Considerations on Re-Use of Sterilizing-Grade Filters - Pharmaceutical Technology

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Considerations on Re-Use of Sterilizing-Grade Filters
The author examines re-use of hydrophilic- or hydrophobic-membrane sterilizing-grade filters in liquid sterilizing applications.


Pharmaceutical Technology


Cleaning filter cartridges

Cleaning is a complex issue that goes beyond simple rinse and re-use. Cleaning involves the removal of all prior batch residual materials from the entire system, including all piping, tanks, valves and filters. A water-for-injection (WFI) flush (or pure solvent flush) following the final rinse must show that the system is clean to a predefined level of cleanliness using validated analytical methods. If any clean-in place (CIP) material is used, it also must be rinsed out completely.

Keep in mind that cleaning may lead to material from the upstream tanks and pipes being filtered out and remain on the filters. This retention can result in leaching into the next product batch. It is the responsibility of each user to develop and validate a proper cleaning method. Users should consult with filter manufacturers on suitability of intended cleaning protocols.

Regarding CIP of a filter used for liquid processing, there are several additional points to consider:
  • Some process fluids can support bacterial growth, which may lead to pyrogenic bacterial endotoxins on the filter as a degradative byproduct of the retained bacterial cells. Endotoxin levels must be kept low. Therefore, carryover of any bacterial growth-supporting fluid from one product cycle to the next is problematic.
  • Once a filter has any appreciable amount of plugging (i.e., lower flow rate or higher pressure differential), the plugged pores do not allow easy flow of fluids and therefore prevent access of cleaning solutions to the plugged pores.
  • The cleaning fluid will preferentially flow through cleaner pathways, leaving the "dirtier" plugged pathways virtually unaffected.
  • Some product residues and cleaning-solution components always stay on a filter to some extent. Any cleaning process needs to be defined in terms of acceptable limits of residual leachable material detected by a defined validated test.

Cleaning and re-use of a filter in a pharmaceutical application can be more or less difficult depending on the magnitude of the following factors:

  • Bacteria bioburden levels in the feed
  • Growth-supporting activity of the product
  • Plugging of the filter
  • Biological activity of the product, product components, or byproducts
  • Resistance of the product, product components, or byproducts to solubilization
  • Adherence of the product, product components, or byproducts to filter materials
  • Difficulty of selecting an aseptic or growth-inhibiting filter storage method compatible with product.

These risks provide a rationale for single-use of disposable filters. Often, when taking risks into consideration, the drug product or process fluid is significantly more expensive than the filter and the risk to product quality and patient safety is too great to make filter re-use attractive.

Conclusion

Re-use of any disposable equipment is subject to risks and hazards that must be controlled to ensure the equipment remains safe and effective and continues to meet its manufacturer's specifications and requirements for use. The following considerations are intended only to identify some of the risks associated with the re-use of sterilizing-grade filters. These concepts should not be construed as universally applicable in all circumstances, nor do they relieve the user of complete responsibility for multiple re-use of these products.

Reprocessing systems for sterilizing-grade filters may include equipment to flush, clean, and re-sterilize the filters. Each piece of equipment used for reprocessing must be appropriately designed, constructed, and validated. Grades of water and other fluids used in reprocessing should be specified in the master record. All chemicals used in reprocessing and all filter effluents, including drug product residues, must be handled and disposed of in compliance with local, regional, and national requirements for operator and environmental safety. Documentation should accurately record the processes carried out and the results of tests for filter performance and safety.

Testing of validated filters for integrity, non-pyrogenicity, and removal of prior fluid residues or byproducts should be conducted before re-use. Validation testing is performed to establish performance and time limits for re-used sterilizing filters in each manufacturing process. Validation should follow FDA guidelines for aseptic processing in that factors such as pH, viscosity, flow rates, pressure, temperature, chemical compatibility, and effects of hydraulic shock should be considered when establishing limits for multiple re-use of filters.

In addition, controls must be instituted and documents maintained to ensure that filters containing residues of product or cleaning agents that could adversely affect effluent drug product quality, safety, or efficacy are not used in subsequent lots. Unlike data from the filter manufacturer, data on re-used filter retention properties, pyrogenicity, and leachable residues are specific to each user process and conditions of use. Despite these cautions and the risks involved, re-use of sterilizing filters is currently practiced by some pharmaceutical companies who have developed product- and process-specific re-use protocols.


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