| Model Number INT2230B |
| Device Problem
Appropriate Term/Code Not Available (3191)
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| Patient Problem
No Code Available (3191)
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| Event Date 06/19/2020 |
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Event Type
Death
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Event Description
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Septic transfusion reaction [transfusion of an infectious agent via product].Date cerus received: 23-jun-2020, 24-jun-2020, 25-jun-2020, 01-jul-2020, 02-jul-2020, 03-jul-2020, 06-jul-2020, 08-jul-2020, 14-jul-2020 (in).The patient involved in this report is a (b)(6) male.Product complaint #: (b)(4).Product code #:int2230b.Set lot #: ce19i27l71 (amicus lot fa20e18122/ pas intersol lot fm20c19042).Illuminator serial #: (b)(4).On 23-jun-2020, cerus received a spontaneous serious adverse event report ((b)(4)) from dr.(b)(6), senior director at (b)(6) laboratory in (b)(6), united states via the cerus chief medical officer (cmo).The initial report was to notify the cerus cmo of (b)(6) intent to send a cerus platelet bag for leak testing to fresenius (b)(4), transfusion medicine and cell technologies division - the contract manufacturer of the platelet bag, following a report of a fatal septic transfusion reaction [pt: transmission of an infectious agent via product] involving an intercept-treated platelet concentrate (pc) transfusion at (b)(6) in (b)(6).Further information on the initial report was received from (b)(6), capa quality engineer, and primary contact at (b)(6); as well as dr.(b)(6), pathologist at (b)(6); and (b)(6), vice-president of research and development at fresenius (b)(4)- transfusion medicine and cell technologies on 24-jun-2020, 25-jun-2020, 01-jul-2020, 02-jul-2020, 03-jul-2020, 06-jul-2020, 08-jul-2020, and 14-jul-2020.Platelet collection: on 14-jun- 2020 07:32h, a double platelet apheresis collection was initiated on the amicus apheresis separator.Of note, two plasma units were also collected from the same donation.The donor of the implicated unit ((b)(4)) was a (b)(6) male with a history of 194 total blood donations, mostly pcs.The (b)(6) has screened the donor and found no complications recorded in his most recent blood donation records (bdrs).The donor denied any risk factors for sepsis and his post donation blood culture requested by (b)(6) in response to the septic event, was negative as of (b)(6) 2020.On the same date, another double platelet apheresis collection was initiated.The donor of the non-implicated unit ((b)(4)) was a (b)(6) male with a history of 126 total blood donations.The (b)(6) has also screened the donor and found his deferral history to be unremarkable with no complications recorded in his most recent bdrs.On (b)(6) 2020 00:11h, (b)(6) split the implicated collection into two pcs and attached each pc to one of two intercept large volume (lv) processing sets.From 01:39h-01:46h, the two units were illuminated as part of treatment with the intercept blood system for platelets.The treatment report showed successful illumination with no indication of illuminator malfunction or irregularities.The first unit (din: (b)(6); product code: e8341v00) was transported to (b)(6) and the co-component (din: (b)(6); product code: e8342v00) was transported to (b)(6).On the same day, from 01:43h-01:49h, the non-implicated unit (din: (b)(6)) was treated with an intercept blood system dual storage (ds) processing set and split into two components (din: (b)(6); product code: e8341v00 and din: (b)(6); product code: e8342v00).On 16-june-2020 07:00h, the implicated intercept platelet unit (din: (b)(6); product code: e8341v00) was received at (b)(6) from (b)(6).On (b)(6) 2020 15:13h-16-28h, the intercept platelet co-component (din: (b)(6); product code: e8342v00), which was sent to (b)(6) was transfused reportedly without incident (patient culture results pending).On the same day, both components of the non-implicated intercept pcs were received at (b)(6) from (b)(6).One of the non-implicated units (din: (b)(6)) was assigned to the patient for transfusion on (b)(6) 2020 as described in the clinical course below.The product code for this unit was not reported at the time of this report.On an unspecified date, the co-component from the non-implicated unit (din: (b)(6)) was also transfused to another patient without incident in an outpatient setting at (b)(6).There was no report of bacteremia or sepsis, and the patient was described to be alert and ambulatory at discharge.Patient's clinical course: this report involves a (b)(6) male patient, who experienced a fatal septic transfusion reaction [pt: transmission of an infectious agent via product] following transfusion of intercept-treated pcs.The patient had multiple underlying medical conditions including nash cirrhosis, non-alcoholic fatty liver, end-stage renal disease on hemodialysis, anaemia, type 2 diabetes mellitus, hypertension, depression, and was noted to be waiting for liver and kidney transplant.The patient's concomitant medications and transfusion reaction history were not provided at this time.On (b)(6) 2020, the patient was transferred from (b)(6) to the emergency department at (b)(6), presenting with a left hip fracture following a fall.It was reported that while the patient was taking a pie out of the refrigerator, he had slipped and fell on his linoleum floor.He denied syncope, chest pain, palpitations, poor oral intake, loss of consciousness, any recent fever, cough, chills, positive sick contacts, and denied striking his head.During the arrival at the medical center, the patient was described as having "a mildly elevated temperature but was afebrile and hemodynamically stable, saturation > 95% on room air".A plain x-ray film demonstrated a comminuted intertrochanteric left femoral fracture.Urinalysis was remarkable for pyuria, however, the patient was asymptomatic from a urinary standpoint.Laboratory test findings: hemoglobin - 8.2 g/dl.White blood cell (wbc) - reportedly within normal range.Platelet count (plt) - 26 x 103/ul.International normalized ratio (inr) - 1.4.Chemistry remarkable for increased glucose - 366 mmol/l.Creatinine - 2.28 mg/dl.Blood urea nitrogen (bun) - 11 mg/dl.Sodium (na) - 134 meq/l.Total bilirubin - 2.9 mg/dl.Blood alkaline phosphatase (alp) - 191 iu/l.Albumin globulin ratio (a/g) - 5.Surgeon advised withholding dvt prophylaxis until the day of surgery and to make patient npo at midnight of (b)(6) 2020 for possible surgery on (b)(6) 2020, pending the post-transfusion platelet count.On (b)(6) 2020 19:30h-23:30h, the patient completed a 4-hour treatment of hemodialysis with 1.3 kg of fluid removed and an ending weight of (b)(6) kg.Patient had no clinical issues during treatment.Surgery was scheduled for (b)(6) 2020 due to low platelet count of 26k.The patient planned to receive platelet transfusions prior to surgery (at least 2 platelet units).On (b)(6) 2020 01:01h, the patient's pre-transfusion vitals were as follows: temperature: 98.2 degrees fahrenheit.Pulse: 83 beats per minute.Blood pressure (bp): 104 / 54 mmhg.Respiratory rate (rr): 16 breaths per minute.Oxygen saturation: 97%.From 01:09h-03:32h, the patient received the first unit of intercept platelets (din: (b)(6)) without any reported incident.At 03:32h, the patient's post-transfusion vitals were as follows: temperature: 98.4 degrees fahrenheit.Pulse: 83 beats per minute.Blood pressure (bp): 105 / 66 mmhg.Respiratory rate (rr): 14 breaths per minute.Oxygen saturation: 93%.At 03:54h, the patient started to receive the implicated second unit of intercept platelets (din: (b)(6); product code: e8341v00) and developed a septic transfusion reaction [pt: transmission of an infectious agent via product].At 05:31h, the transfusion was discontinued (with approximately 100 ml pc left in the bag) following a drop in blood pressure, tachycardia of 132 bpm, and decreased oxygen saturation of 93%.At 06:00h, the blood pressure dropped to 59/20 mmhg.The rapid response resuscitation team was called, and the patient was treated with 1l ns without significant improvement, as well as 0.3 mg of epinephrine with mild improvement and the patient was transferred to the intensive care unit (icu).In the icu, the patient was treated with solumedrol, vancomycin, and zosyn.The attending notified the blood bank of a possible transfusion reaction and a routine transfusion reaction workup was initiated.The workup included a clerical check of the transfusion, inspection of the returned blood bag, contents and the appearance of the returned solutions, tubing and filters all of which appeared normal and without any visible leaks.The patient's dat was negative and urine analysis was positive for the presence of blood.Of note, the same transfusion administration kit was used for the first and second transfusion.At 08:44h, on the same day, samples from the patient were collected for gram stain and culture.At 08:53h, patient samples were received by (b)(6) hospital, pathology laboratory, where the gram stain showed gram-negative bacteria and culture was positive for acinetobacter baumanii, nosocomialis grp.(mostly susceptible, resistant to ciprofloxacin only), leclercia adecarboxylata (sensitive to all atbx), and pcn-resistant staphylococcus saprophyticus which was detected by multiplex pcr.Time to positivity for the leclercia adecarboxylata was approximately ten minutes for aerobic bottle and approximately one hour for anaerobic bottle.At 09:40h, on the same day, samples from the implicated platelet bag were collected for gram stain and culture.At 11:00h, the laboratory notified the blood bank medical director about the patient's laboratory results.Immediately, he consulted with icu personnel as to the possibility of a septic transfusion reaction.Infectious disease was consulted for the plan of care and treatment including adding amikacin to the antibiotic treatment.Preliminary transfusion reaction investigation indicated the possibility of bacterial contamination and endotoxin reaction.At 18:23h, an arterial line was inserted with a cardiovascular consult to ensure placement.At 22:15h, the patient was persistently bradycardic to ~40s bpm on a maximum dose of levophed, vasopressin, and epinephrine, additionally, the mean arterial pressure was in the 50s.Due to the patients poor prognosis, the decision to pursue comfort care was made with the patient's wife's consent.On (b)(6) 2020 01:13h, the patient reportedly succumbed to fulminant sepsis and the outcome for the event of septic transfusion reaction [pt: transmission of an infectious agent via product] was reported as fatal.At 09:27h, on the same day, cultures of the platelet component showed a growth of leclercia adecarboxylata and acinetobacter baumanii complex, both organisms being gram-negative rods.On (b)(6) 2020 09:03h, (b)(6) pathologist confirmed that the platelet cultures growing the same two organisms as in the patient (leclercia adecarboxylata and acinetobacter baumanii complex/nosocomialis grp) was consistent with bacterial contamination of the platelet component, and was likely responsible for the septic shock secondary to gram-negative bacteremia.On (b)(6) 2020 04:48h, cultures from the platelet component and the patient also grew staphylococcus saprophyticus.Of note, the platelet bag was re-cultured because the original culture did not initially grow staphylococcus saprophyticus due to gram negative bacterium overwhelming the culture plate.On (b)(6) 2020, dr.(b)(6) provided photographs of the pc bag to cerus as collected from the hospital floor, which showed approximately 100 ml of product still in the bag and no obvious evidence of leakage.On (b)(6) 2020, the implicated pc bag containing the residual platelet product was sent by dr.(b)(6) to dr.(b)(6).Photographs and bacterial cultures were taken at the (b)(6) laboratory and the pc bag was forwarded to fresenius (b)(4) for pressure and leak testing, and the pc bag was received on 30-jun-2020.On an unspecified date, (b)(6) shakers were swabbed and cultured, and results are pending.Cleaning logs of the shakers are also pending.Dr (b)(6) reported that cleaning of the shakers was usually undertaken on a quarterly basis.Investigations: cerus investigations: fenwal quality review and approval of the manufacturing batch file was completed on 16 nov 2019, followed by cerus approval on 19-nov-2019.On 26-jun-2020, cerus quality assurance director communicated to (b)(6) that a batch history review on the implicated bag (lot # ce19i27l71) indicated there were no other complaints for this batch and that the batch was fully distributed.After receipt of the fatality report, fenwal and cerus initiated an in-depth batch record review.All bioburden results for this batch were compliant, normal and usual.The chemical analyses of the two amotosalen solution formulations used for this batch were compliant, normal, and usual.All inspection results during manufacturing for leaks and damage were compliant, normal and usual.All final leak testing results were compliant, normal and usual.In addition to all standard testing required for product release, additional testing was performed for this batch.The final storage container sub-assemblies used in production of this finished goods batch underwent supplementary leak testing as part of routine operations; there were no leaks detected.This finished goods batch was selected for the quarterly dose audit and was subjected to additional bioburden testing and 100 intercept processing sets underwent sterility testing.The dose audit results passed (bioburden and negative results for 100 additional sterility tests) and met manufacturer and iso (b)(4) acceptance criteria.On (b)(4) 2020, a cerus certified field service engineer checked and verified that intercept illuminator serial number (b)(4) met all functional requirements.This included a calibration verification, and confirmation that no errors were logged during treatment of the implicated unit.On 14-jul-2020, cerus performed an analysis by hplc for residual amotosalen in the pc sample.The amotosalen concentration was 0.27 m, which is consistent with successful addition of amotosalen and illumination of the implicated unit.Fresenius (b)(4) investigation: on 01-jul-2020, the platelet storage container was evaluated at fresenius (b)(4), (b)(4) (lead engineer, quality) and (b)(4) (vp, i&d disposables), with (b)(4) (vp, disposables development - cerus) observing the evaluation.Pictures and video of the testing were provided to cerus by email, including the preliminary report detailed below.Preliminary leak testing results from investigations of the cerus intercept platelet container at fresenius (b)(4).By (b)(4): on 30-jun-2020, a single intercept platelet storage container was received from the (b)(6).The container was associated with the following intercept platelets finished goods product: product code int2230b.Product lot number ce19i27l71.The container was visually inspected, with no obvious leaks or damage observed.The two access ports in the platelet container were pierced, one with the spike from the transfusion set and the other with a sampling port.The pc sample pack was still affixed to the platelet container and appeared to not have been used.The tubing line used to transfer the platelet product into the storage container was sealed off, and a sterile connection device connection was observed on this tubing line (presumably to a transfer pack used to drain the contents of the container prior to shipment).The inside and outside of the container were rinsed with 10% bleach solution to decontaminate the bag.The container was placed between the plates of a restraining fixture and submerged under water.The container was slowly pressurized.A leak was detected at ~1 psi of pressure (manufacturing rating of the bag is 15 psi) in the sheeting directly below the 1st large port (pierced by the transfusion set spike).It was noted that the transfusion set spike was of insufficient length to have caused the leak observed in the container.The container leak could be masked (i.E., cause the leak to temporarily self-seal) by moving the port tube up and down.The container was then observed under magnification.The leak was located in the sheeting below the 1st large port and not in the bead area of the container top seal.Based on the location of the leak, fracture of a brittle bead from the sealing process was ruled out as the root cause.No burns or (b)(6) in the sheeting material were observed in the container; instead, the leak appears to have been caused by mechanical abrasion when the container was scraped against a hard surface.This abrasion was sufficient to create a groove in the sheeting, thus thinning out the sheeting sufficiently to cause a leak.A small putative hole in the thinned-out area of the sheeting was noted.(b)(6) investigation on 02-jul-2020, cerus received a copy of the (b)(6) fda fatality report ((b)(6) case (b)(4)).(b)(6) investigation results to date are summarized below: upon becoming aware of this report on 19-jun-2020, (b)(6) was able to procure the implicated bag from (b)(6) and this was transported to (b)(6) for additional bacterial testing.(b)(6) was unable to collect the samples or the bag frlabs from the co-component transfused at (b)(6).The two plasma products from the same donation (non-transfused) were returned to (b)(6) lab for further culture testing.Donor look back screening was also initiated and indicated no abnormalities, with donor blood culture being negative.At the collection site, a review of records, equipment and supplies was found to be acceptable.As of (b)(6) 2020, (b)(6) lab identified leclercia adecarboxylata from samples taken inside the pc bag as well as a swab taken from the outside the bag.Of note, visual inspection of the bag upon receipt from (b)(6) on 26-jun-2020, revealed that the sampling site coupler on the pc bag appeared to be damaged and the plastic rubber cover was loose.Staff also observed that the white "v" on the upper third/middle section of the pc bag appeared to be paper-like material on the outside of the bag.Photos of the bag were taken by the (b)(6) lab and provided to fresenius (b)(4) and cerus.Results from tests performed at (b)(6) lab were as follows: swabs of the outside- port area and each side of the bag; swabs and material from inside of the bag were plated on selected plates for gram negative and special plates for acinetobacter baumanii.At least 2 different gram-negative organisms are present as of 29-jun-2020; identification of the organism is pending.Some of the swabs from the outside of the bag did grow bacteria, specifically the port area when plated on gram-negative selective plates.Swabs were taken before entering the bag.Bacteria were present on swabs taken from the bottom of the bag that rests against the shaker, when plated on gram- negative selective plates.No bacteria were recovered in the label when plated on gram-negative selective plates.Two colonies were recovered from the label when plated.Additional testing to be performed on the residual index product and plasma units is pending.This (b)(6) investigation was noted to be ongoing and pending further testing.Pending follow up: cultures from the patient who received the co-component at (b)(6) (din: (b)(6); product code: e8342v00) from (b)(6).Shaker swabs and culture results and cleaning log from (b)(6).Culture results on co-collected plasma units from (b)(6).Final investigation results from (b)(6).Final leak testing results from fresenius (b)(4).Assessments: reporter assessment: the hospital reporter (dr.(b)(6)) assessed the event of septic transfusion reaction [pt: transmission of an infectious agent via product] as serious due to being fatal.The reporter considered the causality for the event to be probable/likely in relation to the transfused intercept platelets.The (b)(6) reporter (b)(6) assessed the event of septic transfusion reaction [pt: transmission of an infectious agent via product] as serious due to being fatal.The reporter did not provide an assessment of causality in relation to the transfused intercept platelets or the intercept blood system device, as the investigation is ongoing.Cerus medical assessment: based on a preliminary assessment, the cerus medical reviewer considers that the information as in keeping with a fatal septic transfusion reaction involving an intercept-treated pc contaminated with a.Baumanii, s.Saprophyticus and l.Adecarboxylata.The medical reviewer considers the event of sepsis to be related to the transfusion of a contaminated pc, but probably unrelated to a failure of the intercept blood system for platelets device.Investigations are pending that will likely further inform this opinion.Cerus notes the striking similarities to a non-fatal septic reaction implicating a.Baumanii and s.Saprophyticus with a similar pattern of antibiotic susceptibilities, previously reported to the fda via medwatch by cerus in june 6, 2018 (case (b)(4): manufacturers report # 3003925919-2018-00004).This case that occurred at a (b)(6) hospital involved contamination of pcs despite prior pathogen reduction treatment with the intercept blood system for platelets.Intensive investigation at that time suggested the most likely cause was related to post manufacture contamination of the implicated pc (fridey et al 2020: transfusion - in press).The a.Baumanii and s.Saprophyticus strains were shown to be unique and closely related to strains implicated in three instances of septic transfusion reactions involving non-pathogen reduced pcs that occurred in (b)(6) and (b)(6) a week and 6 months later, respectively.In the latter two cases, evidence of contamination of blood center and or hospital platelet shakers was demonstrated, suggesting that leaks from the pc bag had occurred (jones et al.June 2018 mmwr 68: 23; 519-23), in keeping with post manufacture contamination.Pending further investigation, the cerus medical reviewer argues that the evidence in the current case favors post manufacture contamination of an intercept-treated pc.The intercept process appears to have been performed according to protocol.No deviations from standard operation procedures and treatment with the intercept system or a malfunction of the device occurred.The residual amotosalen concentration in the implicated pc is in keeping with successful treatment with the intercept blood system for platelets.Cerus has previously demonstrated effective inactivation of a.Baumanii and s.Saprophyticus in the reported (b)(6) case.The bacterial strains appear to be similar by antibiotic susceptibility profile.Molecular characterization is pending at the cdc.The records of the entire manufactured lot were reviewed at cerus.There is no history of other complaints involving the same lot (lot size: 5,376 kits) and manufacturing qc was appropriately performed and acceptable, including sterility checks.The transfusion of a co-component unit without a transfusion-related adverse event suggests that the pcs were not contaminated at collection (however, this pc was treated in a separate intercept process and transfused at a different hospital).A presence of "triple-pathogen" culture match from the pc and the patient's blood support a post-intercept-treatment environmental contamination etiology, as contamination with multiple bacterial strains is rarely reported when pcs are contaminated at the time of collection.The presence of a demonstrated leak in the bag is consistent with environmental contamination.The microscopic nature of the hole does not support a manufacturing defect, as all the bag seals and port seals were intact.Rather the demonstration of a gouge (~1 mm in length) in the plastic suggests physical damage to the bag after manufacture.It is not known whether this damage occurred while the bag was in the control of cerus, the blood center or the transfusing hospital.The absence of similar reports involving intercept kits from the same lot argues against damage during the manufacturing or shipment process at cerus.In this case, the implicated pc was stored for 2 days at the blood center and for 3 days at the hospital before transfusion, suggesting that there was sufficient time for damage to the bag and contamination at either location, with proliferation of bacteria before transfusion.The location of the gouge adjacent to a port may be compatible with damage on a platelet shaker where the port is held relatively immobile while the bag is able to move and may come into contact with a small burr on the shaker or adjacent pc.The rarity of the occurrence of septic transfusion reactions involving environmental bacterial strains suggests that the presence of a hole in the bag with contamination is an unusual event, possibility because larger holes would be detected due to leakage during storage.In this case the pc would be discarded.Possible preventative actions: work with blood centers and their hospital customers to educate staff as to the safe storage and handling of intercept kits before and after the treatment process in order to minimize damage to the containers.Work with blood centers and their hospital customers to ensure that intercept-treated pcs are handled, stored and transported in a clean environment.Planned follow up studies at cerus: pending receipt of bacterial isolates and pc samples from the (b)(6), cerus intends to perform pathogen inactivation studies on isolates from the 3 identified organisms.Outcomes of these studies will be reported to the fda on completion.
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Manufacturer Narrative
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The device brand name of this form has been changed from intercept blood system for plasma to intercept blood system for platelets.
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Manufacturer Narrative
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Cerus received a letter from fda (cdrh) dated august 19, 2020, requesting additional information regarding mdr manufacturer report # 3003925919-2020-0001 regarding the fatal sepsis associated with acinetobacter baumanii, leclercia adecarboxylata, and staphylococcus saprophyticus culture positive intercept platelet unit (b)(6).The fda's comments and requests for additional information are provided in questions 1a-f and cerus' response follows.Question 1.Regarding the report of fatal sepsis associated with acinetobacter baumanii, leclercia adecarboxylata, and staphylococcus saprophyticus culture positive intercept platelet unit (b)(6), please submit follow up information regarding all pending testing and assessments, including: a.Platelet shaker swab culture results; cerus response: platelet shaker sampling was not ultimately performed because too much time had passed by the time a resource had been identified by the (b)(6) to perform the testing.B.Co-component ((b)(6); product code: e8342v00) status and culture results, and status of any other component associated with the same donation; cerus response: microbiological testing of the two plasma co-components collected during platelet donation as well as the additional platelet unit ((b)(6); product code: e8342v00) were negative for microbial growth.Neither of the plasma co-components were transfused.The additional platelet unit was transfused, reportedly without incident.Cultures from the patient were not performed.C.Final leakage testing results from (b)(4); cerus response: on june 30, 2020, (b)(4) ((b)(6)) received the intercept platelet storage container of unit (b)(6) (product code: e8341v00) implicated in the septic transfusion reaction case for evaluation.Evaluation was performed by (1) visual inspection (2) underwater leak test and (3) microscopic examination.Additional details of the leak investigation first described in the initial mdr manufacturer report # 3003925919-2020-0001 submitted july 17, 2020 are presented below.(1) visual inspection: the container was removed from the packaging and visually inspected, with no obvious leaks or damage to the container observed.The two access ports in the platelet container had already been pierced, one part with the spike from the transfusion set and the other with a sampling spike.The air pillow for sampling platelet concentrate (pc) was still affixed to the platelet container and appeared to not have been used.The tubing line used to transfer the platelet product into the storage container had been sealed off, and a sterile connection device (scd) connection was observed on this tubing line (presumably to a transfer pack used to drain the contents of the container prior to shipment).Visual observation found no abnormalities in the perimeter seal or along the top seal area around the ports.Several scuff marks were noted on both sides of the container indicating that the container slid across something causing these abrasions.It was noted that the abrasions were on the surface of the container and not very deep into the plastic.(2) underwater leak test: an underwater leak test was then performed on the intercept platelet storage container complaint sample.Prior to testing the complaint sample, the test setup was challenged using three positive control samples that were prepared by puncturing three new intercept platelet storage containers once with a 32-gauge needle.The location of the hole was varied for each container: near the top seal, at the side seal of the container, and at the middle of the container panel.To test the positive control samples, each container was placed in a restraining fixture to prevent overexpansion during pressurization.The air pressure source was connected to the tubing attached to the top of the container, and the restraining fixture and container were submerged underwater in a water bath.Air was slowly introduced into the container until a pressure of 3 psi was reached.The container internal pressure was held at 3 psi to check for leaks by observing for presence of bubbles.For each positive control, air bubbles were detected within 3 minutes, thus indicating the presence of the leak as expected.For the complaint sample container, the following steps were performed: the inside and outside of the container were rinsed with 10% bleach solution to decontaminate the bag.The container was placed in a restraining fixture to prevent overexpansion during pressurization.The air pressure source was connected to the tubing attached to the top of the container; the air pressure was connected to a digital pressure meter (fluke dmp2plus) before being connected to the container.The restraining fixture was placed in a water bath.Air pressure was slowly introduced into the container to check for leaks by observing for bubbles.A leak was detected at approximately 1 psi of pressure in the sheeting directly below the first large port (pierced by the transfusion set spike).It is noted that the transfusion set spike is of insufficient length to have caused the leak observed in the container.During the leak test, it was observed that the container leak could be masked (i.E., cause the leak to temporarily self-seal) by moving the port tube up and down.(3) microscopic examination: the container was then observed under magnification in the area of the leak.It was immediately noted that the leak was in the sheeting below the 1st large port and not in the bead area of the container top seal.Based on the location of the leak, fracture of a brittle bead from the sealing process was ruled out as the root cause.Also, no burns or arcs in the sheeting material were observed in the container.Instead, the leak appeared to have been caused by mechanical abrasion or gouging when the container was dragged / scraped across a hard surface.This abrasion was sufficient to create a groove in the sheeting, thus thinning out the sheeting sufficiently to cause a leak.Conclusion: the customer complaint was confirmed.A small hole was found in the sheeting of the platelet storage container.Probable root cause is not determined.The gouge on the back panel of the container just below the first tear off port is the source of the leak.It is unknown how this gouge was made on the container, but it is unlikely related to the sealing or manufacture of the container.It is possible that physical handling of the container after manufacture is the primary contributor of the defect.D.Outcomes of pathogen inactivation testing by cerus on the 3 bacteria; cerus response: the microbiology department at cerus has performed pathogen inactivation studies on acinetobacter baumanii complex, leclercia adecarboxylata, and staphylococcus saprophyticus isolated from the implicated intercept platelet unit (b)(6) (product code: e8341v00).Isolates were shipped to cerus from wake forest baptist medical center.Pathogen inactivation was assessed by spiking high titers of the organisms, individually, into apheresis platelets suspended in 35% plasma/ 65% intersol (pas-3).The dose of individual platelet units was adjusted to 4.0 × 1011 in a volume of 335 ml to mimic the nominal volume of platelet unit (b)(6).Inactivation studies were performed in triplicate for each organism using intercept processing sets for large volume (lv) platelet units (set code int2230b).Platelet units were illuminated with a single target dose 3.9 j/cm2 uva treatment.Samples of the platelet units were obtained immediately after illumination, after cad incubation and on days 5 and 7 after illumination.Bacterial plating assays were performed according to standard operating procedures.Bacterial colony counts were enumerated, and bacterial titers were calculated based on the total number of colonies per countable dilution.Log reduction was calculated using the input titer as a measure of the limit of reduction.Preliminary data indicate that after photochemical treatment in the intercept platelets lv set, an average of >7.2 ± 0.1 log, >7.0 ± 0.1 log, and >=7.7 ± 0.1 log of a.Baumannii complex, s.Saprophyticus, and l.Adecarboxylata, respectively, were completely inactivated at the post-illumination time point.No colonies of a.Baumannii complex or s.Saprophyticus were detected after 7 days of storage.Breakthrough was detected in 2 out of 3 replicates for l.Adecarboxylata by 7 days, which is attributable to the initial high input titer (7.7-7.8 log colony forming units/ml) being just above the threshold of inactivation.Sequencing of the 16s region (performed at midi labs and charles river laboratories) confirmed that the isolates used in these inactivation studies were a.Seifertii (a member of the a.Baumannii complex), s.Saprophyticus, and l.Adecarboxylata.Additional studies are planned to investigate pathogen inactivation using the intercept blood system for platelets when all three species are spiked simultaneously into individual platelet units.E.Any additional new information/evaluation; cerus response: there is no additional information or evaluation to provide at this time.F.Please provide a summary and assessment of any similar cases in the post marketing period since clearance/licensure; cerus response: as noted in the initial mdr manufacturer report # 3003925919-2020-00001, a case similar to (b)(4) involving a non-fatal septic reaction implicating a.Baumanii complex bacteria and s.Saprophyticus with a similar pattern of antibiotic susceptibilities was previously reported to the fda via medwatch by cerus on june 6, 2018 ((b)(4); manufacturer report # 3003925919-2018-00004).This case occurred at a california hospital and involved contamination of platelet concentrate (pc) despite prior pathogen reduction treatment with the intercept blood system for platelets.Intensive investigation at that time suggested the most likely cause was related to post manufacture contamination of the implicated pc component.Please see the publication by fridey et al.(2020) describing case (b)(4).Reference: fridey jl, stramer sl, nambiar a, moayeri m, bakkuor s, langelier c, crawford e, lu t, lanteri mc, kamm j, miller s, wagner sj, benjamin rj, busch mp.2020.Sepsis from an apheresis platelet contaminated with acinetobacter calcoaceticus/baumanii complex bacteria and staphylococcus saprophyticus after pathogen reduction.Transfusion 60:1960-69.
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Manufacturer Narrative
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The purpose of this follow-up report (fu3) is to provide an update on previously pending items in manufacturer report #3003925919-2020-00001 including (1) final results of pathogen inactivation studies, (2) sequence analysis of pathogens isolated from the contaminated platelet unit implicated in the septic transfusion reaction at wake forest baptist medical center (wfbmc), and (3) final results of the blood center (arc holland) investigation.Also provided below are final reporter assessment and final cerus medical reviewer assessment. on (b)(6) 2020, cerus received three bacterial isolates from wfbmc for pathogen inactivation and growth characterization studies.The studies were aimed at assessing the inactivation of a.Baumannii, s.Saprophyticus, and l.Adecarboxylata separately and together in platelets in 35% plasma/65% pas-3.Bacterial cultures were sent to independent vendors (midi labs and charles river laboratories) to verify the identity of these strains via sequencing.On (b)(6) 2020, cerus received another set of bacterial isolates from arc holland lab.On (b)(6) 2020, preliminary summary report of the pathogen inactivation studies of each bacteria performed at cerus was generated and reported to fda in fu2 to this manufacturer report (#3003925919-2020-00001).On (b)(6) 2021, the final reports of pathogen inactivation studies of each bacteria (study no.1) and a combined study of all three bacteria (study no.2) performed at cerus were received.The results demonstrate the following: -study no 1: in this study, pathogen inactivation was assessed by spiking high titers of a.Baumannii complex, s.Saprophyticus, and l.Adecarboxylata individually into apheresis platelets in 35% plasma/65% intersol (pas-3).Contaminated platelets were processed using the intercept platelet lv processing set in a volume of 335 ml and nominal platelet concentration of 4.0 × 10^11 platelets per unit (n=3 replicates).After photochemical treatment with a single 3.9 j/cm2 uva treatment, >7.2 ± 0.1 log, >7.0 ± 0.1 log, and greater than or equal to 7.7 ± 0.1 log of a.Baumannii complex, s.Saprophyticus, and l.Adecarboxylata, respectively, were completely inactivated at post-illumination.No a.Baumannii complex or s.Saprophyticus were detected after 7 days of storage.Breakthrough was detected in 2 out of 3 replicates for l.Adecarboxylata by 7 days with an initial high input titer.This result indicates the input titer threshold of l.Adecarboxylata that the intercept lv processing set is capable of inactivating to the limit of detection.-study no 2: in this study, high titers of a.Baumannii complex, s.Saprophyticus, and l.Adecarboxylata were simultaneously spiked into apheresis platelets in 35% plasma/65% intersol (pas-3).Contaminated platelets were processed using the intercept platelet lv processing set in a volume of 335 ml and nominal platelet concentration of 4.0 × 10^11 platelets per unit (n=3 replicates).After photochemical treatment with a single 3.9 j/cm2 uva treatment, >7.0 ± 0.2 log of all three of these bacteria were completely inactivated at post-illumination.No bacteria were detected after 7 days of storage.This result indicates that the intercept lv processing set is capable of inactivating a combination of a.Baumannii complex, s.Saprophyticus, and l.Adecarboxylata to the limit of detection.Intercept treatment was efficient to maintain sterility of the units throughout the period of extended storage up to 7 days. as described in fu2 to this report, sequencing of the 16s region (performed at midi labs and charles river laboratories) confirmed that the isolates used in these inactivation studies were a.Seifertii (a member of the a.Baumannii complex), s.Saprophyticus, and l.Adecarboxylata.Additional multi-locus sequence analysis on 7 housekeeping genes of a.Seifertii and 3 housekeeping genes of s.Saprophyticus was performed at charles river.Results from the study revealed that the bacterial isolates from wfbmc and bacterial isolates from a previous sepsis case at ucsf involving post manufacture contamination of platelet concentrates (fridey et al.Transfusion 2020 https://doi.Org/10.1111/trf.15951) were indistinguishable.A publication describing the wfbmc case is also now available (fadeyi et al.Transfusion 2020 https://doi.Org/10.1111/trf.16210) on (b)(6)2020, cerus received a copy of the arc fda fatality report (arc case # dcsc-c-012-tr-sep05923).Arcs final investigation results are summarized below: wfbh (wake forest baptist health) environment test: cultures were performed from 5 different areas (shelves and other areas of the platelet rotator) and the culture showed the following: sample 1.One colony of s.Hominis sample 2.One colony of s.Saprophyticus sample 3.One colony of s.Epidermidis sample 4.Negative sample 5.Negative the s.Saprophyticus isolated from the environment was very different from the s.Saprophyticus isolated from the platelets bag (maldi pca dendrogram).The isolates (from platelet bag and blood culture of recipient) were sent directly to cdc.Arc environmental test: due to the extra cleaning on surface areas that is being done to minimize the exposure to covid-19 and the delay in scheduling the testing, sr.Vp of qa/ra/safety and the cmo determined that environmental testing will not be performed.Further investigation included operational assessments.Collection and manufacturing staff performances were evaluated and were found to be appropriate.Inspection of the blood manufacturing site, including the illuminator and platelet agitators were assessed and found to be both functional and with no apparent surface defects that could account for the damage sustained to the container surface.It was also concluded that the identified damage to the wall of the product container is likely the cause for contamination of the transfused unit, that resulted in the reported incident of septic fatality.The source contributing to this event remained unknown.On (b)(6) 2021, cerus received a corrected arc fda fatality report.Reference to an additional leak, purportedly involving an intercept processing set of the same lot as the septic transfusion case, was removed.All relevant information has been obtained and no further information is expected at the time of this report. the hospital reporter (dr.Emmanuel fadeyi) assessed the event of septic transfusion reaction [pt: transmission of an infectious agent via product] as serious due to being fatal.The reporter considered the causality for the event to be probable in relation to the transfused intercept platelets.The arc reporter (karen chulick) assessed the event of septic transfusion reaction [pt: transmission of an infectious agent via product] as serious due to being fatal.The reporter provided a causality assessment as probable in relation to the transfused implicated intercept platelets.The reporter also indicated that this septic transfusion reaction was not an expected event with blood components from an arc's perspective. cerus medical reviewer considers that the information is in keeping with a fatal septic transfusion reaction involving properly intercept-treated platelet concentrate (pc) subsequently contaminated with a.Baumanii, s.Saprophyticus and l.Adecarboxylata.The medical reviewer considers the event of sepsis to be related to the transfusion of a contaminated pc, but unrelated to a failure of the intercept blood system for platelets device.All investigations to-date further informed this opinion.The cerus medical reviewer argues that further studies described in this fu3 provide additional evidence favoring post-manufacture contamination of an intercept-treated platelet component: the two cerus inactivation studies performed on each contaminant separately (study no.1) and in a combination of all 3 contaminants (study no.2) demonstrate the following: 1.No a.Baumannii complex or s.Saprophyticus were detected after 7 days of storage.The input titer threshold of l.Adecarboxylata that the intercept lv processing set is capable of inactivating, was to the limit of detection.2.The intercept treatment was efficient to maintain sterility of the units with the combined contaminants throughout the period of extended storage up to 7 days.
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Search Alerts/Recalls
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