In general, drugs need to be lyophilized because of their instability in solution. Many antibiotics: such as certain semi-synthetic penicillins, cephalosporins and erythromycin, doxycycline, chloramphenicol salts are manufactured by lyophilization process. It is expected that the level of contamination of such products during production will be low because they are antibiotics. Other types of lyophilizates, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate, and many biological products have no antibacterial effect in solution. In order to minimize the degree of microbial contamination of such drugs, it is usually necessary to remove impurities and bacteria contained in the solution by filtration before the solution is poured into the inner step container.
1 Filtration sterilization of pharmaceutical liquids requires the method of filtering and removing microorganisms in the gas or liquid used in the process in the production of lyophilized preparations by utilizing the principle that bacteria cannot pass through the dense pore filter material. Mainly used for sterilization of heat-labile drug solutions or raw materials.
1.1 Pore size of the drug solution filter The selected drug solution needs to be filtered using a filter of appropriate pore size to remove the total impurities and bacteria of the drug solution. The usual chemical filtration uses a filter of two or more different pore sizes in series to filter. In the actual production process, the filter is usually filtered by a filter with different pore sizes, and sometimes decarburization is required to remove the pyrogen. After the Zui, the liquid is 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 used after the test is passed. Before the blending operation, the operator first checks the original auxiliary materials, name, batch number, and test report, checks the appearance quality, and then weighs the raw materials according to the prescription, and then performs the blending operation. The solution is sterile filtered before being filled, and after filtering, The filter is tested for integrity. When the liquid preparation system uses a method of filtering while filling, 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, Does not affect the sterility of the filtrate.
In order to effectively remove living microorganisms from the process and obtain a sterile drug solution, the nominal pore size of the filter used is usually 0.22 mm or less. In some cases, consider using a double sterilization filter, especially in the case of a liquid filling process or before the filling is completed, without conditions for integrity testing of the filter.
The diameter of the sterilization filter used in the production of the drug generally does not exceed 0.22 μm. The filter must not adsorb the filtered components, nor release the material, and there should be no fibers falling off, and the asbestos-containing filter should be disabled. 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.
1.2 Filter material filter equipment usually has filter column, filter membrane and so on. The filter column is made of materials such as diatomaceous earth or fused glass. Most of the filter membranes are made of polymers, such as cellulose acetate, nitrocellulose, acrylic polymer, polyvinyl chloride, nylon, etc., and the filter membrane pore size is 0.22 μm.
1.3 Filtration Efficiency The degree of sterility assurance during the filtration process is related to the initial bioburden of the filtered liquid and the logarithmic decrease LRV (LogReductionValue) of the filter. LRV is a commonly used logarithm of the ratio of the number of microorganisms before filtration of filtered liquid to the number of microorganisms after filtration under specified conditions. which is:
LRV=lgN0-LgN
Where: N0 is the number of microorganisms before the product is sterilized, and N is the number of microorganisms after the product is sterilized.
LRV is used to indicate the filtration sterilization efficiency of the filter. For a filter having a pore size of 0.22 μm, the filtration sterilization efficiency per HR 2 of the effective filtration area is required to be not less than 7. 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 or filter again with a filter before filling.
Special requirements for 1.40.22μm sterilizing grade filter (1) Filter membrane and structural materials require good compatibility with the product liquid;
(2) The filter can prove its pore size and filter integrity by bubble point test (FDASterileDrugProductsProducedbyAsepticProcessingSeptember, 2004);
(3) The filter material should be subjected to an appropriate and effective bacterial challenge test, that is, the biological property should be confirmed (microbial interception test): it is required to use Pseudomonas falciparum under the production conditions of the actual drug solution instead of water (strain ATCC19146) , Pseudomonas falciparum size: 0.68 μm × 0.31 μm) to verify microbial retention performance (Brevundimonasdiminuta);
(4) The filter material should be able to withstand steam sterilization at 121 °C.
1.5 Basic requirements for the use of liquid filter In the filtration sterilization, 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.
2 Control points of the filtration process 2.1 Determination of the amount of bacteria in the pre-filtration solution The amount of bacteria to be filtered before the sterilization (before filling) should be measured. The preparation of the ingredients or liquids should be strictly controlled to prevent the increase of the degree of microbial contamination that may occur before the solution is filtered. The increase in endotoxin in the drug solution is related to the severity of microbial contamination.
The bioburden test of the drug solution before the final filtration of the drug solution by pre-filtration is useful for determining the amount of bacteria in the solution during sterilization filtration, but it cannot provide the formation of endotoxin in the drug solution and its pollution level. Information situation. Usually, 0.1 ml of the sample of the filtered solution can be taken, the amount of endotoxin is determined by the sputum reagent method (LAL), and at least 100 ml of the sample before the pre-filtration is tested (especially in the presence of Gram-negative bacteria). ) to evaluate the production process.
2.2 Drug liquid bacterial endotoxin control Some patients who use other drugs at the same time (such as infants), or patients with a particularly large volume or dose of injection, are prone to pyrogen reactions, usually, calories determined by normal healthy people by weight The control standard predicts a much more serious response. From this type of clinical consideration, it is required to appropriately strengthen the control of the production process to prevent the production of bacterial endotoxin. This should focus on the control of bacterial endotoxin, raw materials, containers, seals, storage time limits, and production equipment.
In the filtration process, the cleaning, drying and storage of the filtration equipment should be able to effectively control the bioburden (microbial contamination level) and bacterial endotoxin contamination levels.
Filtration equipment should be easy to disassemble, clean, disinfect or sterilize. Without proper control measures, both upstream and downstream of the filtration equipment may be contaminated by bacterial endotoxin.
The sterilization filter and moist heat sterilization remove bacterial endotoxin. In general, bacterial endotoxin on the surface of the device can be inactivated by high temperature or removed by washing. Some online cleaning procedures can be rinsed with water and/or detergent of appropriate purity during the rough wash stage, after which the hot water for injection is used for the final rinse. After the equipment has been cleaned, it should generally be dried unless it is sterilized immediately.
In order to effectively control the potential bacterial endotoxin contamination in the production process, the control time limit for each step of the aseptic process must be specified. The steps to set the time limit control include: preparation of the liquid to sterilization, sterilization filtration, exposure time of the product on the production line, storage time of the sterilized equipment, containers and seals. The control time limits for different production stages should be determined based on the test data. When setting time limits (such as determining the control time limit for the formulation phase), the total number of microbial contamination and bacterial endotoxin contamination levels should be assessed.
For the chemical filtration operation of the preparation process, the upper limit of the total length of time consumed by the product filtration process (zui long time limit) should be specified to prevent microorganisms from penetrating the sterilization filter. The use of time limit control also prevents a significant increase in microbial contamination and bacterial endotoxin contamination upstream of the filter. Increases in the level of microbial and pyrogen contamination will adversely affect the downstream. Therefore, the allowable time limit for clarification or removal of particles should be determined and the basis for setting the criteria should be stated.
2.3 Quality Control of Filtration Process The main quality control measures are: the content of active ingredients in the liquid medicine, the pH of the liquid, the color, the clarity, the weighing of the raw materials, the mutual review, and the accurate recording.
3 The liquid medicine filtering unit sets the liquid medicine through the sterilization filtration, can obviously reduce the concentration of impurities and microorganisms in the compounding solution, and can maintain the sterility of the production flow pipeline system.
When the liquid product in the aseptic production process has been proven to be filter sterilized, it is necessary to sterilize the product specific to the product. The compatibility of the sterilization filter and the product formulation should be confirmed, that is, the compatibility of the filter media with the drug solution should be considered, and the influence of the operating conditions of the ziu difference should be considered. Non-zui final sterilization method for the production of sterile drugs, the aseptic production used in the case of edge filtration, while filling, also requires the use of two filters in series filter method to ensure that the filtration process will never be filtered Damage to the filter of the filter caused the filter to fail.
Zui terminally sterilized sterile products may also require special sterilization filtration. Before the final sterilization of zui, there are sufficient reasons for effective bio-load control. The product needs no sterilization filtration and must be unique to the product and production process. The basic data is used for effective evaluation.
Traditionally, the sterilization filtration process is realized by a sterile compressed air filter press liquid, that is, the raw material liquid in the dosing tank or the chemical storage container is pressure-filtered into the receiving container of the liquid medicine by the pressure of the compressed air, in the dosing tank. A sterilizing filter is installed between the sterile liquid receiver and the sterile liquid receiver. Figure 1 is a schematic view showing the structure of a typical sterile indoor filtrate receiving container.
When performing filtration under a small-scale sealed state, it is optional to use a sealed pressureless container and a silicone rubber tube to obtain a peristaltic pump device filter press liquid. Containers and associated piping systems can be cleaned and sterilized when filtration is carried out under large-scale production conditions. For smaller scale operations, the liquid container and filter assembly can be properly cleaned and cleaned, then autoclaved and sterilized, and aseptically assembled under the protection of Class 100 unidirectional flow clean air.
Whether the filter for sterilization filtration is complete and whether the installation of the filter between the containers is reliable or not should be verified by the integrity test method of the filter.
The integrity test is carried out before filtration or before sterilization, but the filter integrity test must be carried out again after filtration to confirm that the filtration process of the batch is complete and reliable, and the semi-finished product is allowed to be released.
It is better to filter the complete experiment if it can be done in the original location of the device (ie online).
4 freeze-dried liquid solution configuration filter system settings related issues 4.1 the size of the preparation of the majority of freeze-dried powder injections in the case of small quantities and more varieties, in the preparation tank selection and matching should try to filter the capacity of the preparation tank and The scope of application of the structural type is increased, and it should also be noted that the relationship between the batch number and the dispensing system should be matched in accordance with GMP.
4.2 Setting of the sterilizing filter In most cases, at the end of the diluted system, a membrane filter having a pore size of 0.22 μm is always disposed as a sterilization process equipment. There are two situations in the process: one is the formulation process to meet the continuous, large-scale production of the production line. That is, the liquid medicine is filtered while being filled; the other is medium and small scale, and the gap type filter is filled, that is, the liquid medicine is completely filtered and then filled.
(1) The liquid is filtered while filling. In this case, since it is impossible to filter the filter content during the filtration process, online integrity verification is performed at any time to confirm that the filter is not damaged during use. In order to ensure the reliability of the filtrate, two 0.22 μm filters are used in series in the system. As long as both sterilizing filters pass the integrity test before use, there is little chance that both filters will be damaged at the same time during the filter filling process. Therefore, the sterility of the final filtrate of zui can be greatly ensured.
(2) Fill all the liquid medicine after filtering. Since the integrity of the 0.22 μm sterilizing filter after use can be confirmed again after all the liquid medicines have been filtered, the liquid medicine is filled after passing the test. Therefore, the system can be set to only one 0.22 μm sterilizing filter.
4.3 Selection of transport mode after preparation of liquid medicine After the ingredients are dispensed, the liquid medicine is generally transported in two ways: one is pumped (sanitary grade); the other is transported by clean compressed air or clean inert gas. Generally, the water-soluble material can be transported by compressed air. If it is a chemical liquid containing an organic solvent or a chemical liquid which is easily oxidized, an inert gas should be used for the pressure-feeding.
4.4 Ingredient Steps The batching procedure of an antibiotic freeze-dried pharmaceutical batch is as follows: decarbonization through a titanium rod with a pore size of 10 μm, filtration through a polysulfone filter with a pore size of 0.45 μm, and transfer to a thin tank, and adding a full amount of water for injection. The specified capacity (constant volume) was then stirred for 20 min. The mixture was filtered through two polysulfone filters having a pore size of 0.22 μm, and sampled from the sampling port of the second-stage filter to measure the content, pH, color, clarity, and the like. After passing the test, it is filtered through a 0.22 μm microporous membrane filter to the filling room, and the content should be within the internal control range (pH 4.5~5.5).
When the filling process is required, the prepared solution should be filled within 8 hr. In the whole process of filling the liquid, the liquid volume should be strictly controlled.
4.5 Delivery of the drug solution The drug solution is usually delivered in two ways: one is delivered by stainless steel pump; the other is delivered by clean compressed air or clean inert gas. In general, the water-soluble material can be compressed air. If there is a solvent liquid or a liquid that is afraid of oxidation, it is preferable to use an inert gas for the pressure feed.
The liquid medicine after the ingredients should enter the filling process in a sterile, pyrogen-free state and be filled into a glass bottle or tray. Therefore, a filtration device should be provided in the formulation system. Usually, the chemical solution is filtered by carbon in the transport system and then subjected to two-stage sterile filtration. The front stage uses a 0.45 μm pore size filter element, and the latter stage uses a 0.22 μm pore size filter element. The outer casing and fitting material of the filter should be 316L, and the sealing gasket (sheet) is medical grade PTFE. The flow of the filter is based on each batch of material. The secondary filter should be tested for bubble point before use. Each stage should be equipped with hygienic diaphragm pressure gauge, sampling valve and drain valve.
The liquid medicine after the ingredients should be treated under the condition of clean fluid delivery. The whole system should also be cleaned and sterilized according to GMP requirements. The ingredient delivery system should have the functions of online cleaning CIP and online sterilization SIP. The scope of treatment should cover the entire batching system (including: tanks, bodies, filters, sanitary pipes, fittings and valves).
(Source: mechanical and electrical information Author: money should Pu)Face Mask
Anesthesia Medical Co., Ltd. , http://www.sinoanesthesia.com