Relevant explanations on the experimental design of stability studies

The experimental design of stability study should be carried out according to different research purposes, combined with the physical and chemical properties of the drug substance, the characteristics of the dosage form, and the specific prescription and process conditions. Next, we will explain the specific sections by section.

The batch and scale of the sample

Usually influencing factors can be tested with a batch of small-scale samples. Accelerated tests and long-term tests should be carried out with 3 batches of samples above the pilot scale, such as tablets and capsules. Each batch of scaled-up test scale should be at least 10,000 tablets and 10,000 capsules. For large-volume packaged preparations such as intravenous infusions, the number of scaled-up batches should be at least 10 times the total required for each test.

Packaging and placement conditions

1. Packaging materials

Types of packaging materials The currently commonly used pharmaceutical packaging materials can be divided into metal, rubber, glass, plastic, etc. according to their materials.

(1) Metal Metal packaging materials have good barrier properties to light, air and moisture, and have a good protective effect on drugs, especially suitable for drugs with poor chemical stability. In order to ensure the stability of the preparation, it is required that the coating metal does not chemically react with the drug, and is firmly covered, without micropores, cracks, etc.

(2) Rubber Rubber has the advantages of good elasticity, light-shielding and sealing, and is widely used to make bottle stoppers, gaskets, drippers and so on. Commonly used rubber packaging materials include chlorinated butyl rubber stoppers for injection, synthetic polyisoprene gaskets for pharmaceuticals, and silicone rubber gaskets for oral liquids. At present, chlorobutyl rubber is mostly used in medicine packaging.

(3) Glass The glass container has the advantages of stable physical and chemical properties, not easy to react with chemical drugs, air permeability, low moisture permeability, etc., and is one of the most stable materials with chemical properties. It is widely used in the packaging of dosage forms such as injections, topical preparations, and oral solutions. According to the Chinese Pharmacopoeia, according to chemical composition and performance classification, medicinal glass can be divided into high borosilicate glass, medium borosilicate glass, low silica glass and soda lime glass. The water resistance of the particles at 121°C and the water resistance of the inner surface are shown in the table below.

Pharmaceutical manufacturers should select suitable medicinal glass containers based on the physical and chemical properties of the drugs and the results of the compatibility test. For biological products, partial acid, partial alkali, and pH-sensitive injections, a medicinal glass container (or other suitable packaging materials) with a water resistance of 121°C granular method of grade 1 and an inner surface of HC1 grade of water resistance should be selected.

The medicinal glass container should be clean and transparent to facilitate the inspection of visible foreign bodies, impurities and deterioration of the drug solution. Generally, colorless glass should be used for drugs, but for light-sensitive preparations, brown transparent glass packaging can be selected. Its wavelength is 290~450nm The light has good shading performance, and as the thickness of the glass increases, the light transmittance decreases, but it should be noted that the iron oxide contained in the brown glass is easy to fall off into the preparation, and it will catalyze the oxidation reaction.

Pharmaceutical glass should have good thermal stability to ensure that it will not break during high-temperature sterilization or freeze-drying; it should have a certain degree of chemical stability, and it should not exchange substances with drugs that affect the quality of drugs. If the glass does not peel off or fail Causes changes in the pH value of the liquid medicine, etc.

The study of compatibility between glass containers and drugs should mainly focus on the migration of metal ions in glass components to the drug solution. The leaching amount of harmful substances shall not exceed the safe value, and the leaching amount of various ions shall not affect the quality of the medicine. For example, the leaching amount of alkali metal ions shall not cause the pH value of the chemical solution to change. In addition, the buffers, organic acid salts, complexing agent disodium edetate, etc. in the raw materials and formulations of the drug will also have an adverse effect on the tolerance of the inner surface of the glass container, so the compatibility study should be comprehensively carried out. Survey.

(4) Plastic has the advantages of good flexibility, elasticity and tear resistance, strong impact resistance, not easy to break, easy to carry, no need to add air during the infusion process and avoid air pollution of the liquid medicine. It is widely used in the packaging of tablets, capsules, injections, eye drops and other dosage forms. It is the main material in modern medical packaging. Commonly used varieties include polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET) and so on. Its packaging applications mainly include medicinal low-density polyethylene eye drops bottles, oral solid medicinal high-density polyethylene bottles, polypropylene infusion bottles, etc.

Its impact on the stability of the formulation mainly has three aspects:

① Penetration. Outside air, moisture, oxygen, etc. can enter the inside of the package through the plastic cover, and the internal gas, moisture, solution, etc. can also enter the plastic, so the plastic package is easy to cause the oxygen of the drug; relatively, the volatile oil escapes , Moisture absorption, dehydration or even cracking of the emulsion and other physical and chemical changes.

② Leakage. Various additives are added to plastics. After packaging, the molecules of the additives will leak or move into the packaged preparation to cause contamination, which will affect the quality of the drug. Therefore, plastic materials are not suitable for drugs that require long-term storage, especially those that are chemically unstable. .

③ Adsorption. Plastic packaging containers have the effect of adsorbing drugs, which can cause a decrease in the content of the main drug and a decrease in the anti-corrosion ability, resulting in a change in the stability of the drug.

2. Compatibility of pharmaceutical packaging materials and drugs. The study on the compatibility of pharmaceutical packaging materials and drugs is the basis for selecting pharmaceutical packaging materials. When selecting pharmaceutical packaging materials for pharmaceutical preparations, the compatibility of pharmaceutical packaging materials and drugs must be studied. The research results are directly related to the stability of new Chinese medicines. The compatibility test of the drug packaging material and the drug should consider the risk level of the dosage form and the possibility of interaction between the drug and the drug packaging material (see the table below).

Generally, it should include the following parts:

① Research on the impact of pharmaceutical packaging materials on the quality of drugs, including the extraction, migration research and extraction of pharmaceutical packaging materials (such as adhesives, additives, small molecular compounds, and decomposition products produced during processing and use, etc.), and the results of migration research Toxicological assessment, the possibility of a reaction between the drug and the drug packaging material, the absorption or absorption of the active ingredients or functional excipients of the drug by the drug packaging material, the overflow of the contents, and the penetration of foreign objects;

② Research on the effects of drugs on drug packaging materials, to investigate the changes in the integrity, functionality and quality of the drug packaging materials after packaging the drugs, such as the peeling of glass containers, deformation of rubber plugs, etc.;

③ The quality change (drug stability) of the drug after packaging the preparation, including the change of the accelerated test and the long-term test drug quality.

3. Requirements for packaging materials in the stability study of traditional Chinese medicines. The packaging materials and packaging conditions used in the accelerated and long-term tests should be consistent with the packaging to be marketed.

Determination of packaging materials: Generally, the packaging materials or containers are initially determined based on the test results of influencing factors, and then combined with the results of stability studies, materials with relatively long storage periods and whose drug quality and packaging materials are not affected are selected as packaging materials for the market. .

Requirements for suitable packaging materials: The long-term test and accelerated test results should show that there is no significant change in the results of each item at each inspection time point. For drug influencing factor tests, when the drug is tested under naked conditions, some items may change significantly, or even some items do not meet the requirements; and when the same drug is packaged for the same test, each sampling time point There should be no significant changes in the test results of each inspection project.

2. Placement conditions

The stability test is required to be carried out under certain conditions of temperature, humidity, light, etc. The setting of these placement conditions should fully consider the environmental factors that may be encountered during the storage, transportation and use of the drug. For example, according to the international climate zone, China is generally subtropical, and some areas are humid tropical. Therefore, the long-term test adopts a temperature of (25+2)℃, a relative humidity of 60%+10%, or a temperature of (30+2)℃, The relative humidity is 65% soil 5%; which conditions to choose can be determined according to the difference between the climate in southern and northern my country.

The temperature control, humidity control, light and other equipment used in the stability study should be able to better control and monitor the environmental conditions required by the test. For example, it should be able to control the temperature ±2°C, relative humidity ±5%, illuminance +500lx, etc. And can monitor the real temperature, humidity and illuminance.

Time point of inspection

Multiple time points need to be set in the stability study. The setting of the investigation time point should be based on the understanding of the physical and chemical properties of the drug and the trend of stability changes. For example, in long-term trials, the overall inspection time should cover the expected expiration date, and the setting of intermediate sampling points should consider the stability characteristics and dosage form characteristics of the drug. For drugs that are sensitive to certain environmental factors, the investigation time point should be appropriately increased.

investigation

Under normal circumstances, the survey items can be divided into physical stability, chemical stability and biological stability. Physical stability refers to the changes in the stability of the drug due to physical changes (appearance, smell, uniformity, dissolution, suspension, emulsification, etc.), such as changes in tablet hardness and disintegration; the porosity of suspensions , Changes in particle size; emulsification and demulsification of emulsions; stratification of ointments, etc.

Chemical stability refers to the stability change of the drug due to the influence of external factors or chemical reaction with other components in the preparation. The main chemical changes include oxidation, hydrolysis, reduction, photolysis, etc., such as esters, amides, etc. And glycosides and other drugs are prone to hydrolysis reaction. Biological stability refers to the changes in stability caused by the deterioration of medicines caused by microorganisms such as bacteria and molds, such as mildew and corrosion deterioration of some medicines that have not been sterilized. Among these three categories, chemical stability research is the most important and most common, and it is also the main aspect of stability research.

The investigation items (or indicators) of the stability study should be set according to the ingredients and/or preparation characteristics and quality requirements. The items that are easy to change during the drug storage period and may affect the quality, safety and effectiveness of the drug should be selected. In order to objectively and comprehensively evaluate the stability of the drug. Generally, the quality standards and the stability-related indicators in the “Chinese Pharmacopoeia” preparation general rules are the inspection items (see the table below).

When necessary, stability inspection indicators should be selected beyond the scope of the quality standard. For example, for drugs that may cause phase separation, viscosity reduction, precipitation or aggregation due to temperature changes, such as injections, soft capsules, etc., since the impact of temperature changes during transportation or use on quality needs to be considered, freezing and thawing needs to be increased. Test and other stability investigation.

In the stability study, if there is a significant change in the pharmaceutical preparation, such as a 5% change in the content determination, the properties, physical properties and functional tests of the special preparation (such as color, phase separation, hardness, etc.) exceed the standard requirements, and the pH If the dissolution or release of the preparation exceeds the standard, the conditions should be changed before the test.

Active ingredients and their preparations should be investigated for changes in related substances. The effective part and its preparation should pay attention to the changes of each component in its similar components. For compound preparations, attention should be paid to the selection of investigation items and the collection and analysis of the amount of information in the experiment. In order to determine the stability of the drug, it is meaningful to conduct a comparative study on the consistency of the components contained in the same batch at different sampling time points and different batches of samples.

Analytical method

Stability test research should use specific, accurate, precise, and sensitive analytical methods, and verify the methods to ensure the reliability of the stability test results.

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