Root cause analysis of safety incidents in antineoplastic use in children.

OBJECTIVES: to identify and analyze the factors that contribute to safety incident occurrence in the processes of prescribing, preparing and dispensing antineoplastic medications in pediatric oncology patients. METHODS: a quality improvement study focused on oncopediatric pharmaceutical care processes that identified and analyzed incidents between 2019-2020. A multidisciplinary group performed root cause analysis (RCA), identifying main contributing factors. RESULTS: in 2019, seven incidents were recorded, 57% of which were prescription-related. In 2020, through active search, 34 incidents were identified, 65% relating to prescription, 29% to preparation and 6% to dispensing. The main contributing factors were interruptions, lack of electronic alert, work overload, training and staff shortages. CONCLUSIONS: the results showed that adequate recording and application of RCA to identified incidents can provide improvements in the quality of pediatric oncology care, mapping contributing factors and enabling managers to develop an effective action plan to mitigate risks associated with the process.

Application of root cause analysis and TEAMSTEPPS post intravesical gas explosion during transurethral resection of the prostate: a rare case report.

BACKGROUND: An intravesical gas explosion is a rare complication of transurethral resection of the prostate (TURP). It was first reported in English literature in 1926, and up to 2022 were only forty-one cases. Injury from an intravesical gas explosion, in the most severe cases appearing as extraperitoneal or intraperitoneal bladder rupture needed emergent repair surgery. CASE PRESENTATION: We present a case of a 75-year-old man who suffered an intravesical gas explosion during TURP. The patient underwent an emergent exploratory laparotomy for bladder repair and was transferred to the intensive care unit for further observation and treatment. Under the medical team's care for up to sixty days, the patient recovered smoothly without clinical sequelae. CONCLUSIONS: This case report presents an example of a rare complication of intravesical gas explosion during TURP, utilizing root cause analysis (RCA) to comprehend causal relationships and team strategies and tools to improve performance and patient safety (TeamSTEPPS) method delivers four teamwork skills that can be utilized during surgery and five recommendations to avoid gas explosions during TURP to prevent the recurrence of medical errors. In modern healthcare systems, promoting patient safety is crucial. Once complications appear, RCA and TeamSTEPPS are helpful means to support the healthcare team reflect and improve as a team.

Trial and error - Outcome of breech presentation depending on birth mode and root cause analysis of severe adverse events.

OBJECTIVES: The debate about the safest birth mode for breech presentation at term remains unresolved. The comparison of a vaginal breech birth (VBB) with an elective caesarean section (CS) regarding fetal outcomes favors the CS. However, the question of whether attempting a VBB is associated with poorer fetal outcomes is examined in this study. Additionally, the study evaluates factors contributing to a successful VBB and illustrates possible errors in VBB management. STUDY DESIGN: We performed a retrospective analysis of term breech births over 15 years in a Perinatal Center Level I regarding fetal, maternal, and obstetric outcomes by comparing successful with unsuccessful VBB attempt and all attempted VBB vs. CS including a multivariate analysis of predictors for a successful VBB. A root cause analysis of severe adverse events (SAE) was conducted to evaluate factors leading to poorer fetal outcomes in VBB. RESULTS: Of 863 breech cases, in 78 % a CS was performed and in 22 % a VBB was attempted, with 57 % succeeding. Comparing successful with unsuccessful VBB attempts, successful VBB showed significantly lower maternal blood loss (p < 0.001) but poorer umbilical arterial pH (UApH) (p < 0.001), while other fetal outcome parameters showed no significant differences. Predictive factors for a successful VBB attempt were a body mass index (BMI) below 30.0 kg/m2 (p = 0.010) and multiparity (p = 0.003). Comparing all attempted VBB to CS, maternal blood loss was significantly higher in CS (p < 0.001), while fetal outcomes were significantly worse in VBB attempts, included poorer Apgar scores (p < 0.001), poorer UApH values (p < 0.001), higher transfer rate to the Neonatal Intensive Care Unit (NICU) (p < 0.001) and higher rate of respiratory support in the first 24 h (p = 0.003). CONCLUSION: The failed attempt of VBB indicates significantly worse UApH without lower Apgar scores or higher transfer rate to the NICU. The likelihood of a successful VBB is 9% lower with obesity and 2.5 times higher in multiparous women. Attempting a VBB should include detailed pre-labor counseling, regarding predictive success factors, an experienced team, and consistent management during birth.

Patient Satisfaction with the Outpatient Department Services at a Tertiary Care Hospital in Northern India and Root Cause Analysis of the Lowest-Scoring Attribute using Fishbone Diagram.

BACKGROUND: Assessing patients' satisfaction is an easy and cost-effective method of evaluating the outpatient services provided by health-care institutions. OBJECTIVES: The objectives of this study were to determine patient satisfaction among patients attending various outpatient departments (OPDs) at a tertiary care hospital and the factors affecting their satisfaction. MATERIALS AND METHODS: A cross-sectional study was conducted among patients attending various OPDs at a tertiary care hospital in Faridabad. Exit face-to-face interviews were conducted for 334 patients above 18 years of age who availed OPD services followed by pharmacy services. Information regarding sociodemography, rating of satisfaction with various attributes of OPD services on a 5-point Likert scale, and reasons for dissatisfaction was collected. Data were analyzed using SPSS version 22. Root cause analysis for the lowest-scoring attribute was done using fishbone diagram. RESULTS: About 64% of the patients were satisfied with the OPD services. "Attitude and communication of doctors" was the prime contributor to patient satisfaction. "Promptness at medicine distribution counter" was the attribute that scored lowest followed by "waiting time at the registration counter." The mean waiting time for registration was 38.2 min, for consultation with doctor 41.3 min, for collection of samples 49.6 min, and for drug dispensing 61 min. CONCLUSION: The issues related to pharmacy services need to be promptly acknowledged and addressed.

A Systemwide Strategy to Embed Equity into Patient Safety Event Analysis.

BACKGROUND: There is a lack of framework to incorporate equity into event analysis. This quality improvement initiative involved the development of equity tools that were introduced in a two-hour interactive, case-based training across 11 acute care facilities at the largest municipal health care system in the United States. A pre and post survey (which included analysis of a clinical vignette) was also conducted to assess for knowledge and comfort embedding equity in patient safety event analysis, and to measure discomfort or distress during the training. A separate assessment was used to evaluate the tools. EQUITY TOOLS: A visual aid, the Patient Equity Wheel, was created to facilitate more comprehensive and robust health equity discussions by compiling a comprehensive list of equity categories, including internal, external, and organizational dimensions of equity. The Wheel was designed for use during each phase of event analysis. An Embedding Equity in Root Cause Analysis Worksheet was developed to aid in assessing considerations of equitable care in the investigation process and includes questions to ask staff to further assess bias or equitable care factors. INITIATIVE OUTCOME AND KEY INSIGHTS: Participant knowledge and level of comfort increased after training. The most commonly unrecognized categories of bias were Training/Competencies, Structural Workflow, and Culture/Norms. Most participants responded that they had no discomfort or distress during the training. Post-training feedback noted that the tools were being used across the system in various stages of event analysis and have been reported to improve health equity conversations.

Reducing urinary tract infection rates in post-operative surgical patients: A quality improvement intervention.

INTRODUCTION AND OBJECTIVES: The Scarborough Health Network joined the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) in fiscal year 2017-2018 with interest in tracking surgical outcomes in General and Vascular Surgery patients. Results of the ACS NSQIP program revealed poor outcomes in 30-day urinary tract infection (UTI) rates in this population group. Results were in the lowest quartile compared to peer hospitals. To improve patient care, SHN initiated a multi-pronged quality improvement plan (QIP). METHODS: The QIP focused on several improvements: (1) clarify the current state and conduct a root cause analysis, (2) determine a plan to encourage early removal of catheters in post-surgical patients, (3) enhance team communication in the pre-operative, operative and post-operative care environments, and (4) improve education around UTI prevention and treatment. RESULTS: This study demonstrates the success of the quality improvement plan to improve a peri-operative complication in surgical patients. By 2019, SHN saw a significant decrease in UTI rates, and became a top decile performer in ACS NSQIP. CONCLUSIONS: This study demonstrates the feasibility and success of implementing a quality improvement project, and its methods can be adapted at other hospital sites to improve patient care.

An observational study of root-cause analysis of medication errors in elderly with methotrexate toxicity.

INTRODUCTION: Medication errors are inherent in a healthcare system. This results in both time and cost burdens for both the patient and the health system. The aim of this study was to conduct a root-cause analysis of medication errors in elderly patients with methotrexate toxicity, analyze associated factors, and propose solutions. METHODS: This single-center prospective study was designed to identify medication errors in cases of methotrexate toxicity between November 2022 to May 2023. Categorical data and free-text data are used to describe incidents. Harm assessment, factors related to medication errors, and preventability were evaluated for each case. Possible strategies to prevent similar occurrences are discussed. RESULTS: Out of a total of 15 patients who presented during the study period, nine suffered from methotrexate toxicity due to medication errors. Most medication errors occurred during prescribing or dispensing (seven cases). Inadequate knowledge about medication and dosage, inadequate communication was identified as a contributing factor for all medication errors. Patients on long-term methotrexate treatment are at high risk of methotrexate toxicity. CONCLUSION: This study highlights the challenges of health literacy and lacking communication between healthcare providers and patients that can be met through community pharmacy programs for the elderly in lower-middle-income countries.

Root cause analysis of mortality after esophagectomy for cancer: a multicenter cohort study from the FREGAT database.

BACKGROUND: Esophagectomy is associated with significant mortality. A better understanding of the causes leading to death may help to reduce mortality. A root cause analysis of mortality after esophagectomy was performed. METHODS: Root cause analysis was retrospectively applied by an independent expert panel of 4 upper gastrointestinal surgeons and 1 anesthesiologist-intensivist to patients included in the French national multicenter prospective cohort FREGAT between August 2014 and September 2019 who underwent an esophagectomy for cancer and died within 90 days of surgery. A cause-and-effect diagram was used to determine the root causes related to death. Death was classified as potentially preventable or non-preventable. RESULTS: Among the 1,040 patients included in the FREGAT cohort, 70 (6.7%) patients (male: 81%, median age 68 [62-72] years) from 17 centers were included. Death was potentially preventable in 37 patients (53%). Root causes independently associated with preventable death were inappropriate indication (odds ratio 35.16 [2.50-494.39]; P = .008), patient characteristics (odds ratio 5.15 [1.19-22.35]; P = .029), unexpected intraoperative findings (odds ratio 18.99 [1.07-335.55]; P = .045), and delay in diagnosis of a complication (odds ratio 98.10 [6.24-1,541.04]; P = .001). Delay in treatment of a complication was found only in preventable deaths (28 [76%] vs 0; P < .001). National guidelines were less frequently followed (16 [43%] vs 22 [67%]; P = .050) in preventable deaths. The only independent risk factor of preventable death was center volume <26 esophagectomies per year (odds ratio 4.71 [1.55-14.33]; P = .006). CONCLUSIONS: More than one-half of deaths after esophagectomy were potentially preventable. Better patient selection, early diagnosis, and adequate management of complications through centralization could reduce mortality.

Safety incident reporting and barriers (SIRaB) study: Strategies and approaches for investigating patient safety events in a hospital set-up.

BACKGROUND: Unsafe patient events not only entail a clinical impact but also lead to economic burden in terms of prolonged hospitalization or unintended harm and delay in care delivery. Monitoring and time-bound investigation of patient safety events (PSEs) is of paramount importance in a healthcare set-up. OBJECTIVES: To explore the safety incident reporting behaviour and the barriers in a hospital set-up. METHODS: The study had two sections: (a) Retrospective assessment of all safety incidents in the past 1 year, and (b) Understanding the barriers of safety reporting by interviewing the major stakeholders in patient safety reporting framework. Further root cause analysis and failure mode effect analysis were performed for the situation observed. Results were statistically analyzed. RESULTS: Of the total of 106 PSEs reported voluntarily to the system, the highest reporting functional group was that of nurses (40.57%), followed by physicians (18.87%) and pharmacists (17.92%). Among the various factors identified as barriers in safety incident reporting, fear of litigation was the most observed component. The most commonly observed event was those pertaining to medication management, followed by diagnostic delay. Glitches in healthcare delivery accounted for 8.73% of the total reported PSEs, followed by 5.72% of events occurring due to inter-stakeholder communication errors. 4.22% of the PSEs were attributed to organizational managerial dysfunctionalities. Majority of medication-related PSE has moderate risk prioritization gradation. CONCLUSION: Effective training and sensitization regarding the need to report the patient unsafe incidents or near misses to the healthcare system can help avert many untoward experiences. The notion of 'No Blame No Shame' should be well inculcated within the minds of each hospital unit such that even if an error occurs, its prompt reporting does not get harmed.

Root Cause Analysis of Delayed Emergency Department Computed Tomography Scans.

Introduction: A solution for emergency department (ED) congestion remains elusive. As reliance on imaging grows, computed tomography (CT) turnaround time has been identified as a major bottleneck. In this study we sought to identify factors associated with significantly delayed CT in the ED. Methods: We performed a retrospective analysis of all CT imaging completed at an urban, tertiary care ED from May 1-July 31, 2021. During that period, 5,685 CTs were performed on 4,344 patients, with a median time from CT order to completion of 108 minutes (Quartile 1 [Q1]: 57 minutes, Quartile 3 [Q3]: 182 minutes, interquartile range [IQR]: 125 minutes). Outliers were defined as studies that took longer than 369 minutes to complete (Q3 + 1.5 × IQR). We systematically reviewed outlier charts to determine factors associated with delay and identified five factors: behaviorally non-compliant or medically unstable patients; intravenous (IV) line issues; contrast allergies; glomerular filtration rate (GFR) concerns; and delays related to imaging protocol (eg, need for IV contrast, request for oral and/or rectal contrast). We calculated confidence intervals (CI) using the modified Wald method. Inter-rater reliability was assessed with a kappa analysis. Results: We identified a total of 182 outliers (4.2% of total patients). Fifteen (8.2%) cases were excluded for CT time-stamp inconsistencies. Of the 167 outliers analyzed, 38 delays (22.8%, 95% confidence interval [CI] 17.0-29.7) were due to behaviorally non-compliant or medically unstable patients; 30 (18.0%, 95% CI 12.8-24.5) were due to IV issues; 24 (14.4%, 95% CI 9.8-20.6) were due to contrast allergies; 21 (12.6%, 95% CI 8.3-18.5) were due to GFR concerns; and 20 (12.0%, 95% CI 7.8-17.9) were related to imaging study protocols. The cause of the delay was unknown in 55 cases (32.9%, 95% CI 26.3-40.4). Conclusion: Our review identified both modifiable and non-modifiable factors associated with significantly delayed CT in the ED. Patient factors such as behavior, allergies, and medical acuity cannot be controlled. However, institutional policies regarding difficult IV access, contrast administration in low GFR settings, and study protocols may be modified, capturing up to 42.6% of outliers.

A 5-step root cause analysis model for test overutilization: A study on its application to plasma transferrin testing.

OBJECTIVES: This study aimed to develop a root cause analysis (RCA) model for test overutilization, applying it to transferrin overordering at our institution. METHODS: A comprehensive review was undertaken to establish a systematic RCA model. Upon implementation, the questionnaire identifying the root causes of transferrin overordering with infographic intervention was distributed to clinicians and nurses. RESULTS: The RCA model comprises 5 steps: (1) problem identification, (2) causal factor determination, (3) data collection, (4) significant factor identification, and (5) corrective action development and outcome measurement. The major causes of transferrin overutilization were confusion between transferrin and transferrin saturation, as well as unfamiliarity with the laboratory handbook. An infographic reduced postintervention transferrin ordering among clinicians (84.9%, P < .001) and nurses (46.8%, P < .001). CONCLUSIONS: This study presents a 5-step RCA model that offers a customized method to identify the causes of test overutilization. Applying this model to transferrin at our institution revealed 22 leading root causes. Laboratories are encouraged to adopt this RCA model as it can contribute to optimized patient care and more efficient resource allocation.

[Implementation and Effectiveness of Measures to Prevent Recurrence of Incidents Developed through Root Cause Analysis Using Work Flowchart].

PURPOSE: Incidents are recommended to be analyzed by root cause analysis (RCA). Our institution also conducts RCA for incidents and takes measures to prevent recurrence. The purpose of this study was to evaluate the effectiveness of countermeasures against the root causes analyzed by RCA in order to prevent recurrence of incidents. METHODS: Since the treatment planning CT scanner was replaced, incidents of failure to zero adjustment the coordinates of the bed position occurred four times during a three-month period. The RCA was used to investigate the root causes of these incidents and to formulate measures to prevent recurrence. To evaluate the effectiveness of the recurrence prevention measures, we collected the number of recurrence of incidents during the first year after the effectiveness of the recurrence prevention measures, and used the chi-square test to determine the significant difference in the probability of an incident occurring at a significance level of 5% or less. RESULTS: The measures to prevent the recurrence of incidents were to double-check that the coordinates of the bed position were adjusted to zero and to simulate operations based on a work flow that incorporated this double-check. During the first year period following the implementation of these recurrence prevention measures, the number of recurrence incidents was zero, and the probability of their occurrence decreased statistically significantly (p<0.05). CONCLUSION: Thorough double-checks and work simulation based on the work flow are effective methods for preventing the recurrence of incidents.

Learning from Non-Routine Events and Teamwork in Intensive Care Units: Challenges and Opportunities.

Patients admitted to intensive care units (ICUs) have profound and complex illnesses, often fraught with uncertainties in diagnoses, treatments, and care decisions. Clinicians often deviate from best practices to handle ICUs' myriad complexities and uncertainties. Non-routine events (NREs), defined as any aspect of care perceived by clinicians as deviations from optimal care, are latent and frequent safety threats that, if left unchecked, can be precursors to adverse events. Proper identification and analysis of NREs that represent latent safety threats have been proposed as a feasible and more effective approach for performance improvement than traditional root cause analysis for patient safety events. However, NRE studies to date have yet to show the holistic picture of NREs in the contexts of teamwork and time-dependent tasks that are frequently associated with NREs. NREs, an upstream interventional area to understand root causes, team performance, and human-computer interaction, still needs to be expanded. This article presents concepts of NREs, and the use of real-world data (RWD) and informatics methodology to investigate NREs in contexts and discusses the opportunities and challenges to enhance NREs research in teamwork and time-dependent tasks.

Root cause analysis of medication errors of the most frequently involved active substances in paediatric patients.

BACKGROUND: Use of medicinal products in paediatric patients is identified as a risk factor for the occurrence of medication errors. OBJECTIVES: To describe and identify root causes of medication errors in children and adolescents spontaneously reported to Agency for Medicinal Products and Medical Devices of Croatia (Agency). METHOD: Agency's adverse drug reaction database was searched by using the Standardised MedDRA Query: medication errors (Broad) with data lock point set at 30th June 2022. Cases in which medication errors occurred in patients up to 18 years of age were analysed according to the patients' age group and gender, reporter's qualification, seriousness, reported preferred terms and active substances. For the first 30 most frequently reported active substances, an in-depth analysis was performed to identify the root cause of medication errors. RESULTS: Altogether, 6254 reports were spontaneously reported to the Agency, out of which 1947 (31 %) contained at least one preferred term belonging to Standardised MedDRA Query medication errors. More than half of patients experiencing medication errors belonged to the age group 2-11 years (66 %) and male gender (53 %). The most frequently reported ME PTs included accidental exposure to product by a child (64 %) and accidental overdose (17 %). Medication error root causes for the first 30 most frequently involved active substances included misinterpretation of prescribed dosage due to a very small volume resulting in salbutamol overdose; replacing millilitre and milligram units resulting in paracetamol solution overdose; interchange between medicinal products due to primary package similarities resulting in cholecalciferol overdose and interchange between oral solution and syrup resulting in valproate overdose. CONCLUSIONS: Healthcare professionals should counsel caregivers about the importance of keeping medicinal products out of children's reach and provide detailed instructions on how to appropriately use medicinal products.

Team experiences of the root cause analysis process after a sentinel event: a qualitative case study.

BACKGROUND: Root cause analysis (RCA) is a systematic approach, typically involving several stages, used in healthcare to identify the underlying causes of a medical error or sentinel event. This study focuses on how members of a Norwegian RCA team experience aspects of an RCA process and whether it complies with the Norwegian RCA method. METHOD: Based on a sentinel event in which a child died unexpectedly during childbirth in a Norwegian hospital in 2021, the following research questions are addressed: 1. What was the RCA team's experience of the RCA process? 2. Was there compliance with the Norwegian RCA method in this case? A case study was chosen out of the desire to understand complex social phenomena and to allow in-depth focus on a case. RESULTS: The result covered three main themes. The first theme related to the hospital's management system and aspects of the case that made it challenging to follow all recommendations in the Norwegian RCA guidelines. The second theme encompassed external and internal assessment. The RCA team was composed of members with methodological and medical expertise. However, the police's involvement in the case made it complex for the team to carry out the process. The third and final theme covered intrapersonal challenges RCA team members faced. Team members experienced various challenges during the RCA process, including being neutral, dealing with role-related challenges, grappling with ambivalence, and managing the additional time burden and resource constraints. As anticipated in the RCA guidelines, the team's ability to remain neutral was tested. CONCLUSION: The findings of this study can help stakeholders better comprehend how an inter-professional RCA teamwork intervention can affect a healthcare organization and enhance the teamwork experience of healthcare staff while facilitating improvements in work processes and patient safety. Additionally, these results can guide stakeholders in creating, executing, utilizing, and educating others about RCA processes.

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.

Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

What are the experiences of team members involved in root cause analysis? A qualitative study.

BACKGROUND: Conducting root cause analysis (RCA) is complex and challenging. The aim of this study was to better understand the experiences of RCA team members and how they value their involvement in the RCA to inform future recruitment, conduct and implementation of RCA findings into clinical practice. METHODS: The study was set in a health network in Adelaide, South Australia. A qualitative exploratory descriptive approach was undertaken to provide an in-depth understanding of team member's experience in participating in an RCA. Eight of 27 RCA team members who conducted RCAs in the preceding 3-year period were included in one of three semi-structured focus groups. Thematic analysis was used to synthesise the transcribed data into themes. RESULTS: We derived four major themes: Experiences and perceptions of the RCA team, Limitations of RCA recommendations, Facilitators and barriers to conducting an RCA, and Supporting colleagues involved in the adverse event. Participants' mixed experience of RCAs ranged from enjoyment and the perception of worth and value to concerns about workload and lack of impact. Legislative privilege protecting RCAs from disclosure was both a facilitator and a barrier. Concern and a desire to better support their colleagues was widely reported. CONCLUSIONS: Clinicians perceived value in reviewing significant adverse events. Improvements can be made in sharing learnings to make effective improvements in health care. We have proposed a process to better support interviewees and strengthen post interview follow up.

Root Cause Analysis of An Inverse Relationship Between The Ice Nucleation Temperature, Process Efficiency And Quality of A Lyophilized Product.

The aim of this study was to probe an unexpected relationship between the ice nucleation temperature (TIN), process efficiency and product attributes in a controlled ice nucleation (CIN) lyophilization process. An amorphous product was lyophilized with (CIN-5 °C, CIN-7 °C or CIN-10 °C) or without (NOCIN) control of ice nucleation. Process parameters and product attributes were monitored and compared using a series of advanced in-line and off-line process analytical technology (PAT) tools. Unexpectedly, an indirect relationship was observed between TIN and primary drying efficiency for the CIN processes. Further, the CIN-5 °C process was associated with higher product resistance to mass flow than corresponding CIN-7 °C and CIN-10 °C processes. Surprisingly, the air voids in some NOCIN products were larger than CIN-5 °C products but comparable to CIN-7 °C. Heat flux analysis revealed an indirect relationship between TIN and the minimum hold time required to complete solidification. The heat flux analysis also revealed all products underwent complete solidification prior to primary drying. The order of homogeneity in water activity of the products was CIN-5 °C ≥NOCIN>CIN-7 °C. The higher homogeneity in water activity of CIN-5 °C than corresponding CIN-7 °C processes indicated that the lower process efficiency of CIN-5 °C could not be attributed to unsuccessful induction of ice nucleation during CIN-5 °C. High resolution micro-CT imaging and Artificial Intelligence Image analysis revealed cake wall deformation in CIN-7 °C and NOCIN products but not in CIN-5 °C. In addition, NOCIN products had bimodal distribution in air voids with median size range of 4-5 µm and 151.9-309 µm, respectively, hence the lower process efficiency of NOCIN despite the higher D90. Thus, the observed relationship between TIN and process efficiency may be attributed to microstructural changes post freezing. This hypothesis was corroborated by visible macroscopic cake collapse in NOCIN products but not in CIN products after lyophilization at a higher shelf temperature. In conclusion, the advantages of controlling the ice nucleation temperature of a lyophilization process may only be attained through a robust process design that takes into consideration the primary and secondary drying process parameters. Further, combined use of advanced in-line and off-line PAT tools for process and product characterization may hasten the at scale adoption of advance techniques such as CIN.