of these substances has adverse effects on the drug quality, it should be monitored in the stability study. In the stability study, it should also be considered that the packaging container and sealing system may have potential adverse effects on the sample, and this aspect should be paid attention to in the study design process.
（4） Time
The general principle for setting the time point of long-term stability study is that the test shall be conducted every three months in the first year, every six months in the second year, and once a year from the third year. If the validity period (retention period) is one year or less, the long-term stability study shall be conducted once a month in the first three months and once every three months thereafter. In some special cases, the detection time can be flexibly adjusted. For example, based on the preliminary stability study results, more intensive detection can be carried out for the time period when the product changes dramatically. In principle, the long-term stability study should be conducted until the product is unqualified as far as possible. The product validity period shall be set according to the results of long-term stability study. Forced and accelerated stability studies should observe product nonconformities.
The preliminary stability of the product shall be explained when applying for the stability study in the clinical trial stage. When applying for production and marketing, the stability study shall provide an effective basis for the formulation of storage conditions and shelf life (shelf life).
（5） Transportation stability study
Biological products usually require cold chain preservation and transportation, and corresponding stability simulation verification research shall be conducted for the transportation process of products (including stock solution and finished products). In the stability study, the transportation route, means of transportation, distance, time, conditions (temperature, humidity, vibration, etc.), product packaging (outer packaging, inner packaging, etc.), product placement and monitoring (number and location of temperature monitors, etc.) should be fully considered. During stability research and design, the worst conditions during transportation, such as transportation distance, vibration frequency and amplitude, and de cooling chain, shall be simulated. Through the validation study, it should be confirmed that the stability of the product can be maintained under the proposed storage conditions during transportation, and the impact on the product quality when the product is temporarily separated from the proposed storage conditions should be evaluated. For products requiring cold chain transportation, corresponding requirements shall be formulated for the temperature, times, total time, etc. of products leaving the cold chain.
（6） Analysis of results
In the stability study, reasonable results evaluation methods and acceptable acceptance standards should be established. Different test indexes in the study should be analyzed separately; At the same time, the stability of the product should also be comprehensively evaluated.
At the same time, the stability results of different batches of the study should have good consistency. It is recommended to use statistical methods to judge the consistency between batches. For the same batch of products, the stability data collected at different time points shall be subject to trend analysis to judge the degradation. The acceptance standard shall be formulated or revised with reference to the detection value of clinical research samples, taking into account the methodological variation. The standard shall not be lower than the product quality standard.
Through the analysis and comprehensive evaluation of the stability research results, the sensitive conditions, degradation path, degradation rate and other information of the product are clarified, and the storage conditions and validity period (storage period) of the product are formulated.
3、 Marking
According to the results of the stability study, the storage conditions and expiration date of the product shall be specified in the product manual or label. Products that cannot be frozen shall be specified separately. If the product is required to be protected from light, moisture or freezing and thawing, it is recommended to indicate it on the label of various containers and in the instructions. For multi dose products, the maximum service life and storage conditions after opening shall be indicated. For freeze-dried products, the stability of freeze-dried products after dissolution shall be clarified, including the storage conditions and the longest storage period after dissolution.
4、 Terminology
Degradation products: substances produced when products change with time during storage. This change may occur during product production or storage, such as deamidation, oxidation, polymerization, protein hydrolysis, etc.
Intermediate products: substances formed in the production process and used for the next process, excluding the stock solution.
Term of validity: the maximum term of validity (days, months or years) of the product for normal clinical use. The validity period is determined according to the storage life obtained through stability study during product development.
Storage period: the time when stock solution and intermediate products can be stored under appropriate storage conditions.
Long term stability study: the stability study carried out under actual storage conditions is used to formulate the validity period of products and the storage period of stock solution.
Accelerated stability study: stability study at higher than the actual storage temperature. Usually 37 ℃ or room temperature.
Forced condition test: stability study under conditions with severe influence, such as high temperature, light, vibration, repeated freezing and thawing, oxidation, etc.