Those Things About The Stability Study Of Raw Materials Or Preparations - Senieer

Part 1 – Origin of Stability Test Placement Conditions

According to the concept proposed by W.Grimm (DrugsMade in Germany, 28:196-202, 1985 and 29:39-47. 1986), the world is divided into 4 climate zones according to the annual climate conditions.

Climate zone Ⅰ: temperate zone 21°C/45%RH

Climate Zone Ⅱ: Subtropical 25°C/60%RH

Climate zone Ⅲ: dry heat 30°C/35%RH

Climate zone IVA: hot and humid 30°C/65%RH

Climate zone IVB: very hot and humid 30°C/75%RH

Since the three regions of the International Conference on Harmonization of Technical Requirements for Registration of Drugs for Human Use (ICH) only include climatic zone I and climatic zone II, the long-term test placement condition was set at 25 in the coordinated stability study guidelines in October 1993. °C±2°C/60%RH±5%RH; ICH revised the stability study in February 2003 because the products of pharmaceutical manufacturers in ICH countries/regions are generally listed in countries or regions with various climates around the world The storage conditions for long-term tests in the guidelines (Q1A/R2) were adjusted from 25°C±2°C/60%RH±5%RH to 25°C±2°C/60%RH±5%RH or 30° C±2°C /65%RH±5%RH.

Part 2 Types of Stability Tests

(1) Influencing Factor Test

Influencing factor tests mainly include investigating the stability of raw materials or preparations to light, humidity, heat, acid, alkali, oxidation, etc., and it is necessary to fully understand their sensitivity to light, humidity, heat, acid, alkali, oxidation, etc. As well as possible degradation pathways and degradation products, and provide reference information for the selection of packaging materials.

(2) Accelerated Test

Accelerated test is to investigate the stability of raw materials or preparations under the conditions of higher than long-term storage temperature and humidity, to provide a basis for the formulation process design, whether it can still maintain stable quality when deviated from the actual storage conditions, and to determine whether it is necessary to carry out intermediate tests according to the test results. Stability test under certain conditions and determine the placement conditions for long-term tests.

(3) Long-Term Test

Investigate the stability of raw materials or preparations under the proposed storage conditions, and provide data support for confirmation of packaging, storage conditions and expiration date/retest period. In addition, for ready-to-use preparations, or preparations with a certain period of use after multi-dose packaging is opened, compatibility stability tests or stability tests for use after opening should also be carried out according to their specific clinical use.

In summary, all principles of stability study design should be based on the purpose of the study. For example, the light test of the influence factor test is to investigate the sensitivity of the raw material or the preparation to light, and the sample that has been removed from the package should usually be used for the test; Degradation caused by rising ambient temperature, so parallel samples protected from light can be added as controls to eliminate the influence of other factors other than light exposure on the test results. In addition, samples with inner packaging (if necessary, even inner packaging and outer packaging) should be used for testing to investigate the protective effect of packaging on light.

Part 3 Requirements For Stability Test Samples And Considerations For Setting Up Inspection Items

(1) Sample Requirements

The samples for the stability test should be representative, and the stability test for the registration of raw materials and preparations should usually be carried out with at least pilot-scale batches of samples, and its synthetic route, prescription and production process should be consistent with those of commercially produced products or with those of commercially produced products. The key process steps of commercially produced products should be consistent, the quality of test samples should be consistent with the quality of commercially produced products; the packaging containers should be the same or similar to commercially produced products.

(2) General Principles For The Selection Of Inspection Projects

Inspection items should be able to reflect changes in product quality, that is, indicators that are prone to change during placement and may affect its quality, safety and/or effectiveness, and should cover physical, chemical, biological and microbiological characteristics . In addition, items such as moisture absorption weight gain or water loss should be added according to high humidity or high temperature/low humidity test conditions.

1) API Investigation Project

Inspection items usually include: properties (appearance, optical rotation or specific rotation, etc.), pH, solution clarity and color, impurities (process impurities, degradation products, etc.), enantiomers, crystal forms, particle sizes, and loss on drying /Moisture, content, etc. In addition, according to the specific conditions of the species, the inspection items should be set in a targeted manner; such as the viscosity, molecular weight and molecular weight distribution of polymers, etc.; bacterial endotoxin/pyrogen, sterility, visible foreign matter, etc. of sterile raw materials.

2) Preparation Investigation Project

The inspection items of preparations usually include: traits (appearance), impurities (degradation products, etc.), moisture and content, etc. In addition, indicators that can reflect its quality characteristics should also be set according to the characteristics of the dosage form; such as the dissolution rate of solid oral preparations, the release rate of sustained-release preparations, enteric-coated preparations, and transdermal patches, and the mist droplets (granules) of inhalation preparations. Distribution, encapsulation rate and leakage rate of liposomes, etc.

3) Investigation Of The Interaction Between Preparations And Packaging Materials

Migration tests and adsorption tests should be investigated for compatibility studies of preparations with packaging materials or containers. Usually by increasing the content of potential target leachables and functional excipients in the accelerated and/or long-term stability test (note that the drug should be in full contact with the packaging material), the effect of the leachables contained in the drug and the packaging material on the drug is obtained. The adsorption data of ingredients; therefore, the stability test of high-risk preparations (inhalation preparations, injections, eye drops, etc.) should be considered and designed together with the compatibility test of packaging materials or containers.

Finally, in the investigation of the stability of chiral drugs, there is another problem: after the stability of the three-dimensional configuration is investigated in the stability of the raw material drug, the stability of the three-dimensional configuration in the preparation is no longer investigated. The root cause of this problem is that since this problem has been fully studied in the drug substance, there is no need to repeat the investigation in the preparation, especially when the results of the drug substance show that the three-dimensional configuration is relatively stable. In fact, this problem is the same as investigating related substances in preparations. As an important index to reflect quality changes, the inspection of related substances is a necessary quality control index in the stability inspection of raw materials and preparations. Similarly, stereoconfiguration is an important structural feature of chiral drugs, and stereoisomer impurities are also part of related substances. Necessary monitoring of stereoisomer impurities must be carried out in stability studies to fully reflect chiral drugs. stability. In addition, even if it has been proved that the three-dimensional configuration of the drug substance is stable under normal circumstances, it cannot be guaranteed that in the presence of various excipients in the preparation, under specific preparation process conditions (acid, alkali, solution state, high temperature, etc.) , the three-dimensional configuration is still stable. Therefore, it is still necessary to monitor the stability of its stereo configuration in the formulation.

Part 4 Stability Study Of API

(1) Precautions For Influencing Factor Test

Constant humidity conditions can be achieved by using a constant temperature and humidity box or by placing a saturated saline solution in the lower part of a closed container. According to different humidity requirements, choose NaCl saturated solution (15.5°C~60°C, 75%±1%RH) or KNO3 saturated solution (25°C, 92.5%RH).

A proper amount of solid API samples should be placed in a suitable open container and placed in a dispersed manner, with a thickness not exceeding 3mm (the thickness of loose APIs can be slightly higher); if necessary, add a transparent cover for protection (such as volatilization, sublimation, etc.). Liquid APIs should be placed in chemically inert transparent containers.

(2) Precautions For Accelerated Test

According to research and development experience, it is expected that the accelerated test results may be close to the limit of significant changes, so it should be considered in the test design to increase the detection time point, such as 1.5 months, or 1, 2 months. If the long-term test is carried out under the condition of 25°C±2°C/60%RH±5%RH, if the mass of the accelerated test changes significantly at any time point during the 6-month period, the intermediate condition test should be carried out. The intermediate condition is 30°C±2°C/65%RH±5%RH, and the recommended inspection time is 12 months, which should include all inspection items, and the detection should include at least 4 time points of the initial and final time (such as 0, June, September, December).

If the API exceeds the quality standard, it means that the quality has changed significantly. If the storage condition of the long-term test is 30°C±2°C/65%RH±5%RH, no intermediate condition test is required. For APIs intended to be stored in cold storage (5°C±3°C), the accelerated test conditions are 25°C±2°C/60%RH±5%RH.

If the quality of the sample changes significantly under higher test conditions, the corresponding test conditions can be reduced; for example, the temperature is reduced from 50°C or 60°C to 40°C, and the humidity is reduced from 92.5%RH to 75%RH wait. New APIs or generic APIs should include at least 6 months of test data when applying for registration.

In addition, if the quality of the bulk drug intended to be refrigerated has changed significantly within the first 3 months of the accelerated test, the impact on the quality of the short-term deviation from the storage conditions on the label (such as during transportation or handling) should be dealt with Carry out evaluation; if necessary, another batch of samples can be tested for less than 3 months, and the frequency of sampling and testing can be increased; if the quality has changed significantly in the previous 3 months, the test can be terminated.

There are currently no accelerated storage conditions for cryopreserved (-20°C±5°C) APIs; investigators may take a batch of samples and store them at a slightly higher temperature (such as 5°C±3°C or 25°C) ± 2°C) conditions for an appropriate period of time to understand the impact of short-term deviation from the storage conditions on the label (such as during transportation or handling) on its quality. For raw materials intended to be stored below -20°C, accelerated tests may be carried out as appropriate by referring to raw materials for cryopreservation (-20°C±5°C).

(3) Long-Term Test Precautions

The long-term test condition for raw materials intended to be refrigerated is 5°C±3°C. For APIs to be stored in cold storage, if the quality of the accelerated test changes significantly between 3 months and 6 months, the validity period (retest period) should be determined based on the stability data of the actual investigation time under long-term test conditions. The long-term test condition of the bulk drug to be frozen is -20°C±5°C. For raw materials intended to be stored in a freezer, the validity period (retest period) should be determined according to the stability data of the actual investigation time under long-term storage conditions. For APIs intended to be stored below -20°C, tests should be carried out under the proposed storage conditions, and the validity period (retest period) should be determined according to the stability data of the actual investigation time under long-term test storage conditions.

Part 5 Preparation Stability Study

The stability study of the preparation should be designed based on the understanding of the characteristics of the raw material drug and the test results obtained from the stability study of the raw material drug and clinical prescription research, and should explain the possible changes during storage and the investigation of the stability test Project setup considerations. The stability study should examine items that are prone to change during storage and may affect the quality, safety and/or effectiveness of the preparation; the content should cover physical, chemical, biological and microbiological properties, as well as the content of stabilizers (such as , antioxidants, bacteriostats) and functional tests of preparations (such as quantitative drug delivery systems), etc.

(1) Preparation Stability Sample Batch Requirements

Preparation stability sample inspection batch requirements, if conditions permit, different batches of raw materials should be used in the production of different batches of preparations.

(2) Photostability Test

Any light source with an output similar to the D65/ID65 emission standard can be used, such as artificial daylight fluorescent lamps, xenon lamps, or metal halide lamps with visible-ultraviolet output. D65 is an internationally recognized outdoor sunlight standard [ISO10977 (1993)], and ID65 is equivalent to the indoor indirect sunlight standard; light emission below 320nm should be filtered out. Samples can also be exposed to both cool white fluorescent and near-UV light. Cool white fluorescent lamps should have a similar output power as specified in ISO10977 (1993). Near-ultraviolet fluorescent lamps should have a spectral range of 320-400nm, and have maximum emission energy at 350-370nm; ultraviolet light in the two bands of 320-360nm and 360-400nm should occupy a significant proportion.

At least one sample of the registered batch should be used for the test. If the test results show that the sample is stable or unstable to light, one batch of samples can be used for the test; if the research results of one batch of samples cannot confirm that it is stable or unstable to light, two additional batches should be tested samples for testing.

Some preparations have been proved that their inner packaging is completely protected from light, such as aluminum tubes or aluminum cans, and generally only the direct exposure test of the preparation is required. For some preparations, such as infusion solutions and skin creams, etc., the photostability test during use should also be proved. Researchers can design and conduct photostability tests at their own discretion according to the way the preparation is used.

(3) Long-Term And Accelerated Stability Tests

In general, thermal stability of formulations should be assessed under certain storage conditions (within an appropriate range). When necessary, investigate formulation sensitivity to humidity or potential solvent loss. The selected storage conditions and the length of the research time should fully consider the whole process of storage, transportation and use of the preparation.

When necessary, stability studies should be carried out on the preparations used after preparation or dilution to provide the basis for the preparation, storage conditions and expiration date after preparation or dilution on the instructions/label. At the beginning and end of the long-term test, the registration batch should be subjected to a stability test for the recommended service life after preparation and dilution, which is a part of the formal stability test.

In addition, it needs to be stated that a “significant change” in the quality of the preparation is defined as:

①The difference between the content and the initial value is 5%, or the potency does not meet the requirements when measured by biological or immunological methods.

② Any degradation product exceeds the limit specified in the validity period standard.

③ Appearance, physical properties, and functional tests (such as: color, phase separation, redispersibility, precipitation or aggregation, hardness, dosage per press) do not meet the requirements of the expiration date standard. Changes in some physical properties (e.g. softening of suppositories, melting of creams) may occur under accelerated test conditions;

In addition, for some dosage forms, “significant changes” also include:

①The pH value does not meet the requirements;

② The dissolution rate of 12 dosage units did not meet the requirements.

In addition, for preparations that are prone to phase separation, viscosity reduction, precipitation or aggregation, low temperature or freeze-thaw tests should also be considered, and the specific methods are as follows:

1) For Medicines Whose Temperature Range Is Above Freezing Point

The heat cycle test should include three cycles, and each cycle of the low temperature test is to place it at 2-8°C for 2 days, then place it at 40°C for 2 days, and take samples for testing.

2) For Medicines That May Be Exposed Below Freezing Point

The thermal cycle test should include three cycles. Each cycle of the freeze-thaw test is to place it at -20~-10°C for 2 days, and then place it at 40°C for 2 days, and take samples for testing.

3) For Inhalation Of Aerosols

The recommended thermal cycling experiment consists of three or four six-hour cycles in one day at temperatures between subfreezing and 40°C (75-85%RH) for a period of six weeks.

4) For Frozen Medicines

The drug should be investigated for its stability during accelerated melting in a microwave oven or in a hot water bath, unless the labeling specifically prohibits doing so. If verified, other methods can also be used for investigation.

(4) Stability Test Of Formulations Packaged In Non-Permeable Or Semi-Permeable Containers

For pharmaceutical preparations packaged in impermeable containers, sensitivity to humidity or possible loss of solvent may not be considered; since impermeable containers provide a permanent barrier against moisture and passage of solvents. Therefore, stability studies of formulations packaged in impermeable containers can be performed at any humidity.

For aqueous preparations packaged in semi-permeable containers, in addition to evaluating the physical, chemical, biological and microbiological stability of the preparation, its potential water loss should also be evaluated. The water loss test is to place the preparation sample under the low relative humidity conditions listed in the table below to prove that it can be placed in a low relative humidity environment.

For preparations packaged in semi-permeable containers, stored at 40°C and no more than 25% RH for 3 months, if the water loss is 5% different from the initial value, it is considered to have a significant change. However, for small-volume (≤1mL) or single-dose packaged preparations, it is acceptable to store them for 3 months under the conditions of 40°C and no more than 25% RH, and a water loss of 5% or more is acceptable.

Another method can be used to conduct water loss studies under relative humidity conditions (including long-term tests and accelerated tests). That is, the stability test is carried out under high humidity conditions, and then the water loss rate at the reference relative humidity is calculated by calculation. For preparations packed in specific packaging containers, sizes, and contents, the method for calculating their water loss rate at reference relative humidity: use the water loss rate measured at the same temperature and measured relative humidity and the water loss rate in the table below The ratio of water loss rate is multiplied. The premise is that it should be able to prove that there is a linear relationship between relative humidity and water loss rate measured during storage. For example, to calculate the water loss rate at 40°C and up to 25% RH, multiply the water loss rate measured at 75% RH by 3 (the ratio of the corresponding water loss rates).

(5) Stability Test Of Refrigerated And Frozen Preparations

If the preparation to be refrigerated is packaged in a semi-permeable container, a low-humidity test under appropriate temperature conditions should also be carried out to evaluate its water loss. For preparations intended to be stored in cold storage, if the quality of the preparation has significant changes within the first 3 months of the accelerated test, the impact of short-term deviation from the storage conditions on the label (such as during transportation or handling) on its quality should be evaluated; If necessary, a batch of preparation samples can be tested for less than 3 months, and the frequency of sampling and testing can be increased; if the quality has changed significantly in the first 3 months, the test can be terminated, and it is not necessary to continue to 6 months.

For preparations intended for frozen storage, the validity period should be determined according to the data of the actual test time under long-term storage conditions. Although the accelerated test conditions for preparations intended for refrigerated storage are not specified, a batch of samples should be tested for an appropriate time at a slightly higher temperature (such as: 5°C±3°C or 25°C±2°C) to Understand the impact of short-term deviations from the storage conditions on the instructions/labels for the quality of the preparation.

Part 6 Stability Result Analysis

Statistical analysis of quantitative indicators that may change over time (usually the content of active ingredients, levels of degradation products, and other relevant quality attributes, etc.) by comparing the 95% one-sided confidence limit of the mean curve with the acceptance criteria The time point corresponding to the intersection point of , is used as the validity period (re-inspection period). If the analysis results show that the variation between batches is small (statistical test is performed on the slope and intercept of the regression curve of each batch of samples), that is, the P value > 0.25 (no significant difference), it is best to combine the data for overall analysis and evaluation . If the variation between batches is large (P value ≤ 0.25), they cannot be combined for analysis, and the validity period (retest period) should be determined according to the time of the shortest batch.

In principle, the validity period (retest period) of the API should be determined according to the stability data of the actual investigation time under long-term test conditions. If it is proved to be reasonable, the validity period (retest period) beyond the actual observation time range can also be obtained by limited extrapolation based on the actual measurement data obtained under long-term test conditions when registering and applying. The extrapolation should be based on a comprehensive and accurate analysis of the degradation mechanism, including the results of accelerated tests, a good fit of the mathematical model and the obtained supporting stability data of the batch scale, etc.; The same degradation relationship as the existing data also exists outside the observation range”.

Part 7 Determination of Drug Expiry Date

(1) Judgment Of Stability Tests Of Samples Of Different Scales

When applying for drug registration, three batches of accelerated test and long-term sample test data of the pilot test or above-scale samples of the packaging to be marketed should be provided. The accelerated test is 6 months, and the long-term test is at least 12 months. Provide technical support on storage conditions and preliminary expiration dates of drugs. After the drug is on the market, continue to conduct long-term stability tests on production-scale samples to determine the actual validity period of the product.

(2) Judgment Of Changes In Appearance Traits

The situation we often encounter is that the appearance properties have changed, but the content of the main drug and/or degradation products have not changed, which indicates that there is no loss of active ingredients in the drug, if the change is within the range specified in the quality standards for appearance properties, and If it does not affect the quality and curative effect of the product, it shall be indicated on the label: “The drug may undergo some changes in appearance during storage, but these changes will not affect the quality and curative effect of the product.”

If the appearance of the product changes and exceeds the limit specified in the quality standard, for example: the color changes from slightly yellow to yellow, the upper limit of the color is yellow, and it can be determined (using a color chart as much as possible), It should be judged that the drug is invalid. That is to say, judging whether the appearance of the drug has changed is mainly based on whether the quality of the drug has changed, as well as the description and scope of the appearance of the drug in the quality standard.

(3) Judgment Of Changes In Physical And Chemical Properties

The physical and chemical properties mentioned here refer to the physical and chemical properties of the drug, usually including physical and chemical constants, acidity and alkalinity (pH value), friability, disintegration time limit, melting time limit, etc. So far, the mathematical relationship between reaction kinetics and physical and chemical properties has not been found, so it is impossible to use reaction kinetics to calculate the changes in the physical and chemical properties of drugs. At present, it is believed that the test items that do not change in the accelerated test will not change under the condition of long-term sample retention. In addition, determining limits for changes in physicochemical properties is also a very difficult task, especially if we do not know whether these changes in physicochemical properties have an impact on the bioavailability of the drug. In summary, judging whether the physical and chemical properties have changed is mainly based on whether the quality of the drug has changed, as well as the limits specified in the quality standards and the relevant provisions of the general principles of the Pharmacopoeia.

(4) Judgment Of Changes In Chemical Properties

In most cases, the content of the main drug can be calculated by the method of reaction kinetics based on the results of the accelerated test, and it is generally accepted that the content of the main drug should not be lower than 90% of the labeled amount during the entire validity period. , the 10% content fluctuation range is only applicable to the situation where the safety of the degradation product of the main drug is acceptable.

Reaction kinetics is a powerful tool for estimating drug expiration dates. Regardless of whether the calculated data comes from the accelerated test or the long-term sample test, the reaction kinetic type of the sample (zero order, first order, second order, etc.) must be determined according to the chart of C=f(t); then, according to different climate zones The temperature (21°C, 31°C and 41°C, 4°C in some cases) is used to calculate the content of the main drug. Draw a straight line at 90% of the drug content, and the intersection of the curve and the straight line is the estimated validity period of the drug in different climate zones.

If there is no corresponding mathematical relationship between the temperature and the content of the main drug, or the change of drug properties is time-dependent, only the regression analysis of the stability test data can be used to determine the expiration date of the product, but the expiration date of the drug cannot be calculated. At this time, the time and results of the long-term retention sample test are the only basis for determining the validity period of the product.

(5) Judgment Of Changes In Microbial Properties

For non-sterile preparations, microorganisms should be controlled. For products without preservatives in the prescription, the determination of whether the microbial properties have changed is mainly based on the relevant provisions of the general principles of the Pharmacopoeia. For products containing preservatives in the prescription, the content of preservatives should be controlled to ensure that they can function within the validity period of the product; the change of preservative content is not limited by 90% of the labeled amount. For sterile preparations, container sealing challenge test should be carried out to ensure that the product meets the sterility requirements within the validity period. However, microbial properties cannot be extrapolated from the research results of 1-2 batches of samples, because there are many factors affecting microorganisms: such as active ingredients, excipients, production environment and packaging, etc. can all affect the microbial properties of products, which should be paid special attention to.

Part 8 Abbreviated Stability Study Design

There are two types of stability study designs: complete experimental design and abbreviated experimental design. The full experimental design refers to the investigation of all batches of samples at all time points, and the abbreviated experimental design refers to the inspection of all batches of samples not at all time points. Commonly used abbreviated experimental designs are the bracket method and the matrix method.

First of all, it should be clear that not all stability tests can adopt abbreviated experimental design, and the use of abbreviated experimental design is conditional, and it can replace the complete experimental design only under the conditions of some similar factors. Sufficient analysis and evaluation should be carried out before adopting the abbreviated experimental design, but even if adequate analysis and evaluation are carried out, the risk of adopting the abbreviated experimental design is assumed, that is, the experimental results based on the abbreviated design may obtain a validity period shorter than that of the full design .

So, when can you use an abbreviated experimental design? It should be said that abbreviated experimental designs can be used for some preparations, and abbreviated experimental designs are generally not suitable for raw materials. Whether to use the bracket method or the matrix method should be based on careful consideration and scientific judgment, because the applicable situations of the two are different.

8.1 Bracketing

1) Bracket Definition

Bracketing is an abbreviated approach to the design of a stability program; it only conducts complete testing at all time points for certain samples at extreme points of the design factors (eg, strength, pack size, etc.). This design assumes that the stability of the extreme samples is representative of the stability of the intermediate samples. When testing a series of strengths, if the composition of the strengths is the same or very similar (compression of similar granules into tablets of different series of capsules with different filling volumes), the bracket method can be used to design. The bracketing method is also applicable to a series of preparations packed in containers of different sizes or containers of the same size but with different contents.

2) Scope Of Application Of The Bracket Method

Bracketing method can be used in the stability test design of multiple strength samples with the same or similar formulations, examples include but not limited to:

a. Capsules of different specifications made by filling the same mixed granules or powder in different types of empty capsules;

b. Tablets of different specifications compressed into different weights of the same mixed granules or powder;

c. Oral solutions of different specifications that differ only in coloring agents or flavoring agents, etc. The bracket method can also be used for various specifications in which the relative amounts of main drug and excipients vary in the prescription, but it cannot be used for different specifications with different excipients.

Brackets can be used for the same container with different sizes or the same container with different contents. When designing brackets for different container sizes and capacities, it should be made clear that the largest and smallest containers represent the extremes of the packaging. Because, different containers may affect the stability of the product.

3) Risks Of Bracket Design

If the extreme case is not selected properly, or the test results of the extreme case cannot represent the intermediate case, the stability of the intermediate case will be considered to be consistent with the most unstable extreme case, that is, the validity period of the intermediate case cannot exceed the most unstable validity period in extreme cases.

8.2 Matrix method (Matrixing)

1) Definition Of Matrix Method

The matrix method is a simple design method of the stability test program; at the specified sampling time point, only one group needs to be taken from the total number of samples of all factor combinations for determination; at the subsequent sampling time point, all factors are measured Another set of samples from the total sample of factor combinations. This design assumes that the stability of each set of samples being assayed at a particular time point is representative. The design of the matrix method should consider various differences between samples of the same preparation; for example, different batches, different specifications, packaging containers of the same material and different sizes, and in some cases, the packaging containers may be different. Each storage condition should be set separately in its own matrix design. A matrix design cannot be performed on the experimental items. However, after verification, another matrix design scheme can be selected for different test items.

2) Scope Of Application Of Matrix Method

The matrix method can be used in the stability test design of samples of different specifications with the same or similar formulations, examples include but are not limited to:

a. Capsules of different sizes made from the same powder mixture with different filling quantities;

b. Tablets of different specifications compressed from unequal amounts of the same kind of granules;

c. Oral solutions differing only in certain minor excipients (such as coloring or flavoring agents) in the prescription. The matrix method can also be used for multiple specifications with relative changes in the main drug and excipients in the prescription, multiple specifications for different excipients, and different packaging materials. If the matrix method is designed for two packaging materials, the product must not be affected by air, humidity and light.

3) Risks Of Matrix Method

In general, matrix designs (except point-in-time matrix designs) may yield shorter validity periods than full designs. In addition, matrix designs do not have sufficient power to identify main or interactive effects, resulting in erroneous data from different design factors for estimating shelf life. Or the determination factors are reduced too much, so that the test data cannot determine the validity period of the product.

Only the time-point matrix design has the similar ability to detect the difference in the rate of change between the factors as the full design, so it can determine a reliable validity period. This feature is based on the assumption of linearity, and the full determination of all factors at the start and end points.

Part 9 Summary

Stability is a characteristic that drugs must have to meet the circulation and clinical use, and it is also an important content of drug quality control research. The researcher should design the stability test according to the purpose of the research, and analyze and evaluate the test results, paying special attention to the batch size of the registered batch samples and the confidence of the research results in establishing the storage conditions and expiration date (retest period) of commercially produced products .