Development and Proof of Concept of an Audit Toolkit for the Safe Handling of Cytotoxic Drugs in Low- and Middle-Income Countries.

PURPOSE: Chemotherapies are considered high-risk drugs for patient and staff safety. Considering the rising burden of cancer and the increasing use of chemotherapy drugs in low- and middle-income countries (LMICs), promoting continuous improvements in the safety and quality of practices in these settings is essential. This paper describes the development and proof of concept of a toolkit to audit chemotherapy handling practices in the health care facilities of LMICs.
METHODS: A steering committee defined the audit method and the toolkit content. Several checklists were developed to facilitate the audit and data collection. Items included in checklists were derived from key reference works on safe handling. Different tools were validated using Delphi surveys and expert reviews. Audits of pilot sites were performed to test the toolkit's applicability and relevance.
RESULTS: The toolkit contains a 134-item global assessment tool for the different processes at each step of the medication pathway and three step-specific observation checklists to assess different health workers' practices during the prescription, preparation, and administration of chemotherapies. The toolkit also proposes using a surface-wipe sampling method to measure any cytotoxic contamination of the immediate environment. The toolkit was tested in three teaching hospitals in Africa.
CONCLUSION: The toolkit developed was successfully implemented in a variety of LMIC settings, providing a comprehensive evaluation of the quality and safety of the chemotherapy drug handling practices in participating health care facilities. This toolkit can help facilities in LMICs to implement a new approach to continuously improving the quality and safety of their practices and ultimately ensure patient and staff safety.

INTRODUCTION

Chemotherapies are considered high-risk drugs, not only for patients but also for the staff handling them. The risks related to occupational exposure were first described in the literature in the late seventies in the study by Falck et al[1] that reported mutagenic activity in the urine of nurses handling chemotherapy drugs without specific protection. Over the years, the risks of this ongoing challenge were studied and addressed by many experts, from professional organizations, national authorities, and even insurance companies.[2-7] As a result, several recommendations, guidelines, and regulations on safe handling practices were developed. In high-income countries, implementing preventive and control measures wherever chemotherapy drugs were transported, received, stored, prepared, administered, and disposed of became standard professional practice or a legal obligation.

CONTEXT

Key Objective

How to evaluate and promote continuous improvement of safe handling of chemotherapy drugs through a quality-oriented approach in low- and middle-income countries (LMICs)?

Knowledge Generated

The audit method and the different tools developed via this project enabled a comprehensive assessment of the safety of chemotherapy handling in three health care institutions in LMICs. Its implementation in a variety of settings enabled us to verify its applicability by future users.

Relevance

The audit toolkit offers health care facilities in LMICs ready-to-use tools and checklists to assess their safe handling of cytotoxic medicines and ensure patient and staff safety.

The use of chemotherapy drugs in low- and middle-income countries (LMICs) is much more recent. For many years, LMICs shouldered a great burden of infectious diseases and little attention was given to noncommunicable diseases. But recently, the increase in premature cancer deaths in LMICs can no longer be ignored and the burden of cancer has become a public health issue in these countries as well.[8-10] In 2020, GLOBOCAN statistics produced by the International Agency for Research on Cancer estimated 2,977,172 new cases of cancer, 5,720,384 cases of 5-year prevalence, and 1,953,071 cancer-related deaths in countries with medium- and low-human development indexes.[11,12] The economic impact and human development challenges resulting from this rising burden have led the WHO and other stakeholders to take action.[8,13] Substantial efforts have been made to prevent and manage cancer in LMICs, notably by expanding access to affordable, high-quality chemotherapy drugs.

In the coming years, increasing numbers of patients, combined with improved access to chemotherapy, will increase the use of these hazardous drugs. A recent survey on handling practices in LMICs showed that unsafe practices remained a significant safety risk to patients and staff in many places.[14] Strategies to remedy and improve this situation are needed, therefore, especially in lower-income countries.

Introducing a quality-oriented approach to the handling of chemotherapies is essential for ensuring patient and staff safety. The Deming cycle describes four iterative steps (plan, do, study, and act) and has been widely used as a quality improvement model.[15,16] In our context, the assessment or evaluation step consists of ensuring that the good practices that the cycle defines are implemented. Simply disseminating these recommendations is insufficient: their implementation must be ensured. Indeed, several works have highlighted the gap between current scientific knowledge and actual practices, as well as the significant variability in those practices.[14,17-19] There are currently few tools available to assess safe practices in LMICs. Their availability would facilitate the implementation of a continuous quality approach within LMIC institutions. This paper describes the development and proof of concept of a toolkit to audit chemotherapy handling practices in LMIC health care facilities.

METHODS

A steering committee was created within Geneva University Hospitals' Pharmacy Department to lead the project and define the audit method and toolkit. It was composed of the department head, the pharmacist in charge of the cytotoxic drug preparation unit, and the study's principal investigator. Toolkit design was guided by the objectives that it should first provide an overview of the processes and practices implemented throughout the chemotherapy circuit (eg, receiving drugs, storage, transport, prescription, preparation, administration, waste management, disposal, etc) and then compare them with existing best practices and guidelines. Various audit evaluation methods were chosen, such as interviews with key informants, structured observations, and surface-wipe sampling.

Instrument Design

Several tools were developed to facilitate the audit and data collection.

Assessment tool.

The kit's first tool makes a full assessment of every step involved in the processes and practices of handling chemotherapy drugs (eg, receipt, storage, transport, prescription, preparation, administration, waste management, cleaning, and patient counseling). Items addressing aspects of quality and safety were derived from key sources (Table 1) and underwent a first review by the steering committee. A panel of 27 pharmaceutical experts in oncology practices from 13 low-, middle-, and high-income countries subsequently validated those items via a two-round online Delphi survey. A previous publication described the development of this tool in detail.[26]

TABLE 1

Toolkit Design References

Structured observation checklists.

Additionally, we developed three structured observation checklists for noting how different staff applied safety and quality practices during the three main steps of the cytotoxic treatment process: prescription, chemotherapy preparation, and administration. Each checklist was based on professional guidelines and best practices but was adapted to the contexts existing in LMICs (Table 1); each item was reviewed and validated by two or three experts from within our institution.

Surface-Wipe Sampling

Surface-wipe sampling has been widely used in health care settings handling hazardous drugs.[27] This methodology has been recommended for evaluating contamination trends, implementing corrective measures, and increasing workers' awareness about the risks related to handling chemotherapy drugs.[22,27] A variety of surfaces should be selected depending on the setting and how the health care facility works (eg, preparation workbenches and adjacent areas, drug administration areas, etc). For this section of the toolkit, we chose to use methods previously developed and validated by Guichard et al.[28-30]

Sampling was performed by wiping polyester swabs (TX716, Texwipe, Kernersville, NC) moistened with isopropanol 75% over a surface of 100 cm2. After sampling, each swab was preserved separately in a small closed glass container. Samples were transported in insulated envelopes, with ice packs (for < 24 hours), and then frozen to < –20°C until analysis. Samples were analyzed in Switzerland by Cytoxlab[31] using an ultrahigh pressure liquid chromatography coupled with mass spectrometry method, enabling the simultaneous identification of 23 antineoplastic drugs.[29]

Proof of Concept

The principal investigator organized audits in several hospitals in LMICs to test the toolkit's applicability and relevance. Facilities were chosen through professional networks, and participation was voluntary. The same investigator performed audits at the different sites during 4-day visits (Table 2). Data were collected through observations, interviews, and surface-wipe sampling.

TABLE 2

Example of a 4-Day Audit Visit Program

RESULTS

The final toolkit consisted of one assessment tool, three observation checklists, and a surface-wipe sampling method. The Cyto-SAT assessment tool encompasses 134 items in 10 domains and 28 subdomains covering the entire cytotoxic drug handling process in health care facilities (Table 3). A free online service was developed to allow any LMIC hospital to self-assess its practices.[32]

TABLE 3

Results of the Cyto-SAT Evaluation: Percentage of Safe Practices Implemented in the Different Domains and Subdomains at the Three Hospitals

Unlike Cyto-SAT, the three structured observation checklists focus on one process each.

The prescription checklist includes items evaluating whether the chemotherapy prescription is clear and unambiguous and includes all the necessary information to provide safe treatment. It addresses prescription format, prescriber identification, patient-related information, and the chemotherapy protocol (Data Supplement).

The preparation checklist items assess the preparation process and operators' practices to ensure traceability throughout chemotherapy preparation, thus maintaining product integrity, preventing potential medication errors, and limiting the risks of occupational exposure (Data Supplement). This checklist exists in three versions so as to cover every possible situation found in LMICs: (1) chemotherapy preparation in environments without biosafety cabinets (BSCs) and cleanrooms, (2) chemotherapy preparation under a BSC but without a cleanroom, and (3) chemotherapy preparation under a BSC inside a cleanroom.

The administration checklist considers the entire course of care, with items assessing practices before, during, and after chemotherapy administration. It addresses aspects related to hygiene measures, the protection of nurses, checking procedures to limit treatment errors, patient surveillance, and waste management (Data Supplement). This checklist was developed for peripheral intravenous administration (infusion or a direct intravenous route) solely, as this is by far the most common route of administration. Administration via a central venous catheter is very rarely used in LMIC public hospitals because of its high cost.

We tested the toolkit in three teaching hospitals in Africa (Yaoundé in Cameroon, Fès in Morocco, and Dakar in Senegal) between November 2019 and February 2020. All three hospitals treated inpatients and outpatients for cancer. One of the institutions had a centralized chemotherapy preparation unit with two isolators located in a nonclassified room inside the hospital pharmacy. At the other two hospitals, nurses prepared chemotherapies in patients' rooms just before administration, directly at the bedside in one and on a workbench in the other. In each hospital, the investigator used all four data collection tools and took 10-15 surface-wipe samples. The tools developed enabled measurement of how well standards of practice were applied (Table 3) and provided the levels of cytotoxic contamination in the real-world environments of all three sites (Fig 1). All 35 samples revealed some cytotoxic contamination, with a total contamination level of the different drugs tested ranging from 74 ng to 12,401 ng, with a median of 856 ng (first quartile: 255 ng-third quartile: 3,104 ng). The safety and procedural gaps and points requiring improvement that were identified enabled us to draw up an action plan for implementing improvement measures in each hospital (Table 4).

FIG 1

Surface-wipe sampling results in the three hospitals (sum of the 23 cytotoxics tested). (A) Hospital 1: total cytotoxic contamination by surface sample (ng). (B) Hospital 2: total cytotoxic contamination by surface sample (ng). (C) Hospital 3: total cytotoxic contamination by surface sample (ng). FU, fluorouracil.

TABLE 4

Summary of the Three Hospitals' Strengths, Areas Requiring Improvement, and Actions Required Following Their Audit

DISCUSSION

The audit method and the different tools developed via this project enabled a comprehensive assessment of the safety of chemotherapy handling in three health care institutions in LMICs. The toolkit contains one 134-item global assessment tool to evaluate the different processes at each step of the medication pathway and three step-specific observation checklists to assess the practices of different health workers during the prescription, preparation, and administration of chemotherapies. The toolkit also proposes the use of a surface-wipe sampling method to measure any cytotoxic contamination of the immediate environment. The implementation of this audit method in a variety of settings enabled us to verify its applicability by future users.

The different tools enable a quick comparison between the practices currently used and those that are recommended, making it easy to identify areas for improvement. An action plan can then be drawn up on the basis of this thorough evaluation.

In general, the tools developed proved easy to use and were applicable in different contexts. Following our visits to the different hospitals, two additional versions of the observation checklists will be added to the toolkit in the future. The first is a specific version for chemotherapy preparation in an isolator, and the second is a version for the administration of chemotherapy by a central venous catheter for those countries with sufficient resources.

Surface-wipe sampling allowed us to highlight the levels of contamination in the different hospitals' working environments. Contamination levels differed significantly depending on the surfaces sampled. The most contaminated spots were found to be inside the isolators and on the equipment used for preparation. It was both interesting and valuable for each hospital to see which surfaces were the most contaminated and where occupational exposure risks were highest. Compared with the results obtained from samples from European or Swiss hospitals analyzed by Cytoxlab, the amounts of contamination we sampled were much higher (internal data). Although there are no acceptable or recommended limits, the precautionary principle implies reducing environmental contamination by chemotherapies to a minimum, notably through better working techniques, process reorganization, the use of equipment that limits the risks of contaminating personnel, and the application of adequate cleaning or chemical decontamination procedures. Unfortunately, local analysis of the surface-wipe samples was impossible as it required specialist, high-cost equipment. Transporting samples was also challenging as no professional transport company could guarantee to get them to Cytoxlab within 24 hours to ensure their stability.

Although the literature on safe handling practices in LMICs is still scarce, several studies have reported unsafe practices and the need for improvements.[14,18,19,33,34] Our study's findings confirmed that the level of safe practices in some institutions remained very low. Thus, implementing safety standards and continuous quality improvement approaches in this area is of utmost importance as the number of cancer treatments will continue increasing in the coming years. The audit toolkit (available in the Data Supplement) offers LMIC health care facilities ready-to-use tools and checklists to assess their safe handling of cytotoxic medicines and ensure patient and staff safety. Our goal would be for any health facility using our toolkit to conduct regular audits and measurements of their environmental contamination to monitor their progress as they implement their action plan.

Safe chemotherapy handling practices are an essential element in cancer management and ensuring staff and patient safety. Besides this audit toolkit, which is available free of charge through our Pharm-Ed platform,[35] we also provide e-learning courses on various aspects of safe chemotherapy handling practices. Many practical tools (eg, procedures, checklists, etc) and video tutorials are also available to facilitate the implementation of good practices. The overall impact of such a training program on practice improvements within a health care institution or a group of health care institutions is yet to be studied.

In conclusion, the toolkit described in the present work was successfully applied in a variety of LMIC settings and provided comprehensive evaluations of the quality and safety of the chemotherapy drug handling practices in three health care facilities in Africa. The toolkit can help facilities in LMICs to implement a continuous quality improvement approach, implement better practices, and, ultimately, ensure patient and staff safety.