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This paper is from Journal of China Pharmaceutical University, Vol. 51, No. 1, 2020, the research progress of compatibility between pharmaceutical injection and plastic packaging materials.
Abstract: taking plastic packaging materials as an example, the general principles of Pharmacopoeia and departmental guidelines related to the compatibility research of drugs and packaging materials at home and abroad were summarized, and further reference was made to relevant monographs and literatures. The research objectives and specific methods of extraction test and interaction research were summarized and discussed, and the existing problems and solutions in the current compatibility research were proposed, with a view to being relevant The research provides theoretical reference.
Key words: injection; plastic packaging material; compatibility; extraction test; extract
The packaging materials and containers that are in direct contact with drugs are an indispensable part of drugs, which plays an important role in ensuring the safety, stability and effectiveness of drugs. Plastics are widely used in pharmaceutical packaging materials because of their good barrier, high strength, transparent appearance and light weight. The plastic container materials commonly used for drug packaging mainly include polyethylene (PE), polypropylene (PP), polystyrene (PS), polycarbonate (PC), polyvinyl chloride (PVE), etc. the applicable dosage forms include tablets, capsules, injections, eye drops, etc. As a high-risk preparation, the packaging materials and containers play an important role in the quality control and sterility assurance in the whole life cycle of the injection. The common plastic packaging forms are: infusion bottles, multi-layer coextrusion film (bags), plastic (soft) bags, plastic ampoules and pre filled syringes. However, the quality of packaging materials and containers themselves will also have an important impact on the quality of injection. Although plastic containers are widely used in injection packaging materials, they are not as good as glass containers in terms of heat resistance and chemical stability. As injection packaging materials, in order to make the appearance of packaging materials more durable, plastics are often added with stability, lubrication and increase The chemical components of plastic and coloring may migrate into the injection to increase the impurities in the solution, the ink on the plastic package may also introduce benzene series into the injection during long-term storage and use, and some components in the solution (such as preservatives) may also be absorbed by the plastic, so as to reduce the main content and affect the stability and effectiveness of the injection Sex. Therefore, it is very important to strengthen the research standards of compatibility of drugs and packaging materials. In recent years, the research of compatibility has been a high concern of drug regulatory authorities.
1. Research code for compatibility of drug packaging materials at home and abroad
1.1 regulatory requirements of China on compatibility of injection plastic packaging materials
In 2002, the State Food and Drug Administration issued the guiding principles of drug packaging materials and drug compatibility test (ybb00142002), which initially determined the research content of the compatibility of packaging materials; in 2004, standardized the management of drug packaging materials, and the newly established state food and Drug Administration (SFDA) issued the measures for the management of packaging materials and containers in direct contact with drugs (Decree No. 13); in September 2012, for the study of compatibility of plastic packaging materials, SFDA issued the guiding principles of compatibility research technology of chemical injection and plastic packaging materials (Trial), which clarified the design ideas and basic requirements. In addition, Pharmacopoeia of the people's Republic of China: Part IV (2015 Edition) also includes the guiding principles for general requirements of pharmaceutical packaging materials (9621).
1.2 regulatory requirements for compatibility of injection plastic packaging materials in the United States
As early as May 1995, FDA issued the guiding principles for the sealing system of containers for packaging of human drugs and biological products, pointing out the requirements of dynamic drug production management specifications (CGMP), CPSC and USP for packaging containers, and the requirements for packaging containers in the registration materials of new drug clinical trial application (ind), including packaging group Qualification confirmation and quality control of parts.
1.3 EU regulations on compatibility of injection plastic packaging materials
In October 2003, the European Drug Evaluation Agency (EMEA) drafted the guidelines for plastic packaging materials in direct contact with drugs. The European Pharmacopoeia (EP) put forward in "materials and containers", including a series of provisions on plastic packaging materials and containers. In the compatibility test of drug packaging materials, the relevant standards for plastic packaging materials and containers and the amount of additives in them were formulated, providing a preliminary basis for determining whether the packaging materials meet the requirements.
2. Research methods of compatibility between pharmaceutical injection and plastic packaging materials
The basic idea of compatibility research is put forward in the guiding principle of compatibility research technology of chemical injection and plastic packaging materials (Trial) in China. Six steps in the process of compatibility research are described in detail. The compatibility test of injection and packaging materials includes extraction test, migration test and adsorption test.
2.1 extraction test
EMEA defines extraction test as a test method for extracting component samples under extreme conditions with a suitable solvent system to obtain the maximum amount of extractable packaging materials. Usp40-nf3540 provides five extraction methods of solvents, and specifies the extraction methods and extractable limits of three kinds of polyolefin plastic packaging materials. The Japanese Pharmacopoeia (jp17) also prescribes the method for the determination of extractable substances in plastic containers. In the Pharmacopoeia of China and relevant guidelines, there is no clear extraction test conditions and detection methods, but reference extraction solvents such as water for injection, 0.9% sodium chloride injection, pH3.5 buffer, ph8.0 buffer, 10% or 15% ethanol, etc. are given, and extraction conditions include heating, Soxhlet extraction, reflux or ultrasound, etc.
2.2 interaction study
In EMEA's guidelines for plastic packaging materials in direct contact with drugs and China's guidelines for compatibility research technology of chemical injection and plastic packaging materials (Trial), migration test and adsorption test are collectively referred to as interaction study. For injections, interaction tests are used to evaluate the functional properties of packaging materials to ensure that the quality of drugs or active ingredients does not change beyond the limit during placement.
2.2.1 migration test EMEA defines migration as the release of leachables from plastic packaging materials during use. The use process includes production, storage, transportation and administration. The packaging materials interact with the solution directly, and the extract enters the solution. Migration test is carried out after determining the extractable content of the packaging materials. It is necessary to select representative conditions to verify that no substance in the packaging materials will migrate into the drug to change its stability, effectiveness and safety. Migration tests are usually conducted in formal stability studies, including long-term and accelerated tests.
2.2.2 adsorption test refers to the combination of liquid medicine and packaging materials due to the physical and chemical properties of packaging materials or the chemical properties of active ingredients and other soluble substances. Adsorption test is to investigate whether the active ingredients or excipients will be adsorbed or immersed in the packaging materials, resulting in changes in the quality of the preparation. It is mainly aimed at trace, narrow therapeutic window, functional groups easily adsorbed with packaging materials in structure, and drugs containing trace functional excipients in the prescription. The adsorption test is usually carried out at the same time as the stability test to determine whether the packaging material has adsorption effect on the preparation by detecting the change of the main drug composition in the preparation. If necessary, the negative control group shall be set up, and the packaging materials (such as glass, etc.) which are generally considered not to adsorb the liquid medicine shall be selected as the control for parallel setting out and testing.
3. Problems and solutions in the study of compatibility of pharmaceutical injection and plastic packaging materials
Although Pharmacopoeia general rules and relevant guidelines have been formulated in various countries to promote the standardization of packaging material compatibility research, there are still some problems to be solved.
3.1 supervision of plastic packaging containers for pharmaceutical injection
First of all, it can be seen from the provisions of the codes of other countries that drug regulatory agencies in various countries not only control the content of compatibility of packaging materials, but also regulate the protection, safety and functionality of packaging materials. Developed countries and regions such as Europe, America and Japan have strict requirements on the quality control of packaging materials and containers, which is conducive to ensuring the quality of pharmaceutical preparations Therefore, we should strengthen the supervision of injection packaging materials.
Secondly, the role of packaging material manufacturers and pharmaceutical research and development enterprises in compatibility research is not specified in the relevant documents published in China. The author believes that packaging material manufacturers should be the main body of extraction test research, and relevant enterprises should actively select different types of solvents for comprehensive research and submit them as packaging material filing materials. The relevant research results can also be used as reference for pharmaceutical research and development enterprises, and provide preliminary judgment for packaging material selection, so as to avoid resources caused by repeated research conducted by different pharmaceutical research and development enterprises Waste, improve the efficiency of new drug research and development; at the same time, packaging material manufacturers should also take the initiative to provide users with the main additives in packaging materials, so that the preparation research and development enterprises can carry out targeted monitoring and control.
3.2 supervision of compatibility study of pharmaceutical injection and plastic packaging materials
At present, there is no clear and mature method for the compatibility research of packaging materials in China, which brings some troubles to the enterprises when they carry out the compatibility research of packaging materials. At the same time, it also challenges the new drug evaluation department to determine the rationality of the research methods selected in different application materials. Therefore, the introduction of practical technical guidelines for packaging material compatibility research as soon as possible is conducive to unify the evaluation scale, reduce the cost of new drug research and development, and accelerate the process of drug packaging material compatibility research in China.
In addition, there are no clear regulations for the element impurities that must be paid attention to in the compatibility study of plastic packaging materials. By referring to national regulatory documents, guidelines and relevant literature, in addition to class 1 and class 2A element impurities specified in ICH Q3D, Pharmacopoeia of various countries also specifies other elements that should be paid attention to in different packaging materials (Table 1). The author found that, due to the lack of clear requirements in China, most enterprises or research institutions will choose as many elements and impurities as possible to carry out compatibility research, so as to avoid insufficient research and be required by the drug review department for supplementary research. Therefore, in order to standardize the research content, it is necessary to unify the research scope, research ideas, content calculation methods and so on.
Cited in this paper: Zhang Yue, sun Chunmeng, Tu Jiasheng. Research progress on compatibility of pharmaceutical injection and plastic packaging materials [J]. Journal of China Pharmaceutical University, 2020,51 (1): 19-23
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Xie Peng
Final judge: Gu Kai, Chen Ling, Zou Xu