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Guidelines for bactericidal filtration techniques and applications

Define

Bactericidal filtration in this guideline refers to the process of removing microorganisms from liquids or gases by means of physical interception in order to meet the quality requirements associated with sterile medicinal products.

The scope of

This guide covers the design, selection, verification and use of bactericidal filtration systems and applies to the entire life cycle of sterile pharmaceutical products from process development to marketing and production.

Filtration process and system design

Design of filtration process

When designing the filtration process, the suitable filter should be selected and the process parameters should be determined according to the properties of the medium to be filtered and the process purpose.

According to the purpose of the process, 0.22 micron (smaller aperture or the same filtering effect) sterilizing filter should be selected. A 0.1 micron sterilizing grade filter is commonly used for the removal of mycoplasma.

Microbial control should be carried out in the whole process of sterile drug production to avoid microbial contamination. Before the final sterilization and filtration, the microbial contamination level of the medium to be filtered is generally less than or equal to 10cfu/100ml.

When selecting filter material, its compatibility with the medium to be filtered should be fully investigated. The filter shall not adversely affect the quality of the product by reaction with the product, release of substances or adsorption. The filter shall not shed the fiber, and the filter containing asbestos is strictly prohibited.

Reasonable filtration membrane area needs to be evaluated by scientific methods. Too large area may lead to the decrease of product yield and the increase of filtration cost. Too small filtration area may lead to prolonged filtration time, blockage in the middle of the process and even product scrap.

 

Attention should be paid to the rationality of the filtration system structure to avoid the existence of sanitary dead corners. The inlet and outlet of the filter have a certain current limiting effect. According to the process needs, choose the appropriate size of import and export.

When selecting the filter, the process parameters such as filter temperature range, maximum filtration time, filtration flow rate, sterilization conditions, inlet/outlet pressure difference range or filtration flow rate range should be determined according to the actual process requirements, and confirm whether these parameters are within the affordable range.

When selecting the supplier of sterilizing filter, the drug manufacturer shall review the verification documents and quality certificates provided by the supplier to ensure that the filter selected is a sterilizing grade filter. Drug manufacturers should manage the filter manufacturer as a supplier, such as document audit or factory site audit, signing of quality agreement and product change control agreement, etc.

Design of filtration system

When designing the filtration system, the limitations of the filtration process should be fully recognized. Since the filter can not remove all viruses or mycoplasma, heat treatment and other methods can be used to make up for the deficiency of the filter.

As far as possible, measures should be taken to reduce the risk of filtration sterilization. For example, a second sterilized filter should be installed, and the final sterilized filter should be as close to the filling point as possible. Usually through two or more filtering methods of the same or decreasing aperture, collectively referred to as sequential filtering. In the sequential filtration system, if a sterilizing grade filter is added before the final sterilizing filter, and the sterilization between the two filters is ensured, and the microbial contamination level of the control medium before filtration is generally less than or equal to 10cfu/100ml, this case is called a redundant filtration system. In a redundant filtration system, the filter close to the filling point is called the main filter

Filter, the filter at the front is called a redundant filter. After the redundant filter system is used, if the integrity test of the main filter passes, the integrity test of the redundant filter is not required. If the primary filter integrity test fails, the redundant filter must pass the integrity test. Another type of sequential filtration system refers to the system that has been verified in the filtration process and needs a series of (two or more) sterilizing grade filters to achieve the sterilizing effect. Then this series of filters is considered as a sterilizing unit, and all of them must pass the integrity test after use.

Filter location design should consider the release of bacterial gas or liquid, and according to the product batch, pipeline length, installation and sterilization convenience, confirm the filter installation area and location.

The convenience of filter integrity testing and the risk of microbial contamination to the system should be considered in the design of filtration system. After the filter is sterilized, the gas and flush fluids that come into contact with its downstream system must be sterile. The safety and convenience of system sterilization should be fully considered in the design of sterilization filtration system. When using the online sterilization method, the discharge of cold air and condensed water in the system should be considered, so as to ensure that the lowest point of the system temperature can also reach the expected F0 value. When using off-line methods for sterilization, the risks of transfer and installation should be fully considered. For example, attention should be paid to the direction of air flow, the operator’s sterile operation process, and connection options such as sterile connectors may be considered.

For single-use filtration systems that require pre-use integrity testing or pre-flushing, additional considerations should be taken into consideration in the design: pressure resistance of the upstream connection line, sterility of the downstream line, and the availability of sufficient downstream space (such as a bacterial-grade barrier filter or a corresponding volume of sterile bags) for exhaust drainage. If single-use sterile attachment devices are used, there should be documentation that there is no risk of microbial entry and contamination.


Post time: Dec-08-2022