This report is being filed to provide additional information in b.5, h.6 and h.10 and corrected information in d.9, h.3 and h.6.Investigation: the collection bag and the leukocyte reduction filter with the connected tubing, including the bypass line, were received for investigation.Testing injected 570 ml of normal saline into the collection bag and observed a slow flow rate of normal saline through the filter, which was at (b)(4).Following rinsing the filter with normal saline, we disassembled the filter and confirmed that abnormalities such as detached and misaligned filter media were not observed in the filter.The number of filter media used for the filter conformed to the specifications.We also observed the appearance of filter media and confirmed that there were no aggregates adhered to the filter media.We dyed the rinsed filter media with toluidine blue*1 to observe how white blood cells were trapped in the filter media.It was confirmed that the second and third filter media from the inflow side were dyed dark with toluidine blue.*1: white blood cells and fibrin, which may be clogged to the filter membranes, are dyed with this solution.Toluidine blue is a general dye classified as ¿basic dyestuff¿ such as hematoxylin and methylene blue, and it dyes nucleic acid (and its binding protein) darker.In making the blood bags concerned, sealed bags are filled with solution and the line is assembled.These bags are sterilized, stacked, and placed into the blister packs.The top film of each blister pack is heat-sealed.In making leukoreduction filters, filter membranes are formed and put in filter housings.We reviewed the manufacturing record of the lot number in question.There was no equipment trouble causing the issue concerned and we confirmed that the equipment had operated properly and no anomalies had been observed.We also reviewed the manufacturing records regarding particulate removal rates*2 of filter membranes that were likely to be related to filtration performance.It was confirmed that all filter membranes conformed to all standards.(see graph) *2: the filter membranes of the product concerned consist of a rough pore pre-membrane (the first filter membrane) and minute pore main-membranes (the second through (b)(4) filter membranes).The pores of the filter membranes are likely to be minute where the particulate removal rates are high.In other words, the pores tend to rough where the rates are low.If the pores are relatively rough, it may be a factor of white blood cell contamination.Release testing, which includes measurements of solution concentration and volume and a visual inspection, is performed on the product concerned on a sample basis.We reviewed each testing and inspection record of the production number and confirmed that there were no anomalies in all release testing items.The product conformed to the standards.Regarding the retained samples of the lot number concerned, (b)(4) sets were visually examined.There were no abnormalities in their appearances.We used the sets to measure the solution volume and to perform a quantitative test for the composition of the solution in the same manner as the release testing.The results conformed to our in-house standards.Root cause: from the above-mentioned investigation results, we did not observe any abnormalities in the retained samples of the lot number concerned.In the investigation of the filter returned, normal saline flowed through the filter slowly, and the (b)(4) filter media from the inflow side were entirely dyed dark with toluidine blue; therefore, occlusion may have occurred in the filter.Blood may have been filtered by the filter area which was smaller than usual, and the linear speed (flow rate per unit area) increased and consequently leukocyte leakage occurred.In this case, the extension of filtration time is likely to occur concurrently.From the similar incidents which were previously reported, it was inferred the clogged components were aggregated platelets.We consider that platelets, which activated and aggregated for some reason, were trapped by the filter.
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