Stability Studies of Bulk Drugs or Preparations

Stability research runs through the entire stage of drug research and development. This article mainly outlines the general principles and precautions in the drug stability research process from the perspectives of new/generic APIs and the stability of new/generic formulations. effect.

The origin of the storage conditions of the stability test

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

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: Humidity and heat 30°C/65%RH

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

Because the three regions of the International Conference on Coordination of Technical Requirements for the Registration of Human Drugs (ICH) only include climate zone I and climate zone II, the long-term test storage conditions were set as 25 in the stability research guidelines coordinated in October 1993. °C±2°C/60%RH±5%RH; later, because the products of pharmaceutical manufacturers in ICH countries/regions are generally on the market in countries or regions with multiple climates around the world, ICH revised the stability study in February 2003 The guiding principle (Q1A/R2) The storage conditions for medium and long-term tests are 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.

Types of stability test

(1) Test of influencing factors

The influencing factor test mainly includes investigating the stability of the drug substance or preparation to light, humidity, heat, acid, alkali, oxidation, etc., and it is necessary to fully understand its sensitivity to light, humidity, heat, acid, alkali, oxidation, etc. As well as possible degradation pathways and degradation products produced, and provide reference information for the selection of packaging materials.

(2) Accelerated test

The accelerated test is to investigate the stability of the drug substance or preparation under long-term storage temperature and humidity conditions, and provide a basis for the formulation process design and whether it can still maintain stable quality if it deviates from the actual storage conditions. According to the test results, it is determined whether intermediate Stability test under conditions and determine the storage conditions for long-term testing.

(3) Long-term test

Investigate the stability of the drug substance or preparation under the proposed storage conditions, and provide data support for confirming the packaging, storage conditions, and expiration date/re-inspection period. In addition, for the preparations that are used for immediate use, or the preparations that have a certain expiration date after opening the multi-dose package, the compatibility stability test or the stability test for use after opening should also be carried out according to their specific clinical use.

In short, all the principles of stability test design should be based on the purpose of the test. For example, the light test of the influencing factor test is to investigate the sensitivity of the drug substance or preparation to light. Usually, the sample with the package removed should be used for the test; if the test result shows that it is excessively degraded, the first thing to do is to eliminate the surrounding caused by the light Degradation caused by rising ambient temperature, so parallel samples protected from light can be added as a control 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 plus outer packaging) should be used for testing to investigate the protective effect of the packaging on light.

Requirements for stability test samples and considerations for the setting of inspection items

(1) Sample requirements

The samples for the stability test should be representative. The batch requirements for the test samples are shown in Table 1. The registration stability test of APIs and preparations should usually be carried out with samples of at least pilot scale batches. The synthesis route, prescription and production process should be consistent with the commercialized product or the key process steps of the commercialized product. The quality of the sample should be consistent with the quality of the commercial production product; the packaging container should be the same or similar to the commercial production product.

Table 1 Stability test sample batch requirements

(2) General principles for the selection of survey items

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

1) Raw material drug investigation project

The inspection items usually include: properties (appearance, optical rotation or specific rotation, etc.), pH, clarity and color of the solution, impurities (process impurities, degradation products, etc.), enantiomers, crystal forms, particle size, loss on drying /Moisture, content, etc. In addition, investigation items should be set up according to the specific conditions of the variety; such as the viscosity, molecular weight and molecular weight distribution of the polymer; bacterial endotoxin/pyrogen, sterility, and visible foreign matter of sterile APIs.

2) Preparation inspection project

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

3) Investigation of interaction between preparation and packaging material

The migration test and adsorption test of the compatibility study of the preparation and the packaging material or container should be investigated. It is usually through the accelerated and/or long-term stability test (note that the drug should be in full contact with the packaging material) testing indicators such as the content of the corresponding potential target extracts and functional excipients are added to obtain the extracts contained in the drug and the packaging materials to the drug. The adsorption data of the components; therefore, the stability test of high-risk preparations (inhalation preparations, injections, eye drops, etc.) should be 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 stereo configuration is investigated in the stability of the bulk drug, the stability of the stereo configuration in the preparation is no longer investigated. The root cause of this problem is that since sufficient research has been done on this problem in the API, there is no need to repeat the investigation in the formulation, especially when the result of the API shows that the stereo configuration is relatively stable. In fact, this question is the same as investigating related substances in preparations. As an important indicator that reflects quality changes, the inspection of related substances is a necessary quality control indicator in the investigation of the stability of raw materials and preparations. Similarly, stereo configuration is an important structural feature of chiral drugs, and stereoisomer impurities are also part of related substances. In the stability investigation, the necessary monitoring of stereoisomer impurities must be carried out to fully reflect the chiral drugs. The stability. In addition, even if the three-dimensional configuration of the drug substance has been proved to be stable under normal circumstances, it cannot be guaranteed in the presence of various excipients in the preparation and 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 three-dimensional configuration in the formulation.

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