In order to strengthen the supervision of drug production, further guide and standardize the scientific and systematic development of sterilization filtration technology and application, aseptic process simulation test, the State Drug Administration has formulated the "sterilization filtration technology and application guide" and "sterilization". Guide to Process Simulation Test (Sterile Bulk Drugs), "Guidelines for Aseptic Processing Simulation Tests (Aseptic Preparations)", as a guiding document for the implementation of the "Good Manufacturing Practices (2010 Revision)", is hereby published, since 2018 It will  filter materials take effect on October 1st.

announce.

Accessories: 1. Sterilization filtration technology and application guide

2. Aseptic process simulation test guide (sterile bulk drug)

3. Aseptic process simulation test guide (sterile preparation)

State Drug Administration

July 31, 2018

Annex 1 of the State Drug Administration Circular No. 85 of 2018

Sterilization filtration technology and application guide

1. Purpose

In order to guide and standardize the application of sterilization filtration technology in the production of sterile drugs, to ensure the safety, effectiveness and quality of sterile drugs, this guideline is formulated in accordance with the "Good Manufacturing Practices (2010 Revision)" and appendix.

This guide is not legally binding and is used only as a reference for pharmaceutical manufacturers, engineering design, equipment manufacturing, and drug regulatory agencies. This guide was drafted based on current cognitive and technological levels and does not limit the introduction of new technologies and methods. Companies can use proven alternatives to meet the requirements of this guide.

2. Definition

Sterilization filtration in this guide refers to the process of removing microorganisms in liquids or gases by physical retention to achieve the quality requirements associated with sterile pharmaceuticals.

3. Scope

This guide covers the design, selection, validation, and use of sterile filtration systems for the entire life cycle of sterile pharmaceuticals from process development to commercial production.

4. Filtration process and system design

4.1 Design of the filtration process

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

The sterilization filtration process should use a 0.22 micron (smaller pore size or the same filtration efficiency) sterilization stage filter depending on the purpose of the process. A 0.1 micron sterilizing grade filter is typically used for the removal of mycoplasma.

Microbiological control of the entire process of aseptic drug production to avoid microbial contamination. Before the final sterilization filtration, the microbial contamination level of the medium to be filtered is generally less than or equal to 10 cfu/100 ml.

When selecting a filter material, its compatibility with the media to be filtered should be fully investigated. The filter must not adversely affect product quality due to reaction with the product, release of material or adsorption. The sterilizing filter must not shed fibers, and it is strictly forbidden to use filters containing asbestos.

A reasonable filtration membrane area needs to be evaluated after scientific methods. Excessive area may result in decreased product yield and increased filtration costs; too small a filter area may result in prolonged filtration time, blockage in the middle, or even product scrap.

Attention should be paid to the rationality of the structure of the filtration system to avoid the existence of sanitary corners. There is a certain current limiting effect on the inlet and outlet of the filter. The appropriate import and export size should be selected according to the process needs.

When selecting a filter, determine the process parameters such as the filtration temperature range, the longest filtration time, the filtration flow rate, the sterilization conditions, the inlet and outlet pressure difference range, or the filtration flow rate range according to the actual process requirements, and confirm whether these parameters are within the acceptable range. Inside.

When selecting a sterilizing filter supplier, the pharmaceutical manufacturer should review the verification documents and quality certificates provided by the supplier to ensure that the selected filter is a sterilizing filter. Pharmaceutical manufacturers should manage the sterilization filter manufacturers as suppliers, such as document audits or factory site audits, quality agreements, and product change control agreements.

4.2 Design of the filtration system

When designing a sterile filtration system, the limitations of the sterilization filtration process should be fully understood. Since the sterilizing filter cannot completely filter out the virus or the mycoplasma, heat treatment or the like can be used to make up for the deficiency of the sterilization filtration.

Take measures as much as possible to reduce the risk of filtration sterilization. For example, a second sterilized sterilization filter should be installed. The final sterilization filter should be as close as possible to the filling point. Filtering, usually by two or more identical or decreasing apertures, is collectively referred to as sequence filtering. In the sequential filtration system, if a sterilizing grade filter is added before the final sterilizing filter, and the sterility between the two filters is ensured, and the microbial contamination level of the medium before filtration is generally less than or equal to 10 cfu/100 ml, In the case of a redundant filtering system. In a redundant filtration system, a filter close to the filling point is called a main filter, and a filter at the front end is called a redundant filter. After the redundant filter system is used, if the primary filter integrity test passes, the redundant filter does not require an integrity test; if the primary filter integrity test fails, the redundant filter must pass the integrity test. Another type of sequence filtration system refers to a system that has been verified to require a series of (two or more) sterilization-grade filters to achieve sterilization in the filtration process. This series of filters is considered a sterilization. Units must pass the integrity test after use.

Filter position design should consider the release of bacteria or liquids, and confirm the area and location of the filter installation based on product batch size, length of tubing, ease of installation and sterilization, etc.

When designing a filtration system, consideration should be given to the convenience of the filter integrity test and the risk of microbial contamination to the system. After the filter has been sterilized, the gas and rinse liquid that is in contact with its downstream system must be sterile.

When designing the sterilization filtration system, the safety and convenience of system sterilization should be fully considered. When using the online sterilization method, the problem of cooling air and condensate in the system should be considered to ensure that the lowest temperature of the system can also reach the expected F0 value. When using off-line sterilization, the risks of the transfer and installation process should be fully considered. For example: attention should be paid to the direction of the airflow, the aseptic operation of the operator, and connection schemes such as sterile connectors.

If a disposable filtration system is used and a pre-use integrity test or pre-flush is required, additional considerations must be taken in design: the pressure resistance of the upstream connecting line, the downstream sterility, and the downstream provide sufficient space (eg Install a sterilizing barrier filter or a corresponding volume of sterile bag for exhaust drainage. If a disposable sterile connection is used, there should be documentation that there is no risk of microbial contamination.