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How to use microporous sterile filters in the pharmaceutical field


How to use microporous sterile filters in the pharmaceutical field

The critical part of the aseptic preparation process is the sterilization of the preparation, and the sterilization filter plays a vital role in the production of sterile medicine. For drugs with a relatively high degree of heat sensitivity, the heat sterilization will have an irreversible effect on the product. Most of the production processes use microbiological filtration through a double-channel sterilization filter (redundant filtration); Heat-sterilized drugs can also reduce the microbial load of the drug before sterilization by using a filter to reduce the risk of microbial contamination of the drug. Besides, in the production process of the whole sterile drug, the gas directly in contact with the drug is also filtered by the sterilization filter to ensure the sterility of the drug. In the production of aseptic preparations, the selection of suitable sterilization filters for different products plays a crucial role in sterility assurance.

Principle of sterilization filtration

Bacteria cannot pass through dense microporous filters, which are used to remove microorganisms from gases or liquids. Sterilization filters are often used in the production of sterile preparations, especially for the sterilization of non-terminally sterilized sterile preparations, which generally have a pore size of no more than 0.22 pm. The FDA's definition of a sterilizing grade filter: "A sterilizing grade filter must be a sterile filter of downstream filtrate when challenged with >10 CFU/cm of cyanobacteria." The principle of filtration is basically divided into three types. , namely, inertial impact interception, interception, and Brownian diffusion interception. Inertial impact entrapment means that when a fluid containing microbial particles passes through the filter layer, the fluid can only pass through the gap of the fiber. Due to the crisscrossing of the threads, the layers are stacked, forcing the fluid to change the direction and speed of movement regularly. Since the inertia of the microbial particles is higher than the liquid, when the airflow encounters the obstacle and advances around the path, the microbial particles fail to change its direction of motion in time and are stuck and trapped on the surface of the fiber.

The interception function means that when the gas velocity of the fluid passing through the filter layer is low, the inertial impact interception effect is small, and the interception and interception function plays a significant role. When the particle diameter is small, and the mass is light, when it moves slowly toward the fiber with the airflow, the main airflow stream of the particle is blocked by the cord to change the flow direction, bypassing the thread, and forming a boundary retention zone around the thread, and staying The flow rate of the territory is slower, and the particles entering the retention zone are slowly approaching and contacting the fibers and are retained by the adhesion.

Brownian diffusion trapping When a fluid passes through the filter layer, particles of small diameter in the slowly flowing fluid will have significant Brownian motion, causing the particles and fibers to contact and be trapped.

Classification of sterilization filters

At present, filters commonly used in pharmaceutical manufacturing companies have a cylindrical, capsule, and flat plates from the external structure. The sterilizing screen is mainly classified into a hydrophilic (water infiltrated) sterilizing filter and a hydrophobic (water non-wetting) cleaning filter according to the internal filtering material. Hydrophilic filter materials are mainly used for sterilization filtration of water or water/organic solution mixing, such as cellulosic materials (regenerated cellulose, mixed cellulose ester), PVDF modified polyvinylidene fluoride, PVPP polycarbonate. Hydrophobic filter materials are mainly used in solvent, acid, alkali and chemical filtration and gas filtration, such as polycarbonate, polysulfone, polypropylene, PVDF polyvinylidene fluoride, PTFE polytetrafluoroethylene. Different filter materials not only affect the performance of the filter, but also affect the filter's elution and precipitate levels, physical and thermal properties, and the interaction of the filtered fluid. The following is a brief introduction to the different materials of the filter:

Mixed fiber sexy ester: usually can be made into a flat filter membrane for excellent filtration of liquids and gases.

Polypropylene (PP): It can be made into a folded type. The polypropylene series filter core is made of polypropylene filter membrane as the primary Filter Material. It has high mechanical retention efficiency, large flux, the large amount of dirt, extensive chemical compatibility, and shallow. The dissolved matter has a long service life. Due to its full pore size, it is a coarse filter material and is often used in cartridge filters.

Polyvinylidene fluoride (PVDF): It is heat-resistant and chemically stable. It can withstand the high temperature of steam sterilization. It can be made into a hydrophilic membrane. It is widely used in the filtration of water for injection in the pharmaceutical industry. S material.

Polyethersulfone (PES): It is a hydrophilic material that is resistant to temperature and hydrolysis. It is often used in cartridge filters for excellent filtration of highly accurate solutions.

Nylon: Commonly used as an excellent filtration of liquids. Nylon filter adopts nylon microfiltration membrane as a Filter Medium, which is naturally hydrophilic, easy to wet, healthy in strength, good in toughness, and no fiber shedding. Simple filters are more common.

Polytetrafluoroethylene (PTFE): It is a hydrophobic material and can be made into a folded type. The PTFE filter element uses a hydrophobic polytetrafluoroethylene microfiltration membrane or a hydrophilic polytetrafluoroethylene microfiltration membrane as a filter medium. It is a widely used filter material, which is heat-resistant and chemically stable. It is often used for excellent filtration of water, inorganic solvents, and air, and is mostly used for cartridge filters.

Selection and use of sterilization filters

An essential method of sterilization in the production of sterile filtration drugs, which is sold for non-terminally sterilized injections, it is even the only means of removing microorganisms from products. For pharmaceutical manufacturers, the first thing to consider is how to choose a sterilization filter.

Selection principle of the filter

When selecting a filter, it should be based on the following principles and verified accordingly:

(1) There is no adsorption between the filter material of the screen and the filtered component. The filter material cannot release the substance in the filtered part, nor can it have fiber shedding, that is, there should be excellent compatibility between the two...

(2) The integrity of the filter can be accurately detected, such as the use of bubble points, one-way flow test.

(3) The filter material of the selected sterilizing filter can be subjected to steam sterilization at 121 ° C, and the microbial interception test is passed. The selection of suitable sterilizing filters in the production process usually takes a small test through a series of diaphragms, and through the pilot-scale amplification experiment of the capsule filter, the optimal filter model suitable for the production process is determined.

To increase the capacity of the terminal membrane filter and reduce the cost, the filtration combination is often optimized in biopharmaceuticals, and the depth filter and the surface filter are added before the membrane filtration. Since the titanium rod can function as a clarifying filter, the cost is low, and it is often selected as a low filter having a large filtration capacity, and the pore diameter can be selected to be ten μm, five μm or 3 μm. The surface filter has a low cost and is used for pre-filtration before being used for membrane filtration. Generally, it is made of polyethersulfone or polypropylene, and the pore size can be selected from 0.6 μm, 0.45 μm or 0.2 μm. The membrane filter at the end is relatively expensive. Generally, a membrane filter with a maximum filtration rejection is used to achieve the final filtration effect. Typically, it is made of polyethersulfone, and the pore size can be selected to be 0.2 μm and 0.1 μm.

Use of sterilizing filter

From the product point of view, the sterile filtration of liquid medicine should pay attention to the following items: (1) Filtration is best to use level filtration, which can avoid too many microorganisms in the terminal filter and leakage. (2) It is best not to use ultrafiltration membrane to eliminate bacteria, which can not meet the requirements of sterilization. (3) When selecting the filter element, the labeling specification of the filter element should be fully considered, and whether it is the sterilization filter of the absolute aperture: before the filter element is put into use, the microbial challenge test of the sterilization filter element should be carried out; Cleaning, storage, sterilization, etc. are verified. Avoiding repeated use may cause pyrogen and microbial contamination; more importantly, if sterile filtration is used for aseptic processing, multi-channel filter elements should be used as much as possible to reduce the risk of microbial contamination caused by cracking of the filter element.
Sterilization filter

After each batch of use, the sterilizing grade filter should generally be discarded. If you choose to reuse the liquid sterilizing grade filter for pharmaceutical production, verification is required, but the check is quite complicated and usually includes the following points:

(1) Process and method of repeated use.

(2) The worst-case conditions for simulated reuse are required to establish verification parameters.

(3) Under the worst condition parameters, the integrity test is performed, and the filter batch and quantity are selected for the bacteria interception test. The dissolution test is also required, and whether the precipitate detection is to be performed.

(4) It is necessary to prove that the method of cleaning the filter and the cleaning effect between different batches do not affect the quality of the drug when it is repeatedly used.

The root cause of reuse of pleated filter damage is its chemical degradation, localized chemical damage and fluted tip thinning are usually due to the enrichment of fluid at the top of the membrane to create corrosion and exacerbate this effect under steam conditions. Reusable filters, although showing high levels of bacterial retention, can no longer meet the 100% retention rate of Pseudomonas aeruginosa, and cannot be used to detect filters in reuse using standard filter integrity tests. Damage.