No clear guidance is available on filter integrity testing (FIT) requirements in drug substance manufacturing. This paper aims to fill that gap with a risk-based, value-driven approach for FIT testing of sterilizing grade filters used to manufacture low bioburden drug substances.
Viewing related articles
A risk-based approach to filter integrity testing requirements for biologics drug substance manufacturers
Annex 1 of the EudraLex includes recommendations for filter integrity testing (FIT) of filters used for sterile filtration of sterile drug products. Manufacturers of low bioburden drug substances (DS) are seeking guidance on
the appropriate strategy for integrity testing of filters used in bioprocessing. The BioPhorum Closed Systems in CNC Spaces workstream developed a risk-based (and value-driven) approach for FIT testing of sterilizing grade filters used in the manufacture of low bioburden drug substances. This study yielded key criteria which served as the basis of a decision tree model for when and where FIT should be implemented to mitigate the risk of contamination. The findings of the study and the decision tree model were compared to current industry practice. Strong alignment was evident, suggesting the model could be used by DS manufacturers to develop a robust strategy for FIT which is congruent with regulatory guidance – specifically EudraLex Annexes 1 and 2. The risk-based approach is recommended to avoid dilution of effort on unnecessary FIT controls and target critical FIT use-cases that increase process reliability and patient safety outcomes.
SFQRM: Strategy roadmap for the implementation of a risk-based approach to pre-use post-sterilization integrity testing (Pupsit)
Subject matter experts from the SFQRM Consortium has prepared this strategy roadmap with suggested actions and considerations to support the implementation of an effective risk-based approach:
SFQRM: The use of scientific data to assess and control risks associated with sterilizing filtration: a PDA and BioPhorum collaboration
It is generally recognized that post-use filter integrity testing is sufficient to detect filter failure and ensure patient safety unless there is a possibility that a filter passing the post-use test could have allowed bacterial penetration during filtration. This possibility is the phenomenon referred to as filter “flaw masking”, hypothesized to occur when, for example, a filter is damaged during sterilization such that it allows bacterial penetration, but that the damage becomes plugged during the filtration process to such an extent that it allows the filter to exhibit a passing post-use integrity test result. Two workstreams within the SFQRM consortium were designed specifically to evaluate the risk of this filter flaw masking and to understand in what conditions it might occur: Masking Studies, and Bacterial Challenge Test (BCT) Data Mining.
This article presents an update on the efforts of the joint PDA and BioPhorum collaboration workstreams—masking studies, historical data mining, filter manufacturing and use risk assessments and PUPSIT risk assessment and the development of a best practice guide.
This paper is one in a series of publications that are the result of the collaboration, and these should be considered together and viewed holistically in order to determine the best course of action with regard to PUPSIT. This paper examines the test process and looks at the results of potential masking of sterilizing grade filters.
SFQRM: The use of scientific data to assess and control risks associated with sterilizing filtration
This article draws conclusions from the scientific studies, workstreams, and publications delivered by the Sterile Filtration Quality Risk Management (SFQRM) consortium formed between BioPhorum and PDA. It uses those conclusions to provide guidance to industry (sterile drug manufacturers, filter suppliers, and regulators) on the use of quality risk management principles and scientific data to prevent undetected non-integral sterilizing filters.
Eudralex volume 4, Annex 1, the EU GMP for sterile products, requires that ″The integrity of the sterilised filter should be verified before use · · ·″ (1). Implicit in this requirement for a pre-use, post-sterilization integrity test (PUPSIT) is the rationale that the sterilizing filter could sustain damage during sterilization or use (i.e. subsequent to any pre-use test conducted prior to sterilization), causing a defect which would not be detected by the post-use integrity test. That is, that such a defect could be ″masked″ during filtration.
To assess whether a filter defect could be masked by partial filter plugging the Consortium evaluated the impact of bacterial retention testing on the bubble point (BP) of the test filters.
The paper concludes that filtration processes producing bubble point changes sufficient to present a risk of masking defects are not common, and detectable during the routine BCT. Thus the BP ratios observed during routine bacterial retention testing is one means to assess the potential of a given filtration process for masking of defects and can be considered when determining whether a PUPSIT should be implemented.
This chapter of the First edition Biomanufacturing technology roadmap published in 2017, describes the vision, scope and benefits that could be gained in the biopharmaceutical manufacturing industry from the development and adoption of effective in-line monitoring and real-time release capabilities. To help the industry achieve this future state it describes the scenarios considered, the future needs, challenges and potential solutions as well as the linkages and dependencies on other parts of the roadmap. It considers the contribution that disruptive and emerging technologies can play and regulatory considerations before finalizing with conclusions and recommendations.