Subcontracting sterile pediatric and adult chemotherapy preparations activity: A global risk analysis

Abstract Objective The main purpose of this study was to carry out a global risk analysis (GRA) on the subcontracting circuit to determine and evaluate the risks linked to the future subcontracting process and to propose corrective actions for the most critical risks to ensure safety. This study must allow to conclude in an objective way to the feasibility or not of this project. Methods A GRA was performed, conducted by a multidisciplinary working group that met in 20 meetings, corresponding to about 50 h of work. Results We identified 92 scenarios: 13% of scenarios had an initial criticality C1, 40% C2, and 47% C3. The GRA shows that the riskiest scenarios concern the management, material, and equipment with IT system and logistics with transport. The working group identified 25 corrective actions. After implementing those actions, 85% of scenarios had residual criticality C1, 8.5% C2, and 6.5% had residual criticality C3. The working group chose that it was impossible to subcontract part of the activity. Conclusion The GRA conducted in this study highlighted the risks related to outsourcing this activity, evaluated and prioritized them, and recommended corrective actions. Therefore, we conclude that subcontracting the totality of sterile preparations would be harmful to patient care quality and reactivity for vital medical emergencies, such as macrophage activation syndrome, preparation of clinical trials, graft rejection therapies, preparation of very short stability chemotherapy, and the pediatric graft conditioning chemotherapy.


| INTRODUCTION
Over the last 10 years, the French public hospital debt tripled to achieve approximately 30 billion euros. 1 To address the failure of health cost control, French governmental institutions have implemented a radical performance reform. Where complete and unrestricted patient management predominated, effective cost-management performance was essential to balance budgets. Therefore, in a restrictive financial situation and with the human resources redeployment, outsourcing seems to be a way of allowing hospital operations to concentrate on medical care by contracting out services, including equipment maintenance, biological cleaning, and medico-technical operations. 2 Today, institutions aim to extend subcontracting to high-risk areas such as sterile chemotherapy production Guimarâes and Crespo de Carvalho. 3 Indeed, the production of sterile chemotherapy preparations requires many staff and expensive technological equipment. Outsourcing the production would reduce risks linked to low production, allocate time gained on pharmaceutical tasks, absorb costs involved in this activity, upgrade technical skills as well as redistribute staff to other areas of the order site Galy et al. 4 Following these costs arguments, our hospital management suggested outsourcing the pediatric and adult sterile chemotherapy preparation activity to another hospital. Currently, our hospital prepares chemotherapies, particularly for a pediatric department performing hematopoietic stem cell transplants for patients with immune deficiencies and chemotherapies for the adult onco-hematology departments with conventional and intensive care. Some preparations are also made for other pediatric services, such as pediatric nephrology, pediatric intensive care, and medical-surgical continuing care units, neurology, and some adult services like surgical intensive care, nephrology, and multidisciplinary day hospital.
To determine and assess potential hazards related to outsourcing the sterile chemotherapy preparations, the global risk analysis (GRA) was selected in our hospital to lead the a priori analysis. The GRA method is derived from the preliminary risk analysis created initially in 1950s for the aerospace and military departments and widespread to industries.
Adapted to health, the GRA can define the consequences from the causes and corrective actions to be implemented. 1 This study is designed to provide a fully objective conclusion on the applicability of the outsourcing project.

| Sterile centralized preparation for injection unit (CPIU)
Eighteen 149 sterile preparations were realized in 2018; about 50% were chemotherapy and the others were injectable preparations for pediatric use specifically (e.g., defibrotide, antivirals, antifungals). The CPIU is opened Monday to Friday from 9 a.m. to 6 p.m., and Saturday 9 a.m. to 1 p.m. Physicians prescribed chemotherapies on Chimio ® software (published by Computer Engineering, version 5.8). For the patients treated in the outpatient clinic, prescriptions are made 24 h before administration (Day 1). For inpatients, prescriptions can be made the day before or on the administration day (Day 0). The pharmacist reviews and approves the prescription. For this purpose, he/she consults the patient medical file to check the correlation between the treatment prescribed and multidisciplinary consultation meeting decision. The height and weight data, biological assessment, compliance with the intercure, and tolerance to treatment during previous cures are verified too. For short stability preparations, production is performed on the day of administration. For expensive drugs, although the stability of the drug permits to anticipate the preparation, the CPIU waits for the doctors "GO/NO GO" to prepare the chemotherapy (e.g., carfilzomib, brentuximab). Our hospital is also an approved JACIE center (joint accreditation committee of international society for cellular therapy and European bone marrow transplantation). It is accredited by a European organization specialized in hematopoietic stem cell transplantation (HSCT). It is developing an international accreditation system to ensure high quality of patient care and improve the performance of specialized centers in the collection, management, and transplantation of SCT (European Society for Blood and Marrow Transplantation [EBMT], 2021). 5 The SCT transplant activity is performed in the adult hematology departments and in the pediatric immunohematology department. In 2018, the hospital performed about 100 transplants for both pediatrics and adults.

| Implementation of GRA
Analyses were conducted by a multidisciplinary working group from December 2018 to May 2019, consisting of two physicians (pediatric and adult hematologists), pharmacists in charge of the sterile preparation unit, pharmacists familiar with the methodology, a resident, three pharmacy technicians, and nurses. The group worked without any hierarchy and decisions required a common agreement.
The workgroup identified the proposed outsourcing circuit (Figure 1).

| GRA method
The GRA method consists of two sequential steps: GRA system and GRA scenario. The aim of the GRA system is to define the scope of the system under study and to identify all hazardous situations that the system could potentially encounter when contracting out sterile chemotherapy preparations Desroches et al. 6 For this task, the outsourcing process was divided by the working group into five main steps (prescription, sterile chemotherapy preparation, delivery, preparation receipt, and administration to the patient), 6 phases, and 10 subphases ( Table 1).
The hazards list was established similarly to the one proposed by the Ecole Centrale Paris and adapted to our practice. 1 Finally, 8 generic hazards, 12 specific hazards, and 21 hazardous events have been selected (Table 2). By cross-linking hazards and subphases, hazardous situations cartography was built. Each interaction between a hazard and a subphase was evaluated by assigning a score using a scale defined by the working group. This scale categorizes risks into two levels of priority such as high priority (Priority 1), the situation is considered as dangerous and needs to be assessed immediately and low priority (Priority 2), interaction is weak and the situation is safe. The working group focused only on the Priority 1 situations.
The GRA scenario is the second methodology step. It assesses any consequences caused by the hazardous situation and determines the corrective actions required to secure the system. The working group developed scenarios related to each hazardous situation. Each scenario was evaluated according to criticality to prioritize the implementation of corrective actions. For this purpose, severity (S) and frequency (F) scales were defined ( Table 3). The crossing between severity and frequency index generates a criticality (C) index C = S × F, defined by the criticality matrix. Three classes of criticality were identified: C1: acceptable, C2: tolerable under control, and C3: unacceptable (Table 4). Thus, the ranking of each scenario according to the criticality matrix generated the initial risk mapping.
Regarding initial dangers on the radar chart, logistics and material and equipment were the major dangers on the system ( Figure 3). Following corrective action, the majority of system dangers remained tolerable under control, but management and logistics remained unacceptable ( Figure 4). The working group identified 25 corrective actions (Table 5).

| Logistic
Transporting carcinogenic, mutagenic, or toxic for reproduction compounds is highly hazardous and implies training and certification of personnel for the task. Every transport vehicle must be equipped with a decontamination kit in case of an accident and the deliverer should be certified to manage a hazardous chemicals accident.
Note: C1, the risk was considered acceptable; C2, the risk was considered tolerable under control; C3, the risk was considered unacceptable. In addition, traffic risks and long delays can be a deterrent to outsourcing these preparations.

| Materials and equipment: IT system
The working group recommended the development of one electronic database for both sites Rucheton et al. 8 Achieving medical consensus for a single thesaurus for both sites could be long and difficult. In the event of software failure or computer network breakdown, a downgraded mode protocol should be established.

| Human factor
Every new work organization can affect staff with the risk of high resistance to change. Indeed, opposition against change could be a major Step during the sending and receiving phases, and an impact on transport including adjustments in the shuttle schedules initially planned.
The subcontracting process must be founded on an evaluation of the social risk, competition between service providers, financial and tax impact, and quality control of the services supplied. Subcontracting implies a general reorganization of the ordering center. The human factor of resistance to change is too often underestimated.

| Training at both sites
Staff training at the subcontractor's site is critical for chemotherapy preparation, particularly for pediatric protocols. The pediatric population has been identified as at risk for serious adverse events. Hematologists advise the administration of etoposide within 3 h of diagnosis. The subcontractor must be able to satisfy the request on working days as well as on evenings, nights, weekends, or public holidays. Although SAM is a rare disease, AGR recommended internal organization be maintained to ensure a safe response for the patient.
The chemotherapy reconstitution unit also makes sterile intravenous Considering all these data, the working group estimated the risk of outsourcing the preparation of busulfan at a rate too high for patients and recommends that the activity remains in our hospital.

| Impact of a pandemic on our system
We need to adapt our risk management strategy during pandemics, such as the one we are currently experiencing with SARS-Cov-2.
Indeed, we may be confronted with both understaffing in case of sick people or with childcare issues related to containment, and impact on the production and delivery of raw materials (e.g., drugs and medical devices) required for the production of chemotherapy.
To strengthen the resilience of the system, it is necessary to favor a sufficient number of people trained to produce chemotherapy by limiting the decrease in the number of production units. These constraints can be avoided by promoting production units closer to patients, allowing better control of the continuity, resilience, and responsiveness of care. (computer failure), preparation phase (solvent error), storage errors with wrong thermal probes, and destination errors. A circuit adaptation was required to reduce delivery delays and preparation destructions caused by early production (3% of lost preparations).

| CONCLUSION
The outsourcing of adult and pediatric sterile preparations to improve the quality, safety, and efficiency of the system should not be performed in the absence of risks analysis associated with this new organization. The GRA conducted in this study highlighted the risks related to outsourcing this activity, evaluated and prioritized them, and recommended corrective actions. Therefore, we conclude that subcontracting the totality of sterile preparations would be harmful to patient care quality. In that case, we should maintain a residual activity with costs associated. validation; visualization; writingreview and editing.

ACKNOWLEDGMENT
No funding to report.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data are available on request from the corresponding author

ETHICS STATEMENT
Not applicable.