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Microbiological and sterilization investigations and evaluations: - microbiological review: microbiological examination of the complaint sample was performed by external laboratory in order to characterized the microbial growth associated with the complaint sample.The microorganism was microscopically identified as fungi.Mass spectrometric analysis used to identify organism from a clinical pathogen database.No match identified.Unspecified fungus, source unknown, thus assumed to be environmental.Due the challenges with analyzing a clinical sample with potential for blood borne pathogens, there is limited micro biological characterization data available.The microbial characterization points to fungi rather than bacteria contamination.It is unlikely the organism would be derived from the product as the product is terminally sterilized as discussed below.- sterilization review: the hls product was provided as sterile.The product is sterilized by ethylene oxide gas.The product lot in question was traced back to its respective sterilization process.The routine sterilization process is also monitored with biological indicators to demonstrate the efficacy of the sterilization run.The sterilization processes were delivered within specification and biological indicator results from each of the sterilization processes tested negative for growth (sterile).There is no indication that the suspected contamination could be attributed to the sterilization process.-sterilization process and validation review: the sterilization process, identified as cycle 2 is an established sterilization cycle that has been qualified and in use since approximately 2005.The sterilization process has been validated per the industry standards.The process is formally reviewed annually and periodic requalification of the process have been executed to confirm the efficacy of the process the sterilization process has been validated by an overkill sterilization method according to the sterilization standard 11135.This approach is conservative in nature and is based on a reference organism in the form a biological indicator with both high population and high resistance to the sterilization process.Per the standard sterilization processes qualified in this manner are conservative in nature and often use a sterilization treatment in excess of what is necessary to achieve sterility.The latest annual review completed in may of 2022 reviewed the sterilization for year 2021.There were no changes made to the sterilization cycle.The annual review demonstrated a state of control with no history of repeated nonconforming events in regards to sterilization at sterigenics wiesbaden.-microbiological quality review: the microorganism characterization of the contaminated sample was noted as nonspecific fungi source.The microbiological characterization from the complaint sample does not suggest organisms that represent challenge to the sterilization the ethylene oxide sterilization process.The ethylene oxide sterilization process is validated with known a high population and known high resistance bacterial spore of bacillus atrophaeus.According to sandle t.A (2011)*1 and barnett et al.(2007)*2 the most common fungi found in clean rooms are penicillium, aspergillus and trychopyton.Within hechingen site clean rooms the genus penicillium was identified in 9 cases and aspergillus in four (4) cases, while only one (1) trychopyton species was identified.Additionally, nine (9) microbial ids did not determine any species or genus and were determined to be mold.These identifications account for about 1.02% of all microbial ids performed, which is according to sandle t.A (2011)*1 typical for grade c cleanroom areas not considering other mold species present in the clean rooms.The samples were taken over the course of the year, however most of the ids were reported between august and october, as in about 43% of all mold was detected during clean room qualification activities.In 2020 in total 37 ids were reported from aspergillus (4), penicillium (17) and mold (16) accounting for 1.82% of all microbial id samples.Hence when comparing 2021 to 2020 there is no obvious negative trend detectable.Thus there is no information to suggest the source of the organism, related to the reported complaint, is associated with, or arises from, the product.Conclusion: the sterilization process has been validated, periodically reviewed, and periodically requalified to confirm the sterilization process is effective.The characterization of the organism growth is not representative of those that known to present a challenge to the sterilization process.There is no indication the suspected contamination is related to the design of the sterilization process.Packaging of the product: -commonalities with known packaging issues the complaint 559157 was investigated regarding commonalities with known packaging issues.Since there was no packaging material available which could have been examined, only documentation checks, like production date comparisons to known packaging complaints and correlation to previously observed complaints with potential contamination influence could be performed.The investigation showed, that one packaging complaint regarding a damage of the primary sterile barrier originated from lot# 3000165560, which is connected to complaint 559157 could be found.Within the investigation of the corresponding complaint a hole at the primary sterile barrier could be confirmed.Overall no correlation between complaints regarding a compromised sterile barrier of the hls set advanced and the appearance of complaints regarding potential contamination could be observed.Due to the absence of any correlation, it is unlikely that the observed and evaluated packaging issues are causing contaminated products as observed at complaint 559157.Furthermore, a medical assessment was performed with the following outcome: medical assessment (clinical preparation and practice, therapeutic application, and patient-related root causes): an extensive investigation of manufacturing (production and sterilization) packaging, shipment and storage by getinge subject matter experts failed to uncover a root cause(s) that may be associated with this event (maquet cardiopulmonary gmbh, 2022) as a result of the internal investigation, the working hypothesis, based on the available information for this medical assessment (and the broader investigation conclusions), may suggest the device was contaminated during preparation, priming, or at some point during therapy, as opposed to production, manufacturing, packaging, shipping, and storage.The assessment thus focused on three areas: clinical preparation and practice (assembly and priming) and possible patient-related root causes.A number of items, as a result of the evaluation, warrant mentioning and may have been contributory, but, unfortunately, do not offer a conclusive root cause.As an assumption only, the pre-priming of disposables for long durations could promote or at least provide an opportunity for device contamination leading to fungal growth.In this instance, the clinic did not participate in the survey questionnaire, nor did they participate in the follow-up phone interview.As a result, their practice and the possible contribution of pre-priming the circuit for extended periods of time (up to 30 days) prior to application cannot be verified, analyzed, or ruled out as a possible root cause.Any breach in sterile technique or sterile conditions may be a vector for contamination up to and including the therapy application duration.In balance, fungal growth, as suggested this complaint, has not been previously associated with pre-priming.Furthermore, multiple publications have supported the safe practice of pre-priming of extracorporeal circuits for extended periods prior to actual use for extracorporeal cpr protocols and emergency ecmo interventions.(weinber, miko, beck, bacchetta and mongero, 2015; tan, et al., 2018; joint commission, 2021; abrams, et al., 2018).Despite the increasing practice of pre-priming, getinge has conservatively not sanctioned this approach in training materials or in the instructions for use and advocates priming the device immediately prior to use.The examination of the bio-material accumulation appeared to be associated with clot around the luer fitting.Unfortunately, the response of the clinic did not include additional anti-coagulation metrics, apart from aptt, additional metrics such as d-dimer, ecarin clotting time (ect), cbc, and liver function/renal function) were not reported.As a result, no associations can be proposed with respect to the overall effectiveness of the anti-coagulation regime and monitoring.Monitoring anti-coagulation with aptt alone has been recently proposed to have limitations with in patients with covid 19 due to antiphospholipid interference with the laboratory testing results (yao, zhang, zhou, tang and li, 2017), (ahluwalia and sreedharnanunni, 2017) (devreese, linskens, benoit and peperstraete, 2020) a review of the available patient related factors that may contribute to contamination of the extracorporeal circuit was inconclusive.Medications that promote fungal growth in intensive care patients were not included in the report.A non-exhaustive review of the english language literature did not produce a publication or case report similar to this finding.Furthermore, consultation with getinge clinical and medical stakeholders also did not result in any occurrence or anecdotal report similar to this complaint.The trend analysis by the dcu did not identify a similar occurrence prior to this complaint.In summary, an extensive internal investigation (maquet cardiopulmonary gmbh, 2022) failed to identify a vector associated with product contamination based on an internal audit of tightly controlled quality processes in production, manufacturing, shipping and storage.The assessment and evaluation suggests, that the contamination may have occurred during device preparation, priming, or at some point during therapy.Unfortunately, this conclusion is based on limited information.Contamination during these isolated chain of events may be associated with a use error based or a breach of aseptic technique.A patient borne extracorporeal vector cannot be ruled out, but has not been described to date in the literature.The external lab report tentatively suggests a ¿yeast fungus¿ that appears to be an ¿environmental origin¿ given the species was not found in a clinical database of fungal pathogens.The clinic reported there was no negative patient sequelae associated with the complaint, and no reported decrease in product performance of either the hls set or the cardiohelp hardware.No details were provided by the clinic on the outcome of the patient after extracorporeal support.Based on the investigation results the reported failure ¿potential defect vs clot and fungus formation¿ could be confirmed but was most probable not associated with or contributed by a product related malfunction.The exact root cause of the reported event remains unknown.As a immediate action a hhe (health hazard evalution) will be initiated.Within the course of the hhe further actions will be defined.The occurrence rate regarding the above complaint is below the acceptance rate.Thus, no remedial action required.The occurrence rate related to the reported issue is currently being monitored as part of maquet cardiopulmonary¿ s trending program and additional investigations or corrections will be implemented in case of adverse trending.
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