The purpose of this guideline is to guide and standardize the application of sterilization and filtration technology in the production of sterile drugs, ensuring the safety, effectiveness, and stable quality of sterile drugs. Based on the "Good Manufacturing Practice for Drugs (Revised in 2010)" and its appendices, this guideline is formulated.

2. Definition

The sterilization filtration in this guide refers to the process of using physical retention to remove microorganisms from liquids or gases in order to meet the quality requirements of sterile drugs.

3. Scope

This guide includes the design, selection, validation, and use of sterilization filtration systems, applicable to the entire lifecycle of sterile drugs from process development to market production.

4. Filtration process and system design

4.1 Design of filtration process

When designing the filtration process, appropriate filters should be selected and process parameters determined based on the properties of the medium to be filtered and the purpose of the process.

The sterilization filtration process should select a 0.22 micron (smaller pore size or the same filtration efficiency) sterilization grade filter according to the process purpose. A 0.1 micron sterilization grade filter is commonly used for the removal of mycoplasma.

Microbial control is implemented throughout the entire process of sterile drug production to avoid microbial contamination. Before final sterilization filtration, the microbial contamination level of the filter medium is generally less than or equal to 10cfu/100ml.

When selecting filter materials, full consideration should be given to their compatibility with the medium to be filtered. Filters must not have adverse effects on product quality due to reactions, release of substances, or adsorption with the product. The sterilization filter must not shed fibers, and it is strictly prohibited to use filters containing asbestos.

The reasonable filtration membrane area needs to be evaluated through scientific methods. Excessive area may lead to a decrease in product yield and an increase in filtration costs; A small filtration area may result in prolonged filtration time, mid process blockage, and even product scrap.

Attention should be paid to the rationality of the filtering system structure to avoid hygiene blind spots. The inlet and outlet of the filter have a certain flow limiting effect. Suitable import and export sizes should be selected according to the process requirements.

When selecting a filter, process parameters such as filtration temperature range, long filtration time, filtration flow rate, sterilization conditions, inlet and outlet pressure difference range or filtration flow rate range should be determined based on actual process requirements, and it should be confirmed whether these parameters are within an acceptable range.

When pharmaceutical manufacturers choose sterilization filter suppliers, they should review the verification documents and quality certificates provided by the suppliers to ensure that the selected filters are sterilization grade filters. Pharmaceutical manufacturers should manage sterilization filter manufacturers as suppliers, such as conducting document audits or on-site factory audits, signing quality agreements and product change control agreements, etc.

4.2 Design of filtration system

When designing a sterilization filtration system, it is important to fully understand the limitations of the sterilization filtration process. Due to the inability of sterilization filters to completely remove viruses or mycoplasma, methods such as heat treatment can be used to compensate for the shortcomings of sterilization filtration.

Take measures as much as possible to reduce the risk of filtration and sterilization, such as installing a second sterilized sterilization filter, and the final sterilization filter should be as close as possible to the filling point. Usually, sequence filtering is a filtering method that uses two or more identical or decreasing aperture sizes. In a sequential filtration system, if a sterilization grade filter is added before the final sterilization filter, and the sterility between the two filters is ensured, and the microbial contamination level of the pre filtration medium is generally less than or equal to 10cfu/100ml, this situation is referred to as a redundant filtration system. In a redundant filtering system, the filter near the filling point is called the main filter, and the filter at the front end is called the redundant filter. After the redundant filtering system is used, if the integrity test of the main filter passes, the redundant filter does not need to undergo integrity testing; If the integrity test of the main filter fails, the redundant filter must pass the integrity test. Another type of sequential filtration system refers to a system that has been validated in the filtration process and requires a series (two or more) of sterilization grade filters to achieve sterilization effects. Therefore, this series of filters is considered a sterilization unit and must all pass integrity testing after use.

When designing the position of the filter, consideration should be given to the release of bacterial gases or liquids, and the installation area and position of the filter should be confirmed based on product batch size, pipeline length, installation and sterilization convenience, etc.

When designing a filtration system, consideration should be given to the convenience of filter integrity testing and the risk of microbial contamination it may bring to the system. After sterilization of the filter, the gas and flushing liquid that come into contact with its downstream system must be sterile.

When designing a sterilization filtration system, the safety and convenience of sterilization should be fully considered. When using online sterilization methods, consideration should be given to the discharge of cold air and condensed water within the system, in order to ensure that the low temperature point of the system can also reach the expected F0 value. When using offline sterilization methods, the risks of transfer and installation processes should be fully considered. For example, attention should be paid to the direction of airflow, the sterile operation process of operators, and connection schemes such as sterile connectors can be considered.

If a disposable filtration system is used and requires integrity testing or pre flushing before use, additional factors need to be considered in the design: the pressure resistance of the upstream connecting pipeline, the sterility of the downstream, and the ability to provide sufficient space downstream (such as installing a sterilization grade barrier filter or a corresponding volume of sterile bag) for exhaust and drainage. If a disposable sterile connection device is used, there should be documentation proving that there is no risk of microbial contamination entering.

5. Sterilization and filtration verification

5.1 Overview of Sterilization and Filtration Validation

The sterilization filtration validation described in this guide includes two parts: performance confirmation of the sterilization filter itself and validation of the filtration process. The performance confirmation of the sterilization filter and the validation of the filtration process are difficult to replace each other and should be completed independently.

The performance confirmation of the sterilization filter itself is generally completed by the filter manufacturer, and the main confirmation items include microbial retention testing, integrity testing, biosafety testing (toxicity testing and endotoxin testing), flow rate testing, water pressure testing, multiple sterilization testing, extractability testing, particle release testing, and fiber shedding testing.

Filtration process validation refers to the verification process implemented for specific media to be filtered, combined with specific process conditions. It generally includes bacterial retention tests, chemical compatibility tests, extractable or leached material tests, safety assessments, and adsorption assessments. If the product is used as a wetting medium for integrity testing after filtration, relevant product integrity testing verification should also be conducted. The validation of sterilization filtration process can be completed by the user of the filter or a commissioned testing and inspection agency (such as the producer of the filter or a third-party laboratory), but the user of the filter should ensure that the operating parameters and allowable extreme values in the actual production process have been covered during validation and have corresponding supporting documents.

The validation documents of different filter manufacturers are generally not interchangeable, and the sterilization filtration validation documents of the same material from the same manufacturer cannot be directly exchanged unless there is a reasonable statement or document support. If two or more different manufacturers provide filters of the same material or different materials, or filters of the same material (different film-forming processes) from the same manufacturer during the production process, verification should be conducted separately.

5.2 Bacterial retention test

The research purpose of bacterial retention test is to simulate the poor conditions in actual production filtration process, filter product solutions or product substitute solutions containing a certain amount of challenging microorganisms, in order to confirm the microbial retention ability of the sterilization filter.

Defective pseudomonas (with a diameter of approximately 0.3-0.4 microns and a length of 0.6-1.0 microns, must be single, dispersed cells) are the standard challenge microorganisms for bacterial retention tests in sterilization filtration validation. In some cases, defective pseudomonas cannot represent poor conditions, and other bacteria need to be considered. If other bacteria are used, they should be small enough to challenge the retention performance of the sterilization grade filter and represent the small microorganisms found in the product and production process.

Whether to use a filter membrane or a filter in sterilization filtration validation depends on the purpose of the validation. If the purpose of the microbial retention test is to verify the bacterial retention efficiency of specific membrane materials in the filtration process, then using a filter membrane can meet the needs. The filter membrane used in the microbial retention test must be made of the same material as the actual filter used in production, and should include multiple batches (usually three batches). At least one batch should be a low bubble point (low specification) filter membrane. In order to implement poor conditions in microbial challenge experiments, it is generally necessary to use filter membranes with integrity test values that are very close to the filter integrity limit provided by the filter manufacturer (such as not exceeding 110% of the standard integrity limit). If a low bubble point filter membrane is not used in the validation, the bubble point value of the standard solution filter membrane/core used in actual production must be higher than the small bubble point value of the filter membrane actually used in the validation test.

The microbial retention test should select a 0.45 micron pore size filter membrane as the positive control for each test. The challenge of microbial size requires the ability to penetrate a 0.45 micron filter membrane to demonstrate its cultivation to the appropriate size and concentration. Three different batches of 0.22 micron (or 0.2 micron) test membranes and 0.45 micron control membranes need to be tested in parallel online in one experimental system for challenge testing.

Challenge microorganisms should be directly inoculated into drugs for bacterial challenge as much as possible. However, the drug and/or process conditions themselves may affect the viability of challenging microorganisms. Therefore, before conducting bacterial retention experiments, it is necessary to confirm the survival of challenging microorganisms in the drug under process conditions, in order to determine a reasonable bacterial challenge method, namely activity experiments (survival experiments). If alternative solutions are used for testing, reasonable data and explanations need to be provided. For products of the same family, that is, products with the same components but different concentrations, the method of challenging the limit concentration can be used for verification. The filtration temperature, filtration time, filtration batch size, and pressure difference or flow rate can affect the results of bacterial retention tests.

5.3 Extractable and Leachate Tests

The extract exists in the final active pharmaceutical ingredients and drugs, usually contained in extractable substances, but it is difficult to quantify or qualitatively due to limitations in separation and detection methods, as well as the extremely small amount of extract. Extract data under poor conditions should be obtained first and used for the safety evaluation of drugs. Extractable substances reflect the high likelihood of leaching, and whether or not leaching tests are required, the testing and evaluation of extractable substances are crucial.

A comprehensive evaluation of the product (drug) prescription must be conducted before selecting the model solvent for extractable testing. The model solvent used for testing should be able to simulate actual drug prescriptions, and there should be no chemical compatibility issues with the filter. Usually, it should have the same or similar physical and chemical properties as the product, such as pH value, polarity, or ionic strength. If a model solvent or a combination of several solutions is used, a reasonable basis for solution selection must be provided.

The extractable test can be conducted using static soaking or cyclic flow methods, and its influencing factors include sterilization methods, flushing, chemical properties of the filtered fluid, process time, process temperature, and the ratio of filtration capacity to filtration membrane area. Long filtration time, high filtration temperature, multiple steam sterilization cycles, increased frequency and dosage of gamma radiation may all increase extractable levels. The extractable test should be conducted using sterilized filters. The filter used for testing should not be pre washed as much as possible.

The detection methods for extractable and leached substances include quantitative and qualitative methods. Such as non-volatile residue (NVR), UV spectroscopy, reverse phase high performance liquid chromatography (RP-HPLC), Fourier transform infrared spectroscopy (FTIR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), total organic carbon analysis (TOC), etc. In order to ensure the reliability of the analysis method, it is necessary to verify or confirm the analysis method. The choice of which analysis method to use depends on the actual drug and production process, as well as the filter manufacturer's thorough research on the filter.

After completing the extractable or leachable test, a safety assessment should be conducted on the results based on the type and content of extractable or leachable substances in the filter, combined with the concentration, dosage size, administration time, administration route, etc. in the final dosage form of the drug, to evaluate whether there are safety risks associated with extractable or leachable substances.

5.4 Chemical compatibility test

Chemical compatibility testing is used to evaluate the chemical effects of the filter medium on the filtration device under specific process conditions.

The chemical compatibility test should cover the entire filtration device, not just the filter membrane. The design of the experiment should consider the properties of the medium to be filtered, filtration temperature, and contact time. The filtration time during the experiment should reach or exceed the long process time of the actual production process, and the filtration temperature should reach or exceed the high temperature of the production process.

The chemical compatibility test generally includes visual inspection before and after the filter comes into contact with the medium to be filtered; Changes in flow rate during the filtration process; Changes in filter membrane weight/thickness; Changes in integrity test values such as bubble point before and after filtration; Changes in tensile strength of filter membrane; Confirmation of membrane electron microscopy scanning, etc. Based on a thorough understanding of the filter membrane and filter materials, a comprehensive selection of the above-mentioned detection methods should be made.

5.5 Adsorption Test

The process of certain components in the medium to be filtered adhering to the filter may affect the composition and concentration of the medium to be filtered. The adsorbent materials in the filter include the filter membrane, shell, and supporting materials. Factors such as flow rate, filtration time, concentration of the medium to be filtered, concentration of preservatives, temperature, and pH value may all affect the adsorption efficiency.

5.6 Based on product integrity testing

The wetting medium for integrity testing of the filter after use should be clearly defined. If the wetting medium used is a liquid medicine, verification of product integrity standards should be conducted to support the determination of such standards. The scaled down research under laboratory scale is a part of product integrity testing. The second part is to regularly monitor the trend of product bubble point or product diffusion flow under actual process conditions as part of the validation.

5.7 Re verification

After completing the validation of the filtration process, regular evaluations of product properties and process conditions should also be conducted to determine whether revalidation is necessary. Any change in variables such as product, filter, process parameters, etc. requires an evaluation of whether revalidation is necessary. At least (but not limited to) evaluate the following content to determine whether revalidation is necessary:

The flow rate per unit area is higher than the verified flow rate

Filter pressure difference exceeds verified pressure difference

The filtering time exceeds the verified time

Increase the filtration capacity while keeping the filtration area constant

Filter temperature changes

Product prescription change

Change in sterilization conditions or methods for filters

Change in filter manufacturer, change in filter production process, or change in filter membrane material or structural composition

5.8 Gas filtration verification

In addition to the validation of liquid sterilization filtration mentioned above, for the validation of gas filtration, filter users should first evaluate whether the filter manufacturer's validation documents can cover different applications in actual production. Assess the service life and replacement frequency of gas filters. The evaluation should consider the following aspects: filter integrity, appearance, sterilization frequency, operating temperature, usage point, etc.

5.9 Verification of disposable filtration system

Disposable filtration systems typically include other components in addition to filters. When verifying, the impact of other components on the safety and effectiveness of the process and product should be fully considered.

6. Use of sterilization filters and systems

6.1 Use

The placement of the filter should be convenient for its installation, disassembly, testing, and other operations, and should not affect its functional use. The connection between the filter and the supporting equipment, floor, wall, etc. should be firm and reliable. The components of the filter should be tightly connected, well sealed, able to withstand production operating pressure, and have no leakage or deformation. Before installing filters and filter membranes, their specifications, models, and appearance should be confirmed to meet the requirements. During the assembly process, pollution should be avoided as much as possible. The installation should be carried out according to the instructions for using the filter. If there are multiple specifications of filters on site, a second person should review and confirm the filter information, and the review should be recorded.

In order to reduce the impact of particles and other foreign objects generated by the filter on the product, necessary pre flushing can be carried out on the installed sterilization filtration system. The flushing should be carried out in conjunction with the methods provided by the supplier. The flushing method should be validated. During normal operation, the flushing volume should not be lower than the verified low flushing volume. After rinsing, appropriate methods should be used to remove the rinsing solution.

The sterilization filtration system should undergo risk assessment and try to confirm its airtightness as much as possible. The airtightness of the upstream system of the filter can be confirmed through pressure maintenance and online integrity testing. The downstream sealing of the filter can be confirmed by pressure maintenance, and the relevant parameters should be validated.

Sterilization filtration should be carried out within the specified process control parameter range. To ensure the effectiveness of sterilization filtration, key parameters that affect the sterilization filtration effect should be controlled and recorded. The control items should include sterilization filtration temperature, time, pressure, upstream and downstream pressure difference, etc; Sterilization parameters of the system and sterile receiving containers; And the results of filter integrity testing, etc.

In addition to process parameters, key information of the filter should also be recorded (such as item number, batch number, serial number, or other identification number) for traceability purposes.

A training plan should be developed for the enterprise, and relevant training on sterilization filters should be included in the training plan. The training content includes theoretical knowledge and operational skills. Theoretical knowledge training includes usage instructions, working principles, relevant parameters, and validation requirements for filter cartridges and filtration systems provided by filter manufacturers; Operational skills training includes standard operating procedures for the use of relevant filter elements, such as integrity testing training, cleaning and sterilization, drying, storage and other operational training, product sterilization and filtration process training, system tightness testing training, etc. Personnel should undergo theoretical and practical assessments, and only those who pass the assessment can take up their positions. When there are changes in the system or parameters and the relevant standard operating procedures are revised, personnel should be retrained.

When there is a deviation in the sterilization and filtration process, a thorough investigation should be conducted to identify the root cause and take corrective measures. Risk assessment should be conducted for products that have deviations.

6.2 Sterilization

Before use, the sterilization filter must undergo sterilization treatment (such as online or offline steam sterilization, radiation sterilization, etc.). The design and operation process of online steam sterilization should focus on the high pressure difference and temperature that the filter element can tolerate. Before sterilization begins, non condensable gases and condensed water in the system should be discharged from the filter and pipeline equipment. During the sterilization process, the internal cold point of the filtration system should reach the set sterilization temperature. During the entire sterilization process, the pressure difference between the upstream and downstream of the filter element should not exceed the large pressure difference that the filter element can withstand at a specific temperature. After sterilization, clean air or other suitable gases can be introduced to cool down the system. During cooling, a certain positive pressure should be maintained to maintain the sterile state of the system.

When using a sterilizer for sterilization, the pulsating vacuum sterilization method is usually used. The sterilization process should ensure that the filter can be penetrated by steam, thereby sterilizing the filter. Whether using a filter element with a stainless steel sleeve or a bag filter, both the inlet and outlet ends of the filter should be able to pass through steam. Sterilization should refer to the sterilization parameters provided by the filter manufacturer. Excessive temperature may lead to unstable properties of the polymer material on the filter, and may affect the physical integrity of the filter or increase the extractable level.

Filters, disposable bags, hoses, and other devices may be used in sterilization filtration, which can be sterilized using radiation sterilization. Filters, bags, and hoses that have been sterilized by radiation should not be sterilized multiple times due to cumulative dose effects. If steam sterilization is further applied, it may increase the level of extractable substances, unless the irradiation and steam sterilization of the sterilization filter have been validated.

When online steam is used for sterilization of tank respirators, the reverse steam inlet method can be adopted, that is, steam is directly introduced into the tank, then passes through the filter element downstream of the respirator and is discharged upstream. But the reverse pressure difference during sterilization of the filter element should be controlled. This pressure difference should be maintained within the tolerance range of the filter element. It is recommended to use a filter element with a snap in interface during reverse sterilization, and it is not recommended to use a direct insertion filter element.

6.3 Integrity testing

After using the sterilization filter, its integrity must be immediately tested and recorded using appropriate methods. Before using the sterilization filter, a risk assessment should be conducted to determine whether integrity testing should be performed and whether it should be performed before or after sterilization. When conducting integrity testing after sterilization and before use, measures need to be taken to ensure the sterility downstream of the filter. The commonly used integrity testing methods include bubble point testing, diffusion/forward flow testing, or water intrusion testing.

Disinfectants entering the * and B-class clean areas should be sterilized through filtration or other appropriate methods. If using filtration methods for sterilization, the suitability between the disinfectant and the selected filter material should be evaluated. The filter needs to undergo integrity testing after use.

Filters used for direct contact with sterile liquids or sterile equipment surfaces should undergo integrity testing after each batch or multiple batches of continuous production are completed. For other applications, the frequency of integrity testing can be determined based on the results of risk assessment. The integrity testing of gas filters can be carried out using low surface tension liquid wetting for bubble point or diffusion/forward flow testing; Water intrusion testing can also be used. The water intrusion method can be given priority.

For redundant filtering, the main filter should be tested for integrity before use. If the integrity test of the main filter passes, the redundant filter does not need to undergo integrity testing; If the integrity test of the main filter fails, it is necessary to perform integrity testing on the redundant filters. The integrity test results of redundant filters can serve as the basis for product release. Before using the sterilization filter, a risk assessment should be conducted to determine whether integrity testing should be performed, which level of filter or both levels of filters should be tested, and whether the testing should be performed before or after sterilization of the filter. After sterilization testing, consideration should be given to ensuring sterility between the two-stage filters.

Online integrity testing or offline integrity testing can be determined based on process requirements and actual conditions. However, it should be noted that integrity testing is to check the integrity of the entire filtering system, not just the filter itself. Online testing can better ensure the integrity of upstream and downstream connections. When the online testing conditions cannot be met, offline integrity testing can be chosen. At this point, the filter should be kept in the sleeve and disassembled as a whole for direct testing. The filter element should not be disassembled from the stainless steel sleeve for separate testing.

Considering the objectivity of integrity testing results and the reliability of data, automated integrity testers should be used as much as possible at critical usage points. The automated integrity tester should undergo installation confirmation, operation confirmation, and performance confirmation before use. An operating procedure for the use, cleaning, and maintenance of the equipment should be established, as well as a regular preventive maintenance plan (which should include periodic calibration requirements for the equipment).

For the integrity testing of sterilization filters wetted with standard media (water or certain alcohols), the parameter settings should be based on the parameters provided by the filter manufacturer, and the parameters must be verified by the filter manufacturer to prove their correlation with bacterial retention results. Usually, this parameter can be obtained on the quality certificate of the filter.

If non-standard media (usually actual products) need to be used for wetting and integrity testing of sterilization filters in actual processes, the integrity testing limits, such as product bubble point or product diffusion flow standards, must be obtained through validation using actual products as wetting media.

A standard operating procedure for integrity testing should be established, including testing methods, setting of testing parameters, properties and temperature of wetting liquids, wetting operation procedures (such as pressure, time, and flow rate range), testing gases, data recording requirements, etc.

The determination of integrity test results should not be directly based on "pass/fail". The specific numerical values of the test results or the process data in the automatic integrity tester report should be fully recorded and reviewed.

If the integrity test fails, it should be recorded and investigated. Possible influencing factors include insufficient wetting, product residue, incorrect filter installation, system leakage, incorrect filters, incorrect automation program settings, and testing equipment issues. When retesting, the following measures should be taken based on the analysis results, such as strengthening wetting conditions, strengthening cleaning conditions, wetting with low surface tension liquids such as alcohols, testing system airtightness, checking whether the filter model is correct, checking automation program settings, and inspecting equipment. The process and results of retesting should be fully documented.

6.4 Reuse

When designing and manufacturing liquid sterilization filters, only the use in a single batch or the use in multiple consecutive production cycles is generally considered. However, in practical work, sometimes filters are used in the production process of multiple batches and the same product. It is generally believed that the reuse of liquid sterilization grade filters can be defined as the filtration of multiple batches of the same liquid product. The following situations belong to the reuse of liquid filters:

(1) Wash between batches

(2) Inter batch flushing and sterilization

(3) Inter batch flushing, cleaning, and sterilization

On the basis of fully understanding the product and process risks, evaluate whether the filter can be reused repeatedly through risk assessment. Risk factors include: bacterial penetration, filter integrity defects, increased extractables, suitability of cleaning methods for cleaning various components within the product, impact of residual products (or derivatives of sterilized components) on the quality risk of the next batch of products, premature clogging of filters, performance changes caused by aging of filter components, etc. Assessment should consider individualized differences, provide sufficient validation and data support, and continuously monitor during use.

6.5 Special considerations for gas filters

Due to the hydrophobicity of the filter membrane, gas filters allow gases to pass freely. However, condensation caused by changes in system or environmental temperature may result in poor gas filtration and, in severe cases, damage to the system or filter. If necessary, a condensate discharge device should be installed at a reasonable position on the filtration pipeline. For tank breathing filters, the installation of a heating sleeve should be determined based on the actual situation to ensure smooth passage of gas through the filter element.

6.6 Disposable filtration system

Due to the special nature of pre sterilization of disposable filtration systems, it is necessary to confirm whether the outer packaging is intact when unpacking; The product is still within its validity period; The packaging has a pre sterilization label and can be determined to have undergone pre sterilization treatment; And the correctness of the components; Whether there is damage, obvious foreign substances, etc.

During installation, care should be taken not to compromise the downstream sterility of the system, and the use of sterile connectors is encouraged to reduce risks.

When deciding whether to conduct integrity testing before using a disposable filtration system, a risk assessment should be based on the following factors (but not limited to):

Assess the impact of filter integrity failure, including the possibility of introducing non sterile products into sterile areas

Assess the risk of contamination introduced by additional components and operations

Potential damage detected

The possibility of disrupting downstream sterility of the filter during pre sterilization integrity testing

Will the wetting liquid dilute the product or affect its quality properties

The impact of additional time on time sensitive processes

7. Bacterial reduction and filtration process

Compared to sterilization filtration, sterilization filtration is a filtration process that reduces the level of microbial contamination in the medium to an acceptable level through filtration.

Sterilization filtration is usually designed at the front end of the filling process for sterile preparations produced by terminal sterilization processes, or at the front end of the sterilization filtration process for sterile preparations produced by non terminal sterilization processes. The purpose of sterilization filtration is to ensure that the microbial contamination level of the product before final sterilization or sterilization filtration meets expectations.

The antibacterial filtration system should use filters with pore sizes of 0.45 microns or 0.22 microns (or less) to achieve an acceptable level of microbial contamination. The design of the filtration system should aim for controllable process parameters and results, taking into account factors such as filter size, filtered liquid volume, filtration time, filtration pressure difference, and the way and time of receiving and storing liquid. Due to the non sterile nature of the liquid before and after filtration, attention should be paid to the changes in microbial contamination levels in the liquid during design.

Verification should be conducted to confirm that the antibacterial filter will not have a negative impact on the medication. The validation of the bacterial reduction filtration process can be part of the product process validation.

The normal operation of sterilization filtration is an important measure to ensure that the microbial contamination level of the product before final sterilization (or sterilization filtration) meets an acceptable level. The validation of the bacterial reduction filtration process should include chemical compatibility, extractables/extractables, and adsorption. Corresponding standard operating procedures should be established to standardize the use of filters, such as installation, system connection, disinfection or sterilization, integrity testing, etc; Key process parameters such as filtration pressure difference and filtration time should be established for the sterilization filtration process.

When reusing filter cartridges, verification of cleaning effectiveness, multiple sterilization (or disinfection) cycles, etc. should also be conducted. Reusing filter cartridges should have no adverse effects on the filter media and not increase the risk of product contamination and cross contamination. Reusable filter cartridges should not be used for different types of products. Standard operating procedures should be developed to manage important matters such as cleaning, sterilization, storage, and labeling of reusable filter cartridges.

8. Terminology Explanation

(1) Microbial contamination level: the types and quantities of microorganisms present in raw materials, raw materials for APIs, intermediates, or APIs.

(2) Adsorption: The process in which certain components of the medium to be filtered adhere to the filter membrane (or filter), which may affect the composition and concentration of the medium to be filtered.

(3) Sterilization filter: According to ASTM 838-15, challenge the filter with defective pseudomonas with a challenge level greater than or equal to 1 × 107 cfu/cm2 effective filtration area. After appropriate validation, the filter can stably reproduce the production of sterile filtrate.

(4) Effective filtration area: The total surface area of the filter that can be used to filter process media.

(5) Redundant filtration: a multi-stage filtration system used to reduce the risk of sterilization filtration. Install a sterilized sterilization level filter before the final sterilization filter, and ensure the sterility between these two levels of filters. In redundant filtration systems, the first level near the final filling point is generally referred to as the main filter. The first level is called a redundant filter. When the integrity test of the main filter fails under the conditions of redundant filtering, the redundant filter passes the test and the product can still be accepted.

(6) Sequential filtering: a filtering method that uses two or more identical or decreasing aperture sizes.

(7) Integrity testing: a non-destructive physical test related to the bacterial retention ability of filters/filtration devices.

(8) Aseptic connection: A connection method that connects two or more independent systems in a non sterile environment without compromising the sterility of the system.

(9) Barrier filter: a filter that contains both hydrophobic and hydrophilic membranes, capable of filtering both gases and liquids simultaneously.

(10) Chemical compatibility test: a test to determine if there are any adverse reactions or interactions between the filter and the filtered medium.

(11) Disposable filtration system: a filtration process equipment solution typically assembled from polymer components to form a complete filtration system, used for a single or phased production activity, and discarded after a single use.

(12) Extractable substances: Chemical substances that can be extracted from the process medium contact surface of filters and other component materials under special conditions (such as organic solvents, particularly high temperatures, ionic strength, pH, contact time, etc.). Extractable substances can characterize most (but not all) potential leachables in the process medium.

(13) Poor conditions: conditions or states that result in a higher probability of process and product failure than normal processes, i.e. the upper and lower limits of processes within the scope of standard operating procedures. However, such poor conditions do not necessarily lead to substandard products or processes.

(14) Leachate: Chemical substances that migrate from materials in contact or non-contact products into pharmaceutical products or process fluids under storage or conventional process conditions. The extract may be a subset of extractables, or it may include reaction or degradation products of extractables.

(15) Model solvent: an extraction solvent that has the same or similar physical and chemical properties as the actual drug ingredients. The pH of actual drugs, appropriate concentrations of organic solvents, and organic solutes are all the basis for selecting model solvents.

(16) Bubble point: The small pressure required for gas to be extruded from the large pores of a fully wetted porous membrane and form a continuous, stable or large amount of gas.

(17) Diffusion flow/forward flow: Applying a gas pressure below the bubble point, gas molecules diffuse downstream of the filter membrane through fully wetted membrane pores at a flow rate.

(18) Water intrusion test: It measures the resistance of a dry hydrophobic filter membrane to water wetting under a certain pressure. Measure the "apparent" water flow rate formed by a small but measurable decrease in liquid level below the breakthrough pressure of water.

(19) Multi batch continuous production: a production mode that runs multiple batches continuously without cleaning or sterilization in the middle.

(20) Final sterilization: Sterilize products that have completed final sealing to ensure that the probability of microbial survival (i.e. sterility assurance level, SAL) in the product does not exceed 10-6. The standard sterilization time F0 value for wet heat sterilization method should be greater than 8 minutes. Circulating steam treatment does not belong to final sterilization.

9 Reference Regulations and Guidelines

[1] Good Manufacturing Practice for Drugs (revised in 2010) and its appendices;

[2] PDA Technical Report No.40，Sterilizing Filtration of Gases；

[3] PDA Technical Report No.26 Revised 2008，Sterilizing Filtration of Liquids；

[4] USFDA Guidance for Industry，Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice，2004；

[5] EU Guidelines to Good Manufacturing Practice，Annex 1 Manufacture of Sterile Medicinal Products，2008。