Novel Peripheral Intravenous Catheter Securement for Children and Catheter Failure Reduction: A Randomized Clinical Trial.

Importance: Peripheral intravenous catheters (PIVCs) facilitate essential treatment. Failure of these essential devices is frequent and new securement strategies may reduce failure and improve patient outcomes. Objective: To evaluate clinical effectiveness of novel PIVC securement technologies for children to reduce catheter failure. Design, Setting, and Participants: A 3-arm, parallel group, superiority randomized clinical trial was conducted at 2 regional Australian hospitals from February 5, 2020, to January 14, 2022. Children aged 6 months to 8 years who were anticipated to require admission with a PIVC for at least 24 hours of in hospital treatment were eligible. Data were analyzed from May 25, 2022, to February 20, 2024. Interventions: Participants were randomly allocated in a 1:1:1 ratio to standard care, bordered polyurethane (Tegaderm [3M]), integrated securement dressing (SorbaView SHIELD [Medline]), and integrated securement dressing with tissue adhesive (Secureport IV). One catheter was studied per patient. Main Outcomes and Measures: Primary outcome was PIVC failure, defined as premature cessation of PIVC function for any reason prior to completion of planned treatment. Secondary outcomes were PIVC complications (any time dislodgement, occlusion, infiltration, partial dislodgement, extravasation, device leaking, phlebitis, pain), PIVC longevity, intervention acceptability (clinicians, participants, caregivers; 0-10 scale), and pain on removal (participants and caregivers; 0-10 scale relevant to age), adverse events, and health care costs. Results: A total of 383 patients (51% female; median age 36 [25th-75th percentiles, 22-72] months) were randomized 134 to standard care, 118 to integrated securement dressing, and 131 to integrated securement dressing with tissue adhesive. PIVC failure was lowest in integrated securement dressing with tissue adhesive (15 [12%]; adjusted hazard ratio [aHR], 0.47; 95% CI, 0.26-0.84) compared with integrated securement dressing (24 [21%]; aHR, 0.78; 95% CI, 0.47-1.28) and standard care (43 [34%]). Direct costs were significantly lower for integrated securement dressing with tissue adhesive (median, Australian dollars [A$], 312 [A$1 is equal to $0.65 US dollars]; IQR, A$302-A$380) and integrated securement dressing (median, A$303; IQR, A$294-A$465) compared with standard care (median, A$341; IQR, A$297-A$592; P ≤ .002) when considering the economic burden related to failure of devices. PIVC longevity and intervention acceptability were similar across all groups. Conclusions and Relevance: In this study, PIVCs secured with integrated securement dressings and tissue adhesive, in comparison with standard care, bordered polyurethane dressings, were associated with significantly reduced PIVC failure, for children admitted to hospital via the emergency department. Further research should focus on implementation in inpatient units where prolonged dwell and reliable intravenous access is most needed. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12619001026112.

An Improvised Cost-Effective Repair Technique for Management of Broken Luer Connections of Tunneled Dialysis Catheter and Salvage Existing Catheter.

Mechanical problems like break or crack in Luer connectors or hubs, clamps, and tubings are common non-infectious complications of tunneled dialysis catheters (TDC), which may lead to other TDC complications and the need to insert a new catheter. These can be tackled using TDC repair kits or spare parts, which are often not available, resulting in the insertion of a new TDC that increases morbidity, TDC-related procedures, and healthcare costs. We discuss two cases of broken Luer connections of TDC, which were managed by exchanging the broken Luer connector of TDC with the similar Luer connector of a temporary dialysis catheter. Both the repaired TDCs are thereafter functioning well. This improvised technique provides an easy, effective, long-lasting option that salvages the existing TDC and reduces the cost factor.

The clinical and economic impact of extended battery longevity of a substernal extravascular implantable cardioverter defibrillator.

INTRODUCTION: The extravascular implantable cardioverter defibrillator (EV ICD) has extended projected battery longevity compared to the subcutaneous implantable cardioverter defibrillator (S-ICD). This study used modeling to characterize the need for generator changes, long-term complications, and overall costs for both the EV ICD and S-ICD in healthcare systems of various countries. METHODS: Battery longevity data were modeled using a Markov model from averages reported in device labeling for the S-ICD and with engineering estimates based on real life usage from EV ICD Pivotal Study patient data to introduce variability. Clinical demographic data were derived from published literature. The primary outcomes were defined as the number of generator replacement surgeries, complications, and total healthcare system costs due to battery depletion over the expected lifetime of patients receiving EV ICD or S-ICD therapy. RESULTS: Average modeled battery longevity was determined to be 7.3 years for the S-ICD versus 11.8 years for the EV ICD. The probability of a complication after a replacement procedure was 1.4%, with an operative mortality rate of 0.02%. The use of EV ICD was associated with 1.4-1.6 fewer replacements on average over an expected patient lifetime as compared to S-ICD and a 24.3%-26.0% reduction in cost. A one-way sensitivity analysis of the model for the US healthcare system found that use of an EV ICD resulted in a reduction in replacement surgeries of greater than 1 (1.1-1.6) along with five-figure cost savings in all scenarios ($18 602-$40 948). CONCLUSION: The longer projected battery life of the EV ICD has the potential to meaningfully reduce long-term morbidity and healthcare resources related to generator changes from the perspective of multiple diverse healthcare systems.

In Vitro Corrosion Assessment of the Essure® Medical Device in Saline, Simulated Inflammatory Solution and Neutral Buffered Formalin.

The Essure® permanent contraceptive implant, comprised of four alloys (nickel-titanium, 316L stainless steel, platinum-iridium, and tin-silver solder) and Dacron (PET) fibers, has been approved for use in the US for about two decades. However, little has been published on this implant's biomaterials performance, and as this implant gains interest in terms of in vivo performance, methods of implant post-retrieval storage also need to be assessed. This study investigated the electrochemical properties and ion release profile of Essure® during storage in phosphate buffered saline (PBS), 10 mM H2O2/PBS, a simulated inflammatory solution, and 10% neutral buffered formalin (NBF) to investigate the corrosion behavior and metal ion release. First, a galvanic test method was used to measure the galvanic interactions between alloys within the device. Second, an ion-release study over 107 days was performed. Ions were measured using inductively-coupled plasma mass spectrometry and the implants were assessed using digital optical microscopy, scanning electron microscopy, and energy dispersive x-ray spectrometry. The tin-silver (SnAg) solder continuously corroded in PBS and H2O2/PBS. In the presence of H2O2, nickel and titanium ions were released from the nickel-titanium (NiTi) coil, whereas release of these ions was minimal in PBS alone. Overall, corrosion of the SnAg solder, which holds the NiTi and 316L SS together, was significant in both PBS and H2O2/PBS and may result in loss of connection of the NiTi and 316L stainless steel portions of the implant. Storage in NBF exhibited very low corrosion rates for all alloys and low levels of ion release were observed indicating that formalin storage minimally affects the implant's corrosion status. STATEMENT OF SIGNIFICANCE: The Essure® device is an FDA premarket-approved female permanent sterilization device containing four different metal alloys and poly(ethylene terephthalate) polymer fibers. Significant concerns related to this device have been raised by the FDA since its introduction in 2002. This study is the first published in vitro work to specifically assess the corrosion mechanisms in this multi-alloy device and the role of different solution environments, including formalin storage, inorganic physiological saline and a simulated inflammatory condition. Significant evidence of corrosion of the tin-silver solder is documented, the release of Ni and Ti under simulated inflammatory conditions, and the relative inertness of storage of these implants in neutral buffered saline is presented. The tin-silver corrosion corroborates recent clinical evidence of tin corrosion products in tissues adjacent to these devices in vivo.

Comparative Study of the SEM Evaluation, EDX Assessment, Morphometric Analysis, and Cyclic Fatigue Resistance of Three Novel Brands of NiTi Alloy Endodontic Files.

In this study, we compare and analyze the scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), morphometry and cyclic fatigue resistance of Endogal, PathMax, and Smarttrack novel brands of nickel−titanium (NiTi) alloy endodontic files. Material and Methods: Thirty sterile NiTi endodontic rotary files were randomly selected and assigned to one of the following study groups: A: 25.08 F2 Endogal (EDG) (n = 10); B: 25.08 F2 Path Max Pro (PMP) (n = 10); and C: 25.06 Smarttrack (ST) (n = 10). Dynamic cyclic fatigue tests were conducted using a cyclic fatigue device in stainless steel artificial root canal systems with an apical diameter of 250 µm, curvature angle of 60°, radius of curvature of 3 mm, and taper of 6%. Additionally, we analyzed the NiTi endodontic rotary files using EDX, SEM, and morphometry after micro-CT scanning. The results were analyzed using Weibull statistical analysis and ANOVA testing. Results: SEM, EDX, and morphometric analyses showed differences between the three novel brands of NiTi endodontic rotary files. Moreover, statistically significant differences were observed between the number of cycles to failure and time to failure of the three novel brands of NiTi endodontic rotary files (p < 0.001). Conclusions: Smarttrack NiTi alloy endodontic reciprocating files display greater resistance to cyclic fatigue than Endogal and Path Max Pro NiTi alloy endodontic rotary files, due to the reciprocating movement and metallurgical composition.

A real-world study evaluating ultrasound-guided percutaneous non-targeted liver biopsy needle failures and pathology sample-quality assessment in both end-cut and side-notch needles.

OBJECTIVES: To determine biopsy device failures, causative factors, complications and sample quality of the 16G end-cut Biopince™ and side-notch Bard™ needles. METHODS: All ultrasound-guided non-targeted liver biopsies between 01/01/2016 and 31/12/2018 were included. Operator, device, number of failures, complications and repeat biopsies were recorded. Histopathology samples were reviewed for all cases of needle failure and a group with no failures, and graded "yes/no" for the presence of steatosis, inflammation and fibrosis. The pathology slides from these cases were reviewed to assess biopsy sample quality (length and portal tract number). The failure and no-failure groups were compared in terms of device type/histology, and sample quality was compared between the needle types. RESULTS: 1004 patients were included. 93.8% (n = 942) required one needle pass to obtain a sample and 6.2% (n = 62) required >1 pass due to needle failure. Total of 76 needle failures, more with end-cut than side-notch needles (8.7% vs 2.9%) (p < 0.001). No needle failures resulted in complication. The presence of liver fibrosis was associated with fewer needle failures (p = 0.036). The major complication rate was 0.4% (4/1044). A biopsy with >10 portal tracts was obtained in 90.2% of specimens > 20 mm long, compared with 66% of 16-20 mm biopsies and 21% of <16 mm biopsies. The target of >10 portal tracts was achieved in 10/26 (38.5%) of side-notch biopsies and 64/90 (71.1%) of end-cut biopsies (p = 0.004). CONCLUSION: Ultrasound-guided liver biopsy is safe and sample quality is consistently good when a core >20 mm long is obtained. The end-cut biopsy device generated reliably good quality biopsy samples; however, the needle failure rate was significantly higher than the side-cut needle. ADVANCES IN KNOWLEDGE: Ultrasound-guided liver biopsy specimen quality is consistently good when a core >20 mm long is obtained which can be achieved with a single pass using the 16G BiopinceTM end-cut needle, although the needle failure rate is significantly higher than the 16G Max-Core™ Bard™ side-notch needle.

Expiratory aerosol particle escape from surgical masks due to imperfect sealing.

Wearing surgical masks or other similar face coverings can reduce the emission of expiratory particles produced via breathing, talking, coughing, or sneezing. Although it is well established that some fraction of the expiratory airflow leaks around the edges of the mask, it is unclear how these leakage airflows affect the overall efficiency with which masks block emission of expiratory aerosol particles. Here, we show experimentally that the aerosol particle concentrations in the leakage airflows around a surgical mask are reduced compared to no mask wearing, with the magnitude of reduction dependent on the direction of escape (out the top, the sides, or the bottom). Because the actual leakage flowrate in each direction is difficult to measure, we use a Monte Carlo approach to estimate flow-corrected particle emission rates for particles having diameters in the range 0.5-20 µm. in all orientations. From these, we derive a flow-weighted overall number-based particle removal efficiency for the mask. The overall mask efficiency, accounting both for air that passes through the mask and for leakage flows, is reduced compared to the through-mask filtration efficiency, from 93 to 70% for talking, but from only 94-90% for coughing. These results demonstrate that leakage flows due to imperfect sealing do decrease mask efficiencies for reducing emission of expiratory particles, but even with such leakage surgical masks provide substantial control.

Scanning Electron Microscopic Assessment of Stent Coating Integrity in Jailed Wire Technique for Bifurcation Treatment.

OBJECTIVES: To assess the impact of different guidewires on stent coating integrity in jailed wire technique (JWT) for bifurcation treatment. BACKGROUND: JWT is commonly adopted to protect side branch in provisional one-stent strategy for coronary bifurcation lesions. However, this technique may cause defects in stent coatings. The degree of coating damage caused by different types of jailed wires remains unknown. METHODS: A fluid model with a bifurcation was established to mimic the condition in vivo. One-stent strategy was performed with three types of guidewire (nonpolymer-jacketed wire, intermediate polymer-jacketed wire, and full polymer-jacketed wire) tested for JWT. Scanning electron microscopy (SEM) was used to evaluate stent coating integrity and wire structure. The degrees of coating defects were recorded as no, slight, moderate, and severe defects. RESULTS: A total of 27 samples were tested. Analyses of SEM images showed a significant difference in the degree of coating damage among the three types of wire after the procedure of JWT (P < 0.001). Nonpolymer-jacketed wire could inevitably cause a severe defect in stent coatings, while full polymer-jacketed wire caused the least coating damages. Besides, there were varying degrees of coil deformation in nonpolymer-jacketed wires, while no surface damage or jacket shearing was observed in full polymer-jacketed wires. CONCLUSIONS: Although nonpolymer-jacketed wire has long been recommended for JWT, our bench-side study suggests that full polymer-jacketed wire may be a better choice. Further clinical studies are needed to confirm our findings.

Reuse of pacemakers and implantable cardioverter-defibrillators: systematic review, meta-analysis and quality assessment of the body of evidence.

BACKGROUND: Pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs) have reduced mortality and improved the quality of life of cardiac patients. However, the high cost of these devices prevents their large-scale incorporation, particularly in low-income countries, where reusing explanted PMs/ICDs has become an alternative. METHODS: A systematic review and meta-analysis were conducted of studies that compare infection rates, device-related deaths, malfunction and premature battery depletion in patients with reused PM and ICD implants and those with new devices. The quality of the body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: The meta-analysis demonstrated no significant intergroup differences in infection rates (OR 0.98; 95% CI 0.60-1.60), device malfunction (OR 1.58; 95% CI 0.56-4.48) or premature battery depletion (OR 1.96; 95% CI 0.81-4.72) and no device-related deaths. Based on GRADE assessment, confidence in estimates for the outcomes infection rate and device-related death was rated as moderate. CONCLUSION: The results of this analysis enabled us to conclude that PMs and ICDs can be safely and effectively reused. As such, every effort should be made to overcome regulatory, technical and ethical barriers to ensure implantation.

Removal of Intravascular Foreign Bodies With a Simple Low-Cost Method: A Report of 5 Cases.

PURPOSE: Intravascular embolization of hemodialysis and central venous catheters is a rare but potentially serious complication. With the increasing use of catheters in medical practice, we are often faced with this type of complication. Novel, simple, and low-cost techniques are needed for foreign body extraction in order to reduce cardiovascular risks. CASE REPORT: We describe the approach of 5 foreign body embolization cases. Case 1: a 57-year-old woman with end-stage renal failure with a complete fracture and migration of the distal extremity of a hemodialysis catheter. Case 2: a 55-year-old man with an accidental embolization of the distal portion of a hemodialysis catheter. Case 3: a 76-year-old woman with stage IV breast cancer and an accidental embolization of a central venous catheter guidewire. Cases 4 and 5: a 71-year-old woman and a 2-year-old boy with a port-a-cath embolization. All the patients underwent successful minimally invasive removal of the foreign bodies from the thoracic site using 5Fr pigtail catheters. Additional surgery was not required. No further complications, such as damage to the vascular wall, were noted. CONCLUSION: Our experience with the interlacing and traction pigtail show that it is a simple, practical, and low-cost technical alternative and its benefits should be widespread.

Risk of Cardiac Implantable Electronic Device Malfunctioning During Pencil Beam Proton Scanning in an In Vitro Setting.

PURPOSE: Cardiac implantable electronic devices (CIED) are sensitive to scattered secondary neutrons from proton beam irradiation. This experimental in vitro study investigated risk of CIED errors during pencil beam proton therapy. METHODS AND MATERIALS: We used 62 explanted CIEDs from 4 manufacturers; 49 CIEDs were subjected to a simulated clinical protocol with daily 2 Gy relative biological effectiveness fractions prescribed to the phantom. Devices were located at 3 different lateral distances from the spread-out Bragg peak to investigate the risk of permanent or temporary device errors. Additionally, 13 devices with leads connected were monitored live during consecutive irradiations to investigate the risk of noise, over- or undersense, pace inhibition, and inappropriate shock therapy. RESULTS: We detected 61 reset errors in 1728 fractions, and all except 1 CIED were reprogrammed to normal function. All, except 1 reset, occurred in devices from the same manufacturer. These were successfully reprogrammed to normal function. The 1 remaining CIED was locked in permanent safety mode. Secondary neutron dose, as estimated by Monte Carlo simulations, was found to significantly increase the odds of CIED resets by 55% per mSv. Clinically significant battery depletion was observed in 5 devices. We observed no noise, over- or undersense, pace inhibition, or inappropriate shock therapy during 362 fractions of live monitoring. CONCLUSIONS: Reprogrammable CIED reset was the most commonly observed malfunction during proton therapy, and reset risk depended on secondary neutron exposure. The benefits of proton therapy are expected to outweigh the risk of CIED malfunctioning for most patients.

Standardization of cerebrospinal fluid shunt valves in pediatric hydrocephalus: an analysis of cost, operative time, length of stay, and shunt failure.

OBJECTIVE: CSF shunts are the most common procedures performed in the pediatric neurosurgical population. Despite attempts in multiple studies, a superior shunt valve has never been shown. Because of this, the authors aim was to examine the impact of shunt valve standardization at their institution to determine if there is a difference in surgical cost, operative time, or short-term postoperative shunt failure. METHODS: A retrospective analysis at the authors' institution was performed for all new CSF diversion shunts, as well as shunt revisions requiring a new valve, or a new valve and at least a new proximal or distal catheter over a 1-year period (January 1, 2016, to December 31, 2016). After a period of transition, neurosurgeons were encouraged to use only one type of fixed-differential-pressure valve and one type of programmable valve when performing shunt surgeries. These patients who underwent "standardized" shunt surgery over a 1-year period (January 1, 2018, to December 31, 2018) were then compared to patients in the prestandardization epoch. All patients were followed for a 12-month period after surgery. Demographic information, surgical cost, operative time, and postoperative shunt failure data were collected in all patients in the study. RESULTS: The authors analyzed 87 shunt surgeries in patients prior to standardization and 94 shunt surgeries in patients after standardization. The rate of violation of the standardized shunt valve policy after implementation was 5.3% (5 of 94 procedures). When comparing the prestandardization group to those who received the standardized valve, operative costs were less ($1821.04 vs $1333.75, p = 0.0034). There was no difference in operative times between groups (78 minutes vs 81 minutes, p = 0.5501). There was no difference in total number of shunt failures between the two groups at 12 months after surgery (p = 0.0859). The rate of postoperative infection was consistent with the literature at 8%. CONCLUSIONS: In accordance with quality improvement principles, the reduction of unexplained clinical variance invariably leads to a decrease in cost and, more importantly, increased value. In this study, the implementation of a standardized shunt valve decreased operative cost. There were no differences in postoperative shunt failures at 12 months after surgery and no differences in length of surgery. Standardizing shunt valves in the treatment of pediatric hydrocephalus seems to be cost-effective and safe.

Complications of CSF Shunts in Pediatrics: Functional Assessment With CSF Shunt Scintigraphy-Performance and Interpretation.

OBJECTIVE. The purpose of this article is to review the performance method and criteria for interpretation of CSF shunt scintigraphy studies. CONCLUSION. Interpretation of CSF shunt scintigraphy studies requires an in-depth understanding of hydrocephalus, the functioning of CSF shunts and their components, and the mechanisms of failure of such devices. Application of strict interpretive criteria when evaluating CSF shunt scintigraphy studies improves diagnostic yield, providing valuable functional information to the neurosurgical team who manages patients with shunted hydrocephalus.

Assessment of Poor Inhaler Technique in Older Patients with Asthma or COPD: A Predictive Tool for Clinical Risk and Inhaler Performance.

BACKGROUND/OBJECTIVES: Older patients with asthma or chronic obstructive pulmonary disease (COPD) are particularly susceptible to inhaler technique errors and poor clinical outcomes. Several factors may influence their risk, but most studies are inconsistent and contradictory. We developed a tool for the major predictors of individual risk in these patients. DESIGN, SETTING AND PARTICIPANTS: In this multicentre, cross-sectional study, several demographic, socioeconomic and clinical characteristics were collected as potential predictors. Clinical features and inhaler technique performance were the main outcomes. Linear and logistic regression models were set up to identify significant variables. Subgroup analysis was performed according to age, cognitive performance and different types of inhalers. RESULTS: We included 130 participants, mean age of 74.4 (± 6.4) years. Mean years of device use were 5.8 (± 7.3). Inhaler errors affected 71.6% (95% CI 64-78.5) and critical mistakes 31.1% (95% CI 24-38.8). There were respiratory comorbidities in 82.3% of participants, and 56.2% had moderate to severe disease. A predictive score of misuse probability was developed for clinical practice, including points attributable to cognitive score, adherence and having received previous education on a placebo device. Other significant variables of individual risk were having respiratory allergies or comorbidities, smoking status, depression and educational level. Worse performance was detected in cognitively impaired patients older than 75 years who were using dry powder inhalers (DPI). Lung function was associated with smoking load, incorrect dose activation and absent end pause after inhalation. CONCLUSIONS: Individual risk assessment in older individuals should focus on inhaler technique performance (mainly on dose activation and end pause) and adherence, smoking, respiratory comorbidities and cognitive impairment. Placebo device training provided by doctors seems to best suit these patients.

Longevity and Utilization Cost of Rechargeable and Non-Rechargeable Spinal Cord Stimulation Implants: A Comparative Study.

INTRODUCTION: Despite major advancements in features and capabilities of the implantable pulse generator (IPG), real-life longevity and cost-effectiveness studies to guide pain specialists to make the appropriate choice between rechargeable and non-rechargeable IPG are limited. Our study aimed to compare the longevity and cost effectiveness of rechargeable vs. non-rechargeable IPG and SCS systems. METHODS: Data were collected for all SCS implantations performed between 1994 and 2018. The primary goal was to determine IPG longevity, defined as the time interval between IPG implantation and elective replacement due to IPG end of life (EOL). On the other hand, SCS system longevity was defined as the time between SCS implantation and its removal or revision for any reason other than IPG EOL. Kaplan-Meier and log-rank tests were used to assess IPG and SCS system longevities. Cost analysis was performed for cost effectiveness. RESULTS: The median IPG longevity was significantly higher for rechargeable SCS devices than for non-rechargeable SCS devices (7.20 years and 3.68 years, respectively). The median cost per day was similar for both IPGs, $13.90 and $13.81 for non-rechargeable and rechargeable, respectively. The median cost for SCS systems was higher for the rechargeable group ($60.70) compared with the non-rechargeable group ($31.38). CONCLUSIONS: Rechargeable IPG had increased longevity compared to their non-rechargeable counterparts, yet there was no significant difference in the actual longevity due to premature revisions or explantations between both SCS systems. Furthermore, non-rechargeable SCS systems were found to be the more cost-effective option when compared with rechargeable SCS systems.

Physical wastage of immunobiological products in the state of Ceará, Brazil, 2014-2016. / Perdas físicas de imunobiológicos no estado do Ceará, 2014-2016.

OBJECTIVE: to describe discarded wasted immunobiological products provided by the National Im-munization Program (PNI) to the State of Ceará between 2014 and 2016, and the costs of discarded doses. METHODS: this was a descriptive study using data from suspect im-munobiological product evaluation forms and data from disposal approval forms. RESULTS: a total of 317 forms were included, 72.0% of which had a disposal approval form, and 160,767 discarded doses were identified, at a total cost of BRL 1,834,604.75; wastage accounted for 0.45%, 0.93% and 0.53% of the total cost of vaccines in 2014, 2015 and 2016, respectively; the main reason for the wastage identified was electric power shortage (54.9%). CONCLUSION: we identified a large number of discarded wasted doses, with high absolute cost; tighter control is necessary, as failures in conservation dynamics may interfere with the supply of immunobiologicals.

Test Process and Results of Potential Masking of Sterilizing-Grade Filters.

Pre-use/post-sterilization integrity testing (PUPSIT) has been a widely debated topic for the last several years. To a large extent, the debate is because of the fact that scientific data were not available to provide additional clarity that could inform appropriate risk-based judgements and commensurate actions. To gain clarity, the Parenteral Drug Association (PDA) and BioPhorum Organizations Group (BioPhorum) formed the Sterile Filtration Quality Risk Management (SFQRM) consortium in late 2017. The consortium goals have been to fill existing gaps in scientific data as adequately as possible with studies and industry guidance that would provide professionals and license holders with the ability to make informed decisions about appropriate risk-management strategies. 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. In total, the four papers cover the following areas: (1) data mining to determine the influence of fluid properties on integrity test values, (2) filter masking studies and results (this publication), (3) risk assessment and management from filter production to end use, and (4) points to consider in the best practice of the use of PUPSIT. In total, 25 manufacturers and filter suppliers have contributed to the work of the Consortium, deploying their filtration experts and pooling their collective knowledge and applied science experience to address these questions. This effort has also been supported by many independent experts currently available who have contributed to and driven the Filtration Interest Group in the PDA for many years. Both PDA and BioPhorum have prioritized this program and combined their approaches to deliver this comprehensive body of work. We hope that collectively the publications aid decision making and create greater certainty and confidence and above all alignment between suppliers, manufacturers, and regulators alike on these important questions.

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.