Establishment And Validation Of Sterility Assurance On Non-terminal Sterilized Sterile API

During the manufacturing of sterile medicinal products, the manufacturers always focus on avoiding microbial contamination, endotoxin contamination and particulate contamination. Sterilization should not only kill or eliminate all microbial propagule and spore to improve the safety and effectiveness of medicinal products, but also should ensure the stability and clinical effect of the medicinal products. Therefore, it is very important to choose appropriate sterilization method to ensure the product quality.The company where I am working is a drug manufacturing enterprise focusing on non-terminal sterilized sterile API. With the implementation of Good Manufacturing Practice (2010), as well as in line with the international high-end markets such as EU GMP and FDA cGMP, there is need to establish a sterility assurance system on non-terminal sterilized sterile API and conduct corresponding validations.1. Technological characters of non-terminal sterilized sterile APIOn the basis of the process flow for the non-terminal sterilized sterile API in my company, we can make a conclusion that the basic process flow is crude after dissolving entering into the crystallizing tank for crystallization through aseptic filtration, then conducting filtration, washing, drying, milling and packaging. During the manufacturing after aseptic filtration, aseptic processing is adopted which has high requirement on air conditioning purification system, sterilization system and aseptic processing operators. The sterile product can enter human blood directly, microbial, endotoxin and particulate contamination should be controlled during the whole aseptic processing. As sterilization can not be conducted on semi-finished products, and this kind of process has pollution risk due to exposure during manufacturing, therefore, it should pay more attention to the risk due to failure of aseptic processing.2. Major risk of non-terminal sterilized sterile APIThe risk of sterility assurance of non-terminal sterilized sterile API mainly comes from control of microbial contamination level before sterilization, reliability of sterilization process, integrity of container closure, aseptic process simulation validation and sterility assurance management system. This thesis, on the basis of the enterprise’s actual condition and my working experience, and according to the implementation guidance on GMP, makes an analysis on the major risks of non-terminal sterilization and establishes control measures on the risks.3. Validation on sterility assurance of non-terminal sterilized sterile APIValidation is the basic requirement in GMP, and is a part of quality assurance system in drug manufacturers. Validation can ensure the product quality in drug manufacturers meet requirement, so as to protect the life safety of patients. The definition of validation in China GMP (2010) is a series of activities that an operation procedure (method), process or system will produce a result meeting predetermined acceptance criteria. During the development of drug manufacturers, validation is a milestone of the innovative development of GMP, is the necessary basis for the continuous and stable operation of quality management system, and is a higher quality assurance method. The role and function of validation in GMP is meeting requirement of regulations to decrease risk of patients, optimizing manufacturing process to ensure drug quality, and reducing quality cost to improve economic benefit.As to the non-terminal sterilized sterile API, in order to make the production process to meet predetermined specification and ensure the stable operation of the process, validations needed include validation on clean workshop and air conditioning purification system, sterilization equipment validation, aseptic filtration system validation, container closure integrity validation, aseptic process simulation validation, validation on personnel entering in and out of Class B area, validation on disinfection effect of disinfectants and so on. This paper especially makes research on the sterilization filtration process validation and aseptic process simulation test, implementation of microbial challenge, compatibility test, extractables of aseptic filters in industrial production, and implementation of aseptic process simulation test of non-terminal sterilized sterile API, as well as separation method for bacterial colony found in the environment monitoring.The significance and conclusion of the research project1The sterility assurance of the non-terminal sterilized sterile product is based on the principle of risk analysis and system, and the sterility can be ensured when each system can be ensured.2According to the basic principle of China Good Manufacturing Practice (2010)(GMP for short) and international technical guidance, taking the method for establishing sterility assurance system and validation method of non-terminal sterilized sterile API as the appendix of GMP is beneficial for drug manufacturers to better establishing sterility assurance system and validation method.3To analyze and validate the key factors influencing the sterility assurance of non-terminal sterilized sterile API:(1) control of the microbial contamination level before sterilization;(2) reliability of sterilization process;(3) integrity of the container closure;(4) aseptic process simulation validation;(5) good production quality management.4As the domestic drug manufacturers more and more realize the importance of sterility assurance of non-terminal sterilized sterile product, the sterility assurance level of non-terminal sterilized sterile product will continue to improve and be line with the international level through system validation and good production quality management, the quality of non-terminal sterilized sterile product and people’s usage safety will be more guaranteed, and it is also beneficial for non-terminal sterilized sterile product in our country to participate in international competition.