Data Mining to Determine the Influence of Fluid Properties on the Integrity Test Values.

Eudralex volume 4, Annex 1, the European Union Good Manufacturing Practice for sterile products, requires that "The integrity of the sterilised filter should be verified before use" (1). Implicit in this requirement for a 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 ("masked" during filtration). To assess whether a filter defect could be masked by partial filter plugging, we evaluated the impact of the bacterial challenge test (BCT) on the bubble point (BP) of the test filters. The BP tests that are conducted before and after the BCT have been collected and compared for 2086 filters (1571 × test filters and 515 × control filters), representing 531 BCTs on 518 different pharmaceutical products, buffers, and in-process fluids. These tests comprise a cross section of fluids from multiple firms spanning the pharmaceutical and biotechnology industry. A posttest to pretest BP ratio was calculated for each filter and the distribution of these ratios examined to determine whether there were cases of elevation of the BP because of bacterial loading to the point where masking of a filter defect could occur; that is, if a defective filter could pass integrity testing due to apparent reduction in filter pore size because of the bacteria retained during the BCT. Ratios were averaged across all tests for the same test fluid. The mean average ratio was 1.00 ± 0.15, indicating that on the average, elevation of the BP does not occur. To assess the risk of masking a filter defect, observed BP ratios were compared to the ratio of the minimum BP specification of a 0.2 µm filter to that of a 0.45 µm filter of the same membrane type. The lowest such ratio for any membrane type was 1.33. A BP ratio equal to or higher than this ratio was considered a risk for masking, because a 0.45 µm filter could appear to meet the specifications of a 0.2 µm filter. Out of 518 average BP ratios, only eight fluids (1.5%) produced BP ratios meeting this criterion for a masking risk. Potential risk factors associated with these cases are discussed. We conclude that filtration processes producing BP changes sufficient to present a risk of masking defects are not common, and are detectable during the routine BCT. The BP ratios observed during routine BCT are one means to assess the potential of a given filtration process to mask defects and can be considered when determining whether a PUPSIT should be implemented.

Practical Applications of Biofluorescent Particle Counting in Environmental Monitoring Investigations.

Investigations into environmental monitoring (EM) excursions can be prolonged and do not always result in clear root causes or corrective and preventative actions. This article outlines how biofluorescent particle counting (BFPC) can be used in investigations to eliminate the inherent delays of culture-based methods. The application for investigations supplements routine EM, acting as a risk-reduction tool enabling real-time detection of viable microorganisms in air samples and supporting root cause analysis and remedial actions. The article includes guidance on how to use the technology, a real case study involving a mold excursion, and examples of business benefits achieved by various companies.

Continuous Microbiological Environmental Monitoring for Process Understanding and Reduced Interventions in Aseptic Manufacturing.

This paper provides recommendations for quality oversight, manufacturing operations, and industry perspective of regulatory expectations to enable aseptic facilities to move toward real-time and continuous microbiological environmental monitoring, thereby reducing interventions and future replacement of Grade A settle plates and nonremote active air sampling. The replacement of traditional monitoring with biofluorescent particle-counting systems provides an improvement in process understanding and product safety and reduces operator manipulations, assuring product quality and real-time process verification. The future state pharmaceutical technology roadmaps include gloveless isolators with real-time and continuous monitoring for aseptic manufacturing.LAY ABSTRACT: This paper advocates the use of an alternative and relatively new method of monitoring the air for contamination in biopharmaceutical manufacturing facilities. The alternative method is based on a type of instrument the authors refer to as a biofluorescent particle counter (BFPC). The BFPC method has the advantage of being able to detect airborne microorganisms continuously and to record the actual time of detection. The replacement of traditional monitoring with BFPC systems can provide better data, which can be used to improve the understanding of contamination risks in complex manufacturing processes, ultimately providing more confidence in product safety. The authors present data showing the suitability of BFPC. This immediate result is very useful for picking up early any possible contamination and should, therefore, provide a better way to monitor and control the risk of contamination. As traditional monitoring methods require manual manipulation, an additional advantage of BFPC systems is that they can reduce manual manipulations. Elimination of all interventions is a goal in the industry, because although they are tightly controlled, interventions are an unwanted potential source of contamination.