Abstract: Starting from the overview of filter materials, the selection points of the sterilizing filter are expounded. At the same time, the correct sterilizing filter is selected through the evaluation of the quality risk management method, and combined with the relevant production operation control, the sterilization of the small volume injection is reduced. Pre-microbial load.
Key words: sterilization filter; quality risk; small volume injection; integrity test; online monitoring
As the safety of pharmaceuticals (especially aseptic preparations) has received increasing attention, the production of sterile preparations has also been increasingly regulated by pharmaceutical regulatory agencies, sterilization and aseptic processing of sterile preparations. Key production steps such as sterilization filtration are gradually magnified in the supervision of the high intensity and frequency of Zui, and this is indeed a key control point for sterile preparations. The author's unit has a small-volume injection line, and the production products are non-zui terminal sterile sterile preparations, which are mainly combined with sterilization filtration and aseptic operation and supplemented by zui final 100 °C water bath sterilization to achieve no Bacterial control requirements. In this paper, through the selection of sterilization filter and the aseptic quality risk analysis of relevant key control links, a large technical and management improvement has been made, which reduces the risk of sterility quality of small volume injection.
Overview of sterile filtration materials
Currently, the main filter materials commonly used in filters are:
(1) mixed cellulose ester, commonly used to make a circular single-plate filter for fine filtration of liquids and gases;
(2) Polypropylene (PP), which is made into a folded type, is commonly used in a barrel filter, has a large pore size, is hydrophilic, and is a coarse filter material;
(3) Polyvinylidene fluoride (PVDF), which is a fine filter material, heat and chemical resistant, and has good steam sterilization tolerance. It can be made into a hydrophilic filter membrane, which is widely used in the pharmaceutical industry. And filtration of water for injection;
(4) Polyethersulfone (PES), which is made into a folded type, is commonly used in cartridge filters, has good temperature and hydrolysis resistance, and is hydrophilic material, which is used for fine filtration of high precision solutions;
(5) Nylon, made of folding type, commonly used in cartridge filters, hydrophilic materials, often used as fine filtration of liquids;
(6) Polytetrafluoroethylene (PTFE), made of folded type, commonly used in cartridge filters, hydrophobic materials, which is a widely used material, heat and chemical resistant, commonly used in water, inorganic solvents and Fine filtration of air.
In addition, the filter material is classified into two types: hydrophilic (water-infilable) and hydrophobic (water-infiltrated) in terms of water. Hydrophilic filter materials are mainly used in the filtration and sterilization filtration of water or water/organic solution mixture; hydrophobic filter materials are intercepted or "guided" into the filter through water, mainly used in solvents, acids, bases and chemistry. Product filtration, tank/equipment respirator, process gas, fermentation intake/exhaust filtration.
Selection of sterilization filter
In the production of small-volume injections, microorganisms in the gas or liquid used in the process are removed by filtration using the principle that bacteria cannot pass through the dense pore filter.
2.1 sterilizing filter aperture selection
The prepared liquid needs to be filtered using a filter of appropriate pore size to remove impurities and bacteria from the liquid. The usual chemical filtration uses a filter of two or more different pore sizes in series to filter. In the actual production process, the liquid is usually filtered by a filter with different pore sizes, and then filtered through a microporous filter with a pore size of 0.22 μm.
When filtering the liquid, pay special attention to confirm the pore size of the sterilization filter and its integrity in the production process. That is, the filter membrane of the sterilization filter should be tested for bubble point, and the test can be used only after passing the test. When the liquid preparation system uses the method of filling while filtering, the system should use two sterilization filters in series to ensure that even if a filter membrane is damaged during the filtration and filling process, it will not be caused. Affect the sterility of the filtrate.
2.2 filter material
The sterilizing filter material must not adsorb the filtered components, nor release the material, and no fibers may fall off. For small-volume injection sterilization filtration, the material should be selected for hydrophilicity and can be filtered with high precision.
Special requirements for 2.30.22μm sterilization filter
(1) The filter membrane and structural materials are required to have good compatibility with the product liquid; (2) the filter can prove the pore size and the integrity of the filter through the bubble point test; (3) the filter material Appropriate and effective bacterial challenge tests should be carried out, ie biological properties should be confirmed (microbial retention test): Pseudomonas faecalis (strain ATCC19146, defect falsification) is required to be used under actual production conditions rather than water production conditions. The size of the bacterium: 0.68 μm × 0.31 μm) verified the microbial retention performance (Brevundimonas diminuta); (4) The filter material should be able to withstand steam sterilization at 121 °C.
2.4 filtration efficiency
The degree of sterility assurance during filtration is related to the initial bioburden of the filtered liquid and the logarithmic decrease in value LRV of the filter. LRV is used to indicate the filter sterilization efficiency of the filter. For a 0.22 μm filter, the filtration sterilization efficiency per HR 2 of the effective filtration area should be LR7. Therefore, when filtering and sterilizing, the total amount of contamination of the filtered product should be controlled within the specified limits. To ensure filtration sterilization, two filters can be used in series to filter.
2.5 sterilizing filter requirements
In the sterilization filtration, it is generally impossible to monitor the key parameters of the filter in the whole process (the size and distribution of the membrane pore size, the integrity of the membrane and the LRV). Therefore, the filter integrity test should be performed before and after each filtration sterilization, that is, the bubble point test or the pressure maintenance test or the gas diffusion flow test. Confirm the effectiveness and integrity of the filter during the sterilization filtration process. In general, the sterilization filter should not be used for more than one working day.
Filters and membranes should be cleaned prior to use and sterilized or autoclaved with high pressure steam. Replace the filter and the batch before cleaning the filter and then replacing the filter.
2.6 Selection of sterilization filter
Through the above analysis, we selected a 0.22μmM illipore polyvinylidene fluoride (PVDF) and Pall polyethersulfone (PES) and nylon material filter as an alternative terminal sterilization filter for the feed liquid.
At present, among the 0.22μm sterilization filter suppliers, Pall and Millipore are excellent. Both companies have more than 50 years of filter management and R&D history, each with its own characteristics. The former liquid filter It mainly consists of polyethersulfone (PES) and nylon, while the latter is made of polyvinylidene fluoride (PVDF).
Sterilization filter integrity test
In order to ensure the filtration effect of the sterilization filter, the integrity test of the filter before and after use is required to ensure that the filtration is effective. At present, the main integrity testing methods include test methods such as forward flow, bubble point and water intrusion. The mainstream testers include Pall's Flowstar and Millipore's Intergritest.
With the implementation of the 98 version of GMP and the implementation of new drug GMP certification inspection standards, the integrity test of filters is increasingly valued by enterprises and drug inspection officials, almost every inspection must be checked, especially the key The integrity testing of filters for processes and critical control steps has been the first to focus on each type of inspection.
In the filter of the above materials, the integrity of the mixed cellulose ester and polypropylene (PP) is difficult to detect and is generally regarded as undetectable, so it cannot be a good terminal sterilization filter, and there is a large sterility. Quality risk.
Analysis of Sterile Filtration and Related Improvements from the Perspective of Quality Risk Analysis
4.1 Aseptic quality risk analysis of small volume injections
The basic program flow chart of ICHQ9 quality risk management is shown in Figure 1. Based on the basic procedure flow of ICHQ9 quality risk management, we analyzed the aseptic quality risk of small volume injections. Because the product is filtered by the terminal 0.22μm sterilizing filter, and the production process features of zui 100°C and 30min water bath sterilization, the F0 value of the sterilization procedure is too low to meet F0>8, and the simple water bath sterilization is also The sterilization effect cannot be achieved and the sterilization is not complete. In addition, on the basis of ensuring the effect of sterilization filtration, the microbial load before sterilization can be reduced, and the sterilization can be achieved by combining 100 ° C and 30 min water bath sterilization.
Based on this, we conducted a risk analysis of the main operational steps before sterilization in actual production:
(1) Risk assessment of raw materials and internal packaging materials. Potential risk: Uncontrolled microbial quantity before product sterilization can lead to microbial quality defects.
(2) Risk assessment of cleaning and sterilization of product liquid preparation pipelines. Potential risk: cleaning and sterilization of the liquid preparation pipeline at night, lack of effective monitoring, the actual operation and sterilization key parameters can not be guaranteed, the sterilization effect can not be guaranteed, can lead to the loss of control of the microbial content before sterilization.
(3) The sterilization effect and integrity risk assessment of the liquid sterilization terminal sterilization filter. Potential risks: Recording of key parameters for sterilization of terminal sterilization filters and integrity testing before and after use, defects in on-site monitoring will result in uncontrolled microbial content prior to sterilization.
(4) Risk assessment of contamination caused by aseptic production environment and personnel. Potential risks: Out of control of the production environment and introduction of operators leading to loss of control of microorganisms prior to sterilization.
4.2 related improvements in sterile filtration
Based on the above quality risk analysis, we have developed technical and management improvement measures to reduce the risk of sterile filtration quality, mainly as follows:
(1) Purchasing standards control the microbial limit of raw materials; use the inner packaging purchased at a fixed point, the package is tight, to prevent wet and insect pollution; the injection water is kept at a temperature above 65 °C; the micro-reports are regularly inspected according to the SOP for the total return and other points of use. Endotoxin; reduces the risk of microbial load on raw materials and inner packaging materials.
(2) Correctly select the sterilizing filter, strengthen the integrity test and the on-line monitoring of the cleaning and sterilization of the liquid preparation pipeline and the sterilizing filter.
Among them, 0.22μmM illipore of polyvinylidene fluoride (PVDF) and Pall's polyethersulfone (PES) and nylon material filter were selected as the alternative terminal sterilization filter for the feed liquid; using Millipore's IntergritestTM4 as the integrity tester Perform pre-use and post-use integrity tests to ensure good integrity.
An on-line monitoring recorder was designed and fabricated to meet the key parameters such as temperature, pressure and time of on-line sterilization at 121 ° C and 30 min in the actual liquid preparation pipeline and terminal filter. The sterilization effect is challenged by the sterilization effect, the sterilization effect is good, and the online recorder is used very well, so that the key parameters of the night operation are recorded and controlled, which reduces the risk of night operation.
(3) Daily monitoring of sedimentation bacteria in clean areas, monthly monitoring of floating bacteria, and regular disinfection of clean areas to ensure that the rare environment is 10,000, and the encapsulation is a local level of environmental control under the 10,000-level background. Claim. And the potting utensils are cleaned and sterilized before each batch of medicines are produced, and the sterilization conditions are 121 ° C, 30 min. Each type of potting equipment is used exclusively to reduce the risk of contamination caused by the aseptic production environment and personnel.
Conclusion
Through the correct selection of the above-mentioned sterilization filter and the analysis of the sterility quality risk of small-volume injections and the corresponding technical and management improvement measures, we can see from the statistical analysis of the annual product review of our small-volume injections. The risk of sterilizing quality of small-volume injections is reduced, and a good expected effect is achieved.
[references]
[1] State Food and Drug Administration. Guidelines for the verification of pharmaceutical production. Beijing: Chemical Industry Press, 2003
[2] ICHQ9 Quality Risk Management Guide, 2005
[3]Qian Yingqi. User Requirements (URS) for the Design of Filtration System in Freeze-Dry Process. China Pharmaceutical Equipment, 2008(5)
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