Filter sterilisation of products which cannot be sterilised in their final container
8.79 If the product cannot be sterilised in its final container, solutions or liquids should be sterilised by filtration through a sterile sterilising grade filter (with a nominal pore size of a maximum of 0.22 µm that has been appropriately validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously sterilised container. The selection of the filter used should ensure that it is compatible with the product and as described in the marketing authorization (see paragraph 8.135).
8.80 Suitable bioburden reduction prefilters and/or sterilising grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the final sterilising filter. Due to the potential additional risks of a sterile filtration process, as compared with other sterilisation processes, an additional filtration through a sterile sterilising grade filter, as close to the point of fill as possible, should be considered as part of an overall CCS.
8.81 The selection of components for the filtration system and their interconnection and arrangement within the filtration system, including pre-filters, should be based on the critical quality attributes of the product, justified and documented. The filtration system should minimize the generation of fibres and particles, not cause or contribute to unacceptable levels of impurities, or possess characteristics that otherwise alter the quality and efficacy of the product. Similarly, the filter characteristics should be compatible with the fluid and not be adversely affected by the product to be filtered. Adsorption of product components and extraction/leaching of filter components should be evaluated (see paragraph 8.135).
8.82 The filtration system should be designed to:
- Allow operation within validated process parameters.
- Maintain the sterility of the filtrate.
- Minimize the number of aseptic connections required between the final sterilising grade filter and the final filling of the product.
- Allow cleaning procedures to be conducted as necessary.
- Allow sterilisation procedures, including sterilisation in place, to be conducted as necessary.
- Permit in-place integrity testing, of the 0.22 µm final sterilising grade filter, preferably as a closed system, both prior to, and following filtration as necessary. In-place integrity testing methods should be selected to avoid any adverse impact on the quality of the product.
8.83 Sterile filtration of liquids should be validated in accordance with relevant Pharmacopeia requirements. Validation can be grouped by different strengths or variations of a product but should be done under worst-case conditions. The rationale for grouping should be justified and documented.
8.84 During filter validation, wherever possible, the product to be filtered should be used for bacterial retention testing of the sterilising grade filter. Where the product to be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test should be justified.
8.85 Filtration parameters that should be considered and established during validation should include, but are not limited to:
i. The wetting fluid used for filter integrity testing:
- It should be based on the filter manufacturer’s recommendation or the fluid to be filtered. The appropriate integrity test value specification should be established.
- If the system is flushed or integrity tested in-situ with a fluid other than the product, appropriate actions are taken to avoid any deleterious effect on product quality.
ii. Filtration process conditions including:
- Fluid pre-filtration holding time and effect on bioburden.
- Filter conditioning, with fluid if necessary.
- Maximum filtration time/total time filter is in contact with the fluid.
- Maximum operating pressure.
- Flow rate.
- Maximum filtration volume.
- Temperature.
- The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter.
8.86 Routine process controls should be implemented to ensure adherence to validated filtration parameters. Results of critical process parameters should be included in the batch record, including but not limited to the minimum time taken to filter a known volume of bulk solution and pressure difference across the filter. Any significant difference from critical parameters during manufacturing should be documented and investigated.
8.87 The integrity of the sterilised filter assembly should be verified by integrity testing before use (pre-use post sterilisation integrity test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilising grade filter that is used to sterilise a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. The integrity test process should be validated and test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that PUPSIT may not always be possible after sterilisation due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of a non-integral filtration system. Points to consider in such a risk assessment should include but are not limited to:
* PUPSIT 컨셉트 기본 골격 [ (연결In - 압력센서-Integrity tester connect-Sterile Filter-Air & Liquid out-연결out) + 각종 bag ]
i. In depth knowledge and control of the filter sterilisation process to ensure that the potential for damage to the filter is minimized.
ii. In depth knowledge and control of the supply chain to include:
- Contract sterilisation facilities.
- Defined transport mechanisms.
- Packaging of the sterilised filter, to prevent damage to the filter during transportation and storage.
iii. In depth process knowledge such as:
- The specific product type, including particle burden and whether there exists any risk of impact on filter integrity values, such as the potential to alter integrity-testing values and therefore prevent the detection of a non-integral filter during a post-use filter integrity test.
- Pre-filtration and processing steps, prior to the final sterilising grade filter, which would remove particle burden and clarify the product prior to the sterile filtration.
8.88 The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product) should be verified by testing after use, with the filter remaining in the filter assembly or housing.
8.89 The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. Where gas filters are in place for extended periods, integrity testing should be carried out at installation and prior to replacement. The maximum duration of use should be specified and monitored based on risk (e.g. considering the maximum number of uses and heat treatment/ sterilisation cycles permitted as applicable).
8.90 For gas filtration, unintended moistening or wetting of the filter or filter equipment should be avoided.
8.91 If the sterilising filtration process has been validated as a system consisting of multiple filters to achieve the sterility for a given fluid, the filtration system is considered to be a single sterilising unit and all filters within the system should satisfactorily pass integrity testing after use.
8.92 In a redundant filtration system (where a second redundant sterilising grade filter is present as a backup but the sterilising process is validated as only requiring one filter), post-use integrity test of the primary sterilising grade filter should be performed and if demonstrated to be integral, then a post- use integrity test of the redundant (backup) filter is not necessary. However, in the event of a failure of the post-use integrity test on the primary filter, post-use integrity test on the secondary (redundant) filter should be performed, in conjunction with an investigation and risk assessment to determine the reason for the primary filter test failure.
8.93 Bioburden samples should be taken from the bulk product and immediately prior to the final sterile filtration. In case where a redundant filtration set-up is used, it should be taken prior to the first filter. Systems for taking samples should be designed so as not to introduce contamination.
8.94 Liquid sterilising grade filters should be discarded after the processing of a single batch and the same filter should not be used continuously for more than one working day unless such use has been validated.
8.95 Where campaign manufacture of a product has been appropriately justified in the CCS and validated, the filter user should:
- Assess and document the risks associated with the duration of filter use for the sterile filtration process for a given fluid.
- Conduct and document effective validation and qualification studies to demonstrate that the duration of filter use for a given sterile filtration process and for a given fluid does not compromise performance of the final sterilising grade filter or filtrate quality.
- Document the maximum validated duration of use for the filter and implement controls to ensure that filters are not used beyond the validated maximum duration. Records of these controls should be maintained.
- Implement controls to ensure that filters contaminated with fluid or cleaning agent residues, or considered defective in any other way, are removed from use.
Filter sterilisation of products which cannot be sterilised in their final container
8.79 If the product cannot be sterilised in its final container, solutions or liquids should be sterilised by filtration through a sterile sterilising grade filter (with a nominal pore size of a maximum of 0.22 µm that has been appropriately validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously sterilised container. The selection of the filter used should ensure that it is compatible with the product and as described in the marketing authorization (see paragraph 8.135).
8.80 Suitable bioburden reduction prefilters and/or sterilising grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the final sterilising filter. Due to the potential additional risks of a sterile filtration process, as compared with other sterilisation processes, an additional filtration through a sterile sterilising grade filter, as close to the point of fill as possible, should be considered as part of an overall CCS.
8.81 The selection of components for the filtration system and their interconnection and arrangement within the filtration system, including pre-filters, should be based on the critical quality attributes of the product, justified and documented. The filtration system should minimize the generation of fibres and particles, not cause or contribute to unacceptable levels of impurities, or possess characteristics that otherwise alter the quality and efficacy of the product. Similarly, the filter characteristics should be compatible with the fluid and not be adversely affected by the product to be filtered. Adsorption of product components and extraction/leaching of filter components should be evaluated (see paragraph 8.135).
8.82 The filtration system should be designed to:
8.83 Sterile filtration of liquids should be validated in accordance with relevant Pharmacopeia requirements. Validation can be grouped by different strengths or variations of a product but should be done under worst-case conditions. The rationale for grouping should be justified and documented.
8.84 During filter validation, wherever possible, the product to be filtered should be used for bacterial retention testing of the sterilising grade filter. Where the product to be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test should be justified.
8.85 Filtration parameters that should be considered and established during validation should include, but are not limited to:
i. The wetting fluid used for filter integrity testing:
ii. Filtration process conditions including:
8.86 Routine process controls should be implemented to ensure adherence to validated filtration parameters. Results of critical process parameters should be included in the batch record, including but not limited to the minimum time taken to filter a known volume of bulk solution and pressure difference across the filter. Any significant difference from critical parameters during manufacturing should be documented and investigated.
8.87 The integrity of the sterilised filter assembly should be verified by integrity testing before use (pre-use post sterilisation integrity test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilising grade filter that is used to sterilise a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. The integrity test process should be validated and test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that PUPSIT may not always be possible after sterilisation due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of a non-integral filtration system. Points to consider in such a risk assessment should include but are not limited to:
* PUPSIT 컨셉트 기본 골격 [ (연결In - 압력센서-Integrity tester connect-Sterile Filter-Air & Liquid out-연결out) + 각종 bag ]
i. In depth knowledge and control of the filter sterilisation process to ensure that the potential for damage to the filter is minimized.
ii. In depth knowledge and control of the supply chain to include:
iii. In depth process knowledge such as:
8.88 The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product) should be verified by testing after use, with the filter remaining in the filter assembly or housing.
8.89 The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. Where gas filters are in place for extended periods, integrity testing should be carried out at installation and prior to replacement. The maximum duration of use should be specified and monitored based on risk (e.g. considering the maximum number of uses and heat treatment/ sterilisation cycles permitted as applicable).
8.90 For gas filtration, unintended moistening or wetting of the filter or filter equipment should be avoided.
8.91 If the sterilising filtration process has been validated as a system consisting of multiple filters to achieve the sterility for a given fluid, the filtration system is considered to be a single sterilising unit and all filters within the system should satisfactorily pass integrity testing after use.
8.92 In a redundant filtration system (where a second redundant sterilising grade filter is present as a backup but the sterilising process is validated as only requiring one filter), post-use integrity test of the primary sterilising grade filter should be performed and if demonstrated to be integral, then a post- use integrity test of the redundant (backup) filter is not necessary. However, in the event of a failure of the post-use integrity test on the primary filter, post-use integrity test on the secondary (redundant) filter should be performed, in conjunction with an investigation and risk assessment to determine the reason for the primary filter test failure.
8.93 Bioburden samples should be taken from the bulk product and immediately prior to the final sterile filtration. In case where a redundant filtration set-up is used, it should be taken prior to the first filter. Systems for taking samples should be designed so as not to introduce contamination.
8.94 Liquid sterilising grade filters should be discarded after the processing of a single batch and the same filter should not be used continuously for more than one working day unless such use has been validated.
8.95 Where campaign manufacture of a product has been appropriately justified in the CCS and validated, the filter user should: