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The stability of drugs means that APIs and formulations maintain their physical, chemical, biological and microbial properties. Through stability studies of APIs and preparations under different conditions (such as temperature, humidity, light, etc.), we can grasp the laws of drug quality changes over time, providing a basis for the determination of drug production, packaging, storage conditions and shelf life, to ensure the safety and clinical efficacy of clinical medication. Stability study is one of the main contents of drug quality control research and is closely related to drug quality research and the establishment of quality standards. Stability studies have phased characteristics and run through the entire process of drug research and development. They generally start with pre-clinical studies of drugs and should continue to be carried out during clinical studies of drugs and after marketing.
Drug stability testing can help identify possible degradation pathways and mechanisms of drugs during storage and use. By testing drugs under different environmental conditions such as temperature, humidity and light, researchers are able to predict the degradation behavior of the drug, providing a scientific basis for developing appropriate storage conditions.
Help ensure the safety and effectiveness of drugs. Once drugs break down, they may produce toxic by-products, or their effectiveness may be reduced, affecting treatment effectiveness. Through stability studies, pharmaceutical companies can ensure that drugs consistently perform their intended therapeutic effects throughout their shelf life.
Stability testing directly affects the legal and compliant marketing of drugs. For the registration and marketing of new drugs, regulatory agencies such as the FDA and EMA often require detailed stability data. These data are not only an important basis for evaluating drug quality, but also an important reference for designing drug packaging.
Help optimize drug formulation and packaging. Based on the test results, drug developers can adjust the formulation of the drug or select more suitable packaging materials to improve the stability and tolerability of the drug and ultimately reduce production costs.
Stress testing is carried out under extreme conditions beyond normal use or storage conditions. It can distinguish product stability differences between different prescription processes in a short period of time, thereby saving research and development time and improving research and development efficiency. At the same time, it can provide reference for temperature and humidity selection for long-term and accelerated stability, and can also provide support for later product impurity research and method analysis.
High temperature test: Place the sample open in a suitable clean container, place it at 60 °C for 10 days, take samples on the fifth day, and conduct tests according to key stability inspection items. If the content of the test article is less than the specified limit, the above test will be carried out in the same way at 40 ℃; if there is no significant change at 60 ℃, the 40 ℃ test will not be carried out.
High humidity test: The sample is placed in a constant humidity closed container with an open opening, placed at 25 °C and a relative humidity of 90% and 5% for 10 days, and samples are taken on the 5th and 10th days, tested according to key stability inspection items, and accurately weighed before and after the test to investigate the moisture absorption and deliquescence properties of the test article.
Strong light exposure test: Light inspection can be divided into fluorescent lamps and strong light. The light intensity of fluorescent lamps is 200-300 lux. This inspection item mainly provides basis and support for the formulation of light duration for large-scale production and clinical drug administration. The strong light intensity is 4500±500 lux, which can provide a reference for product light stability and impurity research.
It mainly investigates the impact of temperature and humidity on drugs. The conditions are lower than the pressure test requirements and higher than normal storage conditions (e.g., 40 °C and 75% RH for pharmaceuticals). The purpose is to study the stability of drug preparations by accelerating the chemical or physical changes of drugs, and provide necessary data and information support for product formulation design and process improvement, quality research, packaging design, product transportation, and storage.
Real-time stability is a test conducted by storing samples under specified actual storage conditions. Its purpose is to provide a basis for establishing the expiration date of the drug. According to ICH guidelines, products need to be tested four times in the first year at three-month intervals (three months, six months, nine months and twelve months). After the first year is over, testing is required twice the second year, six months apart, and then once a year until a failed result is obtained. Once a failed result is obtained, testing is no longer performed, but the obtained data is evaluated to determine the product's shelf life.
Any pharmaceutical preparation will face transportation problems after leaving the factory, so transportation stability studies should be carried out for pharmaceutical preparations. In the preliminary research, shaking conditions can be used to simulate transportation and inspect product stability to understand in advance whether the product is stable during transportation, vibration, and shaking, which can provide reference for subsequent product transportation stability research. As the time to market approaches, it is necessary to conduct real transportation stability inspections based on the product market conditions by conducting transportation distance, vibration amplitude and frequency. If a refrigerated drug is stored, it is also necessary to investigate the impact of temperature problems such as removing the cold chain on the drug preparation.
Studies on factors influencing stability in use, long-term and accelerated tests were conducted without the drug being opened or unused. Therefore, it is impossible to understand the stability of the product during the drug's use, so it is necessary to carry out in-use stability studies. For sterile lyophilized powder, the drug reconstitution time, compatibility stability, and use time need to be investigated. If the administration time exceeds 4 hours, the microbial status of the product needs to be evaluated. For multi-dose products such as insulin, stability studies need to be carried out based on clinical use time and puncture number, and it is necessary to ensure that all physical and chemical, related substances, microorganisms and other indicators meet the requirements during use.
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At least three primary batches representing the final formulation and packaging were selected and a baseline assessment was conducted to document the starting status. This includes key parameters such as chemistry, physics, and microbial properties and performance. These batches must be representative of the production process.
Samples were placed in a series of controlled environments that simulate the conditions that the product may encounter during storage, transportation and use. Common testing conditions include accelerated conditions (such as 40 °C/75% RH), long-term conditions (such as 25 °C/60% RH), and other temperature and humidity combinations.
Samples were taken for analysis at predetermined time points, usually 0, 3, 6, 9, 12, 18 and 24 months. Analytical items should include appearance, content, degradation products, dissolution, pH, seal integrity and microbial stability based on product characteristics.
During the data evaluation stage, the stability characteristics of the formulation were determined by analyzing the data of various parameters at different time points. Finally, based on relevant regulations and scientific data, determine the expiration date and storage conditions of the preparation, and write a report to file and support the drug registration application.
The International Council for Harmonisation (ICH) has developed a set of globally recognized guidelines to standardize stability testing practices, ensuring consistency, reliability, and regulatory compliance across regions. These guidelines address the requirements for stability testing of drug substances, drug products, and biopharmaceuticals, providing a framework that encompasses all stages of the drug lifecycle. Below is an expanded overview of key ICH guidelines relevant to stability testing:
ICH Q1A(R2) is the cornerstone guideline for stability testing, detailing the data requirements to establish shelf life, storage conditions, and packaging suitability. Key highlights include:
Storage conditions: Specifies controlled environmental conditions for testing in different climatic zones (e.g., Zone I-IV, covering temperate to hot/humid climates).
Testing protocols: Recommends testing intervals (e.g., 0, 3, 6, 9, 12 months in the first year) and subsequent annual evaluations.
Product variability: Emphasizes the importance of evaluating both the active pharmaceutical ingredient (API) and final drug product to ensure compatibility with its container closure system.
This guideline addresses the effects of light exposure on drug substances and products. Photostability testing is essential for products sensitive to UV and visible light, as it evaluates potential degradation and informs the design of protective packaging.
ICH Q1C focuses on stability testing requirements for new dosage forms of previously approved drugs. The guideline ensures that reformulated or repackaged products meet the same safety and efficacy standards as the original formulation.
This guideline introduces flexible approaches to stability testing, particularly for large product families or multiple packaging configurations. These designs streamline testing without compromising data quality.
Bracketing: Testing only the extremes of certain variables (e.g., highest and lowest strengths of a drug).
Matrixing: Testing a subset of total samples, with the assumption that results apply to the entire batch.
ICH Q1E provides guidance on the statistical evaluation of stability data, enabling manufacturers to establish accurate retest periods or shelf life. This guideline emphasizes trending analysis and statistical modeling to detect variability and predict long-term stability.
Biotechnological and biological products pose unique stability challenges due to their molecular complexity and sensitivity to environmental factors. ICH Q5C provides recommendations specific to these products, including:
Monitoring susceptibility to temperature, oxidation, and light exposure. Evaluating critical quality attributes such as protein integrity, aggregation, and activity. Assessing packaging interactions, particularly for products stored in polymeric containers.
The adoption of ICH guidelines by regulatory authorities in Europe, the United States, Japan, and beyond has facilitated a global approach to stability testing. This harmonization ensures that pharmaceutical companies can align their practices with international standards, reducing duplication of efforts and expediting market access.