Brief introduction of the application of air filter in the preparation of drug freeze-drying process

In general, the reason why drugs need to be freeze-dried is the instability of the solution Many antibiotics in the whole proportioning system (including tank, body, air filter, air filter, medium efficiency filter, primary efficiency filter, air conditioning filter, bag filter, sanitary pipeline, pipe fittings and valves): for example, some semi synthetic penicillin, cephalosporin and erythromycin, doxycycline and chloramphenicol salts are produced by freeze-drying process It can be estimated that the pollution level of such products in the process of consumption is very low, because they are antibiotics However, other lyophilized agents, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate and many biological products, are not antibacterial in solution In order to reduce the microbial pollution level of this kind of drugs as much as possible, it is required to remove the impurities and bacteria contained in the solution by filtration before the solution is poured into the inner container We will discuss the application of air filter in the preparation of freeze-drying process of drugs In the consumption of lyophilized preparation, the principle that bacteria can not pass through the dense small hole filter material is applied, and the method that the filter can remove the microorganism in the gas or liquid used in the process It is mainly used for sterilization of unstable pharmaceutical solution or raw materials 1.1 the pore size of the liquid medicine air filter shall be selected The prepared liquid medicine shall be stopped by the air filter with proper pore size to remove the total impurities and bacteria in the liquid medicine Usually, two or more air filters with different apertures are used to filter the liquid medicine in series In the process of practical consumption, filters with different pore sizes are used to filter the liquid medicine in different grades Sometimes, decarbonization is also needed to remove pyrogenic substances After Zui, the liquid medicine is filtered and sterilized through a microporous air filter with a pore size of 0.22 μ M During the filtration of liquid medicine, special attention shall be paid to confirm the pore diameter of air filter for sterilization and its absence in the process of consumption, that is to say, the membrane of air filter for sterilization shall stop the implementation of bubble point and be used after it is qualified Before the distribution operation, the operator shall stop checking the raw and auxiliary materials, title, batch number and test declaration, search the appearance quality, then weigh the raw materials according to the prescription, then stop the distribution operation, stop the sterile filtration before the solution is supplied and filled, and stop the air filter after the filtration When the method of solution preparation system is filtration and filling at the same time, the system should use two primary effect filters in series to ensure that the filter membrane of an air filter is damaged in the process of filtration and filling, and the sterility of the filtrate will not be affected In order to effectively remove living microorganisms from the process and obtain sterile liquid medicine, the nominal pore diameter of air filter is 0.22mm or less on weekdays In some cases, it is necessary to consider the application of double sterilization air filter, especially in the process of filling liquid medicine or before the completion of filling, there is no premise to stop the implementation of no lack of air filter The pore diameter of the sterilization and filtration membrane used in drug consumption is not more than 0.22 μ M The medium efficiency bag filter shall not have adsorption and dye on the filtered components, nor release substances, and shall not have fiber scattered The air filter containing asbestos is prohibited Before using the filter and filter membrane, the cleaning treatment shall be stopped, and the sterilization shall be stopped with high-pressure steam or on-line sterilization The filter shall be cleaned before changing the type and batch 1.2 filter material air filter equipment usually has filter column, filter membrane, etc The filter column is made of diatomite or vertical melting glass Most of the filter membranes are made of polymers, and there are many kinds, such as cellulose acetate, nitrocellulose, acrylic polymer, PVC, nylon, etc the pore diameter of the filter membrane at the sterilization level is 0.22 μ M 1.3 the sterility assurance level in the filtration process of filtration efficiency is related to the initial biological load of filtration liquid and the log reduction value of air filter LRV refers to the common logarithm value of the ratio of the number of microorganisms before filtration to the number of microorganisms after filtration on the premise of defined politeness That is: LRV = lgn0 LGN where: N0 is the number of microorganisms before product sterilization, and N is the number of microorganisms after product sterilization LRV is used to disclose the filtration and sterilization efficiency of the display air filter For the air filter with an aperture of 0.22 μ m, the filtration and sterilization efficiency LRV value of each effective filtration area of 1cm2 is required to be no less than 7 Therefore, the total pollution of filtered products should be controlled within the limits of defined politeness In order to ensure the effect of filtration and sterilization, two air filters can be used for filtration in series, or the air filter can be used to stop filtration again before filling Special request for 1.40.22 μ m air filter (1) filter membrane and structure data of air filter, request to have superior compatibility with finished drug solution; (2) air filter can prove its pore size and filter's flawless through bubble point test (fdasteriledrugproducts produced by aseptic processing filter, 2004); (3) the filter material should be implemented by appropriate and effective bacteria, that is, the biological property should be confirmed (microbial interception Implementation): under the premise of practicing the consumption of liquid medicine instead of water, the defective Pseudomonas (atcc19146, the size of defective Pseudomonas: 0.68 μ m × 0.31 μ m) should be used to verify the microbial interception function (brevundimonasdiminuta); (4) the filter material shall be able to withstand steam sterilization at 121 ℃ 1.5 in the process of filtration and sterilization, the basic requirements for the application of liquid medicine air filter are that the critical parameters of air filter in the whole process (the size and dispersion of filter membrane aperture, the absence of filter membrane and LRV) cannot be stopped for monitoring Therefore, before and after each filtration and sterilization, it is necessary to implement the filter without any defect, that is to say, the gas bubble point is implemented or the pressure is maintained or the gas diffusion flow is implemented Confirm the effectiveness and absence of the membrane in the process of sterilization and filtration Under popular conditions, the use of air filter should not exceed one working day 2 Control points of filtration process 2.1 the determination of bacteria carrying capacity of the filtrate should be stopped before sterilization and filtration (before filling) The preparation of ingredients or pharmaceutical solutions should be strictly controlled to avoid the addition of microbial pollution level that may appear before sterilization and filtration Because the addition of endotoxin is related to the serious level of microbial pollution The bioburden test on the suspension of liquid medicine after prefiltering and before Zui final filtration is effective to determine the amount of bacteria in the solution during sterilization and filtration, but it can not provide information on the composition of endotoxin in the liquid medicine and its pollution water On weekdays, 0.1ml of the solution sample that has been filtered can be taken to determine the amount of endotoxin by limulus amebocyte lysate method (LAL) For the solution before pre filtration, at least 100ml of the sample is taken to stop the grinding (especially in the presence of Gram-negative bacteria), and then the consumption process is stopped for evaluation 2.2 the bacterial endotoxin control of drug solution for some patients (such as infants) who also use other drugs, or the patients whose injection volume or dosage is specially large, can easily show the pyrogen reverberation On weekdays, it will be much more severe than the reverberation estimated by the pyrogen control standard determined by the weight of normal Ankang people From this kind of clinical thinking, we should strengthen the control of consumption process to avoid the occurrence of bacterial endotoxin In this regard, we should focus on the control of the original and auxiliary materials, containers, seals, storage time limit, and bacterial endotoxin of consumer equipment In the filtration process, the clean, single and harmonious storage of filtration equipment should be able to effectively control the biological load (microbial pollution level) and bacterial endotoxin pollution level The filtration equipment shall be easy to disassemble, clean, disinfect or sterilize If there is no proper control measures, the upstream of the filtration equipment and the low level may be contaminated by bacterial endotoxin The air filter and moist heat sterilization can remove the endotoxin In general, the bacterial endotoxin on the equipment surface can be inactivated by high temperature method or removed by cleaning For some on-line cleaning procedures, proper purity water and / or detergent can be used to stop rinsing in the rough washing stage, and then hot injection water can be used for Zui final rinsing After the equipment is cleaned, it should be treated monotonously unless it is sterilized immediately In order to effectively control the potential bacterial endotoxin pollution in the process of consumption, it is necessary to define the control time limit for each step of the polite aseptic process The steps of time limit control should be set, including: preparation of drug solution to sterilization, sterilization and filtration, exposure of products on the consumption line, storage of sterilized equipment, containers and seals The control time limit of different consumption stages should be determined according to the implementation data When formulating time limit specifications (such as determining the control time limit in the preparation stage), the total amount of microbial pollution and the level of bacterial endotoxin pollution should be evaluated For the preparation process, the upper limit of the total time consumed in the filtration process of polite products (Zui long time limit) should be defined to prevent the microorganism from penetrating the sterilizing air filter Time limit control can also avoid the microbial pollution and bacterial endotoxin pollution in the upstream of air filter The addition of microorganism and pyrogen pollution level will bring bad elements to the light and cheap Therefore, it is necessary to determine the Zui long time limit for clearing or removing particles in the liquid medicine and clarify the basis for setting specifications 2.3 the primary quality control measures for the quality control of the filtration process are: the content of active ingredients in the liquid medicine, the pH, luster, clearance of the liquid medicine, and the records of the two people's mutual check and review of the raw material weighing, etc 3 The liquid medicine filtration unit sets the liquid medicine to be filtered through sterilization, which can significantly reduce the concentration of impurities and microorganisms in the ingredient solution, and can maintain the sterility of the consumer flow pipeline system When the liquid products in the aseptic consumption process are proved to be able to be filtered and sterilized, the product specific sterilization and filtration shall be required The compatibility of sterilization filtration and product formula should be proved, that is to say, the compatibility of air filter material with drug solution should be possible, and the influence of Zui poor operation premise should be considered The non Zui final sterilization method consumes sterile drugs In the case of filtration and filling at the same time, the filtration method of two air filters in series is also needed to ensure that the filtration failure will not be caused by the damage of the filter membrane of the air filter during the filtration process The sterile products of Zui final sterilization may also need special sterilization and filtration Before the final sterilization of Zui, there are enough reasons to stop the effective biological load control The products do not need sterilization and filtration, and the effective evaluation must be stopped based on the specific basic data of products and consumption process Traditionally, the completion of the sterilization and filtration process is to filter the pharmaceutical solution by sterile compressed air pressure The raw material liquid in the batching tank or the pharmaceutical solution storage container is pressurized and filtered by compressed air to the receiving container of the pharmaceutical solution, and a sterilization air filter is installed between the batching tank and the sterile pharmaceutical solution receiver When the operation is stopped in a small limited sealing condition, the pressure filtration of peristaltic pump device can be obtained by using sealed non pressure vessel and silicone rubber tube