Regulatory guidance on re-use of sterilizing-grade filters
FDA and ICH guidelines.
A review of API and nonsterile drug manufacturing guidance from the US Food and Drug Administration and European Medicines
Agency (EMEA) indicates that neither use nor re-use of sterilizing-grade filters is specifically covered for nonsterile APIs
or nonsterile finished drug products (1–2). Such guidance would also apply to use of sterilizing-grade filters in manufacture
of nonsterile API and biotech APIs from fermentation to downstream purification, including sterile-filtered media, additives,
buffers, and process intermediates. Although use of sterilizing-grade filters in nonsterile API and nonsterile drug manufacturing
(e.g., for bioburden control) may be considered current good manufacturing practice (CGMP), specific guidance for use and
re-use of sterilizing-grade filters is only provided under guidance for sterile drugs.
There is one aspect of ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients that can be considered applicable to the re-use of sterilizing-grade filters even with nonsterile APIs. ICH Q7A states, "Equipment
should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the
intermediates and APIs beyond the official or other established specifications" (2). Under this guidance, the potential impact
of sterilizing-grade filters on the API, including extractables data that may be provided by the filter manufacturer, in cases
where filters are re-used in API manufacturing, the end user should also consider the potential impact on the product of retained
bacteria and insufficiently removed product or cleaning agent residues on the filter surface.
With regard to sterile drug manufacturing, a corresponding statement can be found in 21 CFR 211.65(a) on CGMP for finished pharmaceuticals, which states,
"Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not
be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements" (3).
The same consideration for potential impact of surfaces of re-used filters would apply.
FDA's Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing—Current GMP presents two views with regard to use and re-use of sterilizing filters. For sterile drug products, the guidance states, "Sterilizing
filters should be routinely discarded after processing of a single lot" (4). Although this statement appears nonsupportive
of re-use of sterilizing filters, it is followed by the statement, "However, in those instances when repeated use can be justified,
the sterile filter validation should incorporate the maximum number of lots to be processed." This allowance indicates that
where sterilizing-grade filters are to be re-used, the sterilizing filtration process validation should assess the impact
of cleaning and resterilization in the end-user's process. The guidance goes on to state, "It is important that integrity
testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration."
This guidance applies to individual batches and campaigns of batches. Of critical interest is that the guidance suggests that
filter leaks or perforations presumably capable of compromising sterilizing performance will be detected by integrity testing.
The European Commission's Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (Annex 1 on Manufacture of Sterile
Medicinal Products), states, "The same filter should not be used for more than one working day unless such use has been validated" (5). While
this statement seems to allow extended use and potential re-use of filters, process validation should include consideration
of any re-use effects on the filter. The guidance goes on to state, as in the API guides, that, "The filter should not affect
the product by removal of ingredients from it or by release of substances into it." Here again, the leaching of contaminant
or cleaning residue from used filters before re-use should be considered and absence of any such effects should be validated.
Industry recommendations on re-use of sterilizing-grade filters have been limited to date. The first edition of the Parenteral
Drug Association (PDA) Technical Report 26, "Sterilizing Grade Filtration of Liquids" in 1988 focused exclusively on final
drug sterilization and did not address re-use of sterilizing-grade filters (6). The 2008 revision of this document considers
applications of sterilizing-grade filters in biotechnology and pharmaceuticals manufactured outside the US, and states, "Sterilizing
filters should be routinely discarded after processing of a single lot." But the revision also elaborates on FDA's aseptic
processing guidance on re-use by stating,
"However, in instances where repeated use can be justified, the sterile filter validation, including integrity testing, bacterial
challenge and cleaning should incorporate the maximum number of lots to be processed" (6).
As a co-author of both PDA documents, this author supports PDA's recommendation to subject filters at the extent of re-use
and cleaning cycles to a bacterial challenge.