Stability research is the feedback of the quality of the preparation product, and it is the verification of the applicability of the product formulation process and packaging materials. It is the most important part of the entire pharmaceutical research. It will be the most indispensable part of the entire drug development cycle. Stability test research is the basic content of drug quality control research and is closely related to the establishment of drug standards. There are many things to talk about in stability research. Next, let’s briefly talk about those things about the stability of preparations.
First of all, we need to know what a stability survey is and what is the purpose of the survey? What conditions need to be examined? How much sample volume is needed?
The purpose of the stability test is to investigate the law of changes in the formulation over time under the influence of temperature, humidity, and light, to provide a scientific basis for the production, packaging, storage, and transportation conditions of the drug, and to establish the validity period of the drug through the test.
(1) Stability test includes influencing factor test, accelerated test and long-term test. The influencing factor test was conducted with 1 batch of pharmaceutical preparations. The accelerated test and long-term test require 3 batches of test products.
Influencing factors: Under more severe conditions than the accelerated test. Its purpose is to explore the inherent stability of the drug, understand the factors that affect its stability, possible degradation pathways and degradation products, and provide a scientific basis for the preparation production process, packaging, storage conditions and establishment of degradation product analysis methods.
Under normal circumstances, high temperature conditions of 60°C (40°C as an alternative), high humidity conditions of RH92.5% (RH75% as an alternative), and light conditions (5000 Lux) will be investigated. The inspection time points are 5, 10, and 30 days. Focus on changes in content, related substances, and dissolution behavior. Pay attention to degradation products and provide important basis for packaging form and process.
Accelerated test: Explore the stability of the drug by accelerating the chemical or physical changes of the drug, and provide necessary information for preparation design, packaging, transportation, and storage. Place it for 6 months at a temperature of 40°C and RH75%. The equipment used should be able to control the temperature ±2°C, the relative humidity ±5%, and be able to monitor the real temperature and humidity. Samples were taken at the end of the first month, two months, three months, and six months of the test period, and the tests were conducted according to the key stability inspection items.
Long-term test: It is carried out under conditions close to the actual storage of the drug, and its purpose is to provide a basis for formulating the validity period of the drug. The test product requires 3 batches, commercially available packaging, placed under the conditions of temperature 25℃±2℃, relative humidity 60%±5%, sampling once every 3 months, respectively at 0 months, 3 months, and 6 Months, 9 months, and 12 months are tested according to the key stability inspection items. It is still necessary to continue the inspection after 12 months, and take samples for testing at 18 months, 24 months, and 36 months. Compare the result with month 0, and use the actual stability data to determine the expiration date of the drug.
(2) The test product of the pharmaceutical preparation should be the product of the scale-up test, and the prescription and production process should be consistent with the mass production. For pharmaceutical preparations such as tablets and capsules, the scale of each batch of scale-up test should be at least 10,000 preparation units. For large-volume packaged preparations such as intravenous infusions, the number of scale-ups in each batch should be at least 10 times the total required for each test. The required quantity of special varieties and special dosage forms shall be determined separately according to the situation.
(3) The quality standards of the test products should be consistent with those used in pre-clinical research, clinical trials and mass production.
(4) The packaging of the test product used in the accelerated test and the long-term test should be consistent with the marketed product.
(5) To study drug stability, it is necessary to adopt specific, accurate, precise, and sensitive drug analysis methods and related substances (including degradation products and other products generated by changes) inspection methods, and verify the methods to ensure Reliability of drug stability test results. In the stability test, attention should be paid to the inspection of degradation products.
(6) Since the number of scale-up tests is smaller than that of mass production, the applicant should undertake that after obtaining approval, when transferring from scale-up tests to mass production, accelerated tests are still required for the three batches of products that have passed the production verification initially. And long-term stability test.
Stability research is a long process, and the stability test focuses on the degradation products. The stability of a drug specifically refers to its ability to maintain the same physical and chemical properties and biological properties. If the stability of the drug is poor and the quality changes due to component degradation, not only may the efficacy of the drug be reduced, but the generated impurities may also have obvious toxic and side effects, which will affect the safety and effectiveness of the drug. Therefore, the purpose of the drug stability test is to investigate the law of drug changes over time under the influence of factors such as temperature, humidity, light, etc., to provide a scientific basis for the production, packaging, storage, and transportation conditions of the drug, and to establish the validity period of the drug through the test. To ensure the safety and effectiveness of medication.
In the stability test investigation, the “significant change” of the API means that the results of the quality inspection have not met the requirements of the limits specified by the drug standards.
① The content has changed more than 5% from its initial value, or it does not meet the standard limit when using biological or non-investment methods to detect the potency.
② Any degradation product exceeds its standard limit.
③ The appearance, physical properties, and functional inspections do not meet the limits of the corresponding drug standards; however, changes in the physical properties under accelerated conditions can be excluded (such as the softening of suppositories, the melting of emulsions).
④The pH does not meet the standard limit.
⑤The dissolution rate of 12 dosage units does not meet the standard limit. The design idea of the stability experiment, the ideal situation is that the drug remains stable in each safety experiment, clinical trial evaluation, formulation research and stability experiment. All process activities must be fully monitored and recorded as detailed as possible to maintain the validity and logic of information records, so that stability conclusions can be obtained based on data.
In the process of stability investigation, special attention should be paid to the stability of the crystal form, to observe the stability of the crystal form material state to high temperature, high humidity, and light conditions; the pressure method can be used to investigate the stability of the crystal form material state to pressure, and observe Whether the phenomenon of crystal conversion has occurred.
The methods used are XRD, DSC, IR and so on. Quality comes from design. Stability is a complex experiment. To be successful, a good design plan is essential, including sample batches, batch sizes, conditions, testing methods, sampling time, instrument verification, drafting, review, and approval , Result summary, result analysis and evaluation, etc., should be fully considered, otherwise it is very likely that the experiment will encounter setbacks or failures due to insufficient consideration. The goal of stability investigation is to produce qualified samples, which can maintain the quality of medicines before being used by patients.
During transportation, the product will not degrade in quality. How to improve stability is the ultimate goal of our experiment. How to improve stability?
①Choose appropriate excipients. Excipients are the soul of the formulation and play a decisive role in product stability.
②Choose the appropriate packaging material, which can change the influence of the drug on factors such as humidity, heat and light.
③ Increasing functional auxiliary materials or measures, such as antioxidants, nitrogen filling, etc. can prevent the degradation of the bulk drug or the main drug in the preparation.
Stability research is a long and complicated process. It is very important to understand the stable and unstable characteristics, influencing conditions, and degradation laws of drugs, which need to be continuously summarized and improved in the practice of specific projects.
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