Abstract
Objective To estimate the global journey of a generic clonazepam pill to map steps of production, distribution, and disposal.
Data sources PubMed; Google Scholar; industry and market reports; gray literature; pharmaceutical databases (eg, PharmaCompass); export records; pharmacies in Hamilton, Ont; industry professionals and leaders such as pharmaceutical company vice presidents, professors, a supply chain insurance company, and sustainable procurement consulting companies; and an international not-for-profit company.
Study selection Data related to clonazepam’s standard pharmaceutical production process, life cycle system boundaries, and most probable production locations were included in this review.
Synthesis This study depicts the estimated journey of a clonazepam pill's production and distribution, with the prescription being filled in Vancouver, BC. It begins with the extraction of salts to produce the active pharmaceutical ingredient. The main centres for clonazepam’s active pharmaceutical ingredient and excipient salt extraction and production are in India and China. Quality testing and stocking occur elsewhere, such as within the European Union. The product is then shipped back to India for the next manufacturing stages. Excipients are shipped from China to India and are incorporated into formulation and tableting. The product is then sent to global markets for the final stages of pill formation and regional distribution. After shipment through Europe and Asia, the journey continues through several locations within the United States, specifically New Jersey, for the final stages of manufacturing. Once manufacturing is finalized in New Jersey, the pill is shipped to and repackaged in Tennessee for distribution and then sent to Canadian industry clusters, typically within the greater Toronto area in Ontario. Pills are then shipped to pharmacies and hospitals in Vancouver, BC, for consumer use. The total distance travelled in this scenario is approximately 63,162 km, not including the entire process of producing and shipping excipients or local retailer shipments.
Conclusion Health care prescribing practices have tangible environmental impacts and manufacturers should continue to invest in operational streamlining to reduce greenhouse gas emissions.
Greenhouse gas (GHG) emissions from the health care system are generated through resource procurement, energy consumption, direct release of anesthetic gases, and waste production.1 Canada’s health sector, excluding anesthetic gases, produces 4.6% of national GHG emissions, ranking high alongside the United States (10%), Australia (7%), and the United Kingdom (3% to 4%).1,2 The UK National Health Service’s (NHS’s) assessment of GHG emissions within England’s health care system demonstrated that medications account for 25% of emissions.3 This is greater than the GHG emissions produced by the energy usage of NHS buildings and health care–related transportation combined.4 Nevertheless, there remains a lack of transparency and understanding of GHG production throughout pharmaceutical supply chains.
A 2021 review by the UK Department of Health and Social Care estimated at least 10% of prescription drugs in primary care were unnecessary.5 Deprescribing is one of the easiest and most cost-effective strategies to reduce health care emissions.6 Owing to medication optimization initiatives such as Deprescribing.org, family physicians are familiar with the potential patient harms of overprescribing and are becoming aware of the climate co-benefits.7
The exact process of measuring GHG emissions for pharmaceuticals is not well known.8 A life-cycle analysis (LCA) is a tool for assessing the environmental impact of products by analyzing the journey from extraction to disposal.9 The pharmaceutical sector has been slow to perform LCAs due to limited inventory data, confidential production processes, and complex supply chains.9 Knowing the carbon footprint of medications could inform physician prescribing practices and guide emission reduction policies within the health care system. Our analysis focuses on the global supply chain of pharmaceutical materials and takes an LCA approach, looking at the travel routes and destinations for a medication’s journey, rather than completing an exhaustive footprint analysis. Herein we follow clonazepam, shedding light on the intricate supply chain involved in the creation of a single medication.
METHODS
Determination of clonazepam as a focus
Clonazepam is a commonly prescribed second-line treatment for various medical conditions such as insomnia, anxiety, and seizure disorders.10 It is often overprescribed and can be detrimental to patients. It has side effects such as addiction, falls, and dementia; is expensive for the health care system; and is environmentally harmful.5,11 We chose clonazepam as a focus because there are alternative medications with lower addiction potential and nonpharmacologic interventions with similar treatment results (eg, social prescribing).12,13 Moreover, a reduction in prescribing habituating medications, such as clonazepam, aligns with excellence in clinical care and would help decrease health care emissions.14 Finally, as a common generic medication, clonazepam has several suppliers and we speculated it would yield the most data.
Life-cycle analysis approach
We (M.S., E.K., N.M., F.P.) partnered with 3 master’s students (H.K., A.S.G., F.R.), and their supervisor (G.K.) from the Faculty of Engineering at McMaster University in Hamilton, Ont, to produce a thesis project. This included a literature review to determine the components of a standard pharmaceutical production process, the life cycle’s system boundaries (system boundaries define what processes and stages of a product’s life cycle are considered in an assessment and which are not), and the most probable production locations.15
Every medication has 2 major components: active pharmaceutical ingredients (APIs) and excipients. Active pharmaceutical ingredients are the component that has pharmacologically therapeutic properties, and excipients enhance the therapeutic properties of APIs and are the inactive substances used as carriers that facilitate absorption, excretion, and flowability, and prevent denaturation. We determined the system boundaries include API production; excipient production; chemical synthesis, formulation, and testing; market distribution including packaging and costs; and customer consumption and disposal15-19 (Figure 1).
Life-cycle analysis system boundary
Literature review and data collection
From May to August 2024, we searched PubMed and Google Scholar with key words related to pharmaceutical life cycle, drug manufacturing, carbon emissions, sustainability processes, distribution, and procurement. We assessed industry and market reports, gray literature, pharmaceutical databases (eg, Medicine Carbon Footprint Formulary, PharmaCompass), and export records. This allowed us to determine geographic hotspots. We reached out to pharmacies in Hamilton (location of research team) and inquired about shipment origins, confirming components of the Canadian supply chain.
We also contacted industry professionals and leadership via email, LinkedIn, telephone calls, and informal in-person discussions. This included pharmaceutical company vice presidents, professors, a supply chain insurance company, and sustainable procurement consulting companies, but these provided limited additional information. We contacted an international not-for-profit company with experience in medication production that confirmed portions of the journey.
SYNTHESIS
An LCA approach was used to determine notable regional contributors to the environmental footprint without accounting for GHG emissions at each step.* Figure 2 displays our best estimation of clonazepam’s global journey, starting in Asia and ending in Vancouver, BC (location selected to illustrate the journey’s global scope). While many manufacturing steps are not specifically included (eg, excipient extraction involves extensive production steps that are not included in Figure 2A due to their complexity), we have depicted a plausible process highlighting central locations throughout clonazepam’s life cycle.
Global journey of clonazepam: A) Clonazepam transportation routes and distances. B) API and excipient salt extraction and production. C) Journey through North America.
Clonazepam’s journey starts with the extraction of salts to produce the API. The main centres for clonazepam API and excipient salt extraction and production are in India and China (Figure 2B). Quality testing and stocking occur elsewhere, such as within the European Union due to high quality standards and similar quality requirements to Canada.20,21 The product is then shipped back to India for the next manufacturing stages. Excipients are shipped from China to India and are incorporated into formulation and tableting.22,23 It is then sent to global markets for the final stages of pill formation and regional distribution.24 While cargo ships are displayed on our map, planes are also used for expedited shipments.25
After shipment through Europe and Asia, the journey continues through several locations within the United States (Figure 2C). New Jersey is one of North America’s largest intake points for the final stages of manufacturing.22 Once manufacturing is finalized in New Jersey, the pill is shipped to and repackaged in Tennessee for distribution and then sent to Canadian industry clusters, typically within the greater Toronto area in Ontario.26,27 Pills are then shipped to Vancouver pharmacies and hospitals for consumer use. However, the life cycle of a pill does not end in its consumption. Metabolites of the pill are excreted in urine, and if they enter aquatic environments, can have lasting ecologic and human health impacts.28,29
The total distance travelled in this scenario is approximately 63,162 km, not including the entire process of producing and shipping excipients or local retailer shipments (Figure 2). Although outside the scope of this analysis, a detailed carbon footprint would require a carbon equivalent calculation for every step of this journey. Pharmaceutical companies are expected to release emissions data in 2028 due to the NHS’s transparency efforts.30
DISCUSSION
Our research shows the extensive global effort involved in the production of a commonly prescribed medication. Each step is associated with GHG emissions, resource consumption, and energy usage. Our analysis identified India and China as hubs of clonazepam production, with shipping to quality testing and regional distribution points in Europe and North America, respectively.
While we were not able to calculate exact carbon dioxide emission data from our estimated production pathway, there are many environmental costs of producing and delivering one generic pill to a patient. In fact, the environmental impacts of production extend well beyond the life cycle described in this article. Emissions and waste affect local ecosystems, contaminate drinking water, and pose health risks to surrounding communities.29 This disproportionally harms vulnerable communities, notably Indigenous, Black, and low-income populations.31
A global approach to address pharmaceutical emissions should focus on reducing shipping distances and creating eco-friendly supply chains. This can include using renewable energy in transportation and distribution networks, as well as labelling production and supply chain emissions with environmental product declarations and ecolabels that include environmental impact data.32 A simple equation can be used to estimate a product’s environmental impact, which includes the mass of goods transported, distance travelled, and an emission factor of the product.33 There are also programs and standards such as the Science Based Targets initiative and CDP (formerly Carbon Disclosure Project) that require suppliers to list their emission reduction goals and actions.34 This creates a method of rating and comparing companies based on their carbon footprint and environmental impact. Moreover, reducing shipping distances would not only decrease emissions, but it would also make the system more resilient to natural disasters and political strife.24,35
Along with changes within pharmaceutical manufacturing, health care sector leadership is needed to drive impactful changes. As a leader in the field, the NHS has ensured their suppliers are actively decarbonizing through their supplier engagement program.3 By 2030, the NHS will no longer purchase pharmaceuticals from suppliers that do not meet or exceed their net zero commitments.3 Other countries are following suit. For example, Australia signed a public statement committing to work with the United Kingdom and the United States in supply chain decarbonization.36 This type of leadership pushes industry to shift to more sustainable and transparent practices.18
Policy-makers in Canada can also hold manufacturers responsible for their carbon footprint.37 Our federal and provincial governments could push the pharmaceutical industry to adopt renewable energy systems, regional supply chains, and the ecolabelling of all medications. Physicians can play an advocacy role by asking governments and hospital leadership to replicate supplier engagement programs like the NHS.
In terms of actions for family physicians, deprescribing unnecessary medications when clinically appropriate will have an impact on GHG emissions. Having structured education, proactive training, and patient-centred approaches are common ways to encourage deprescibing.38 An analysis of metered-dose inhaler GHG emissions found that understanding the carbon footprint of the various types of inhalers may have incentivized family physicians to be more aware of their prescribing and diagnostic actions.39 There is an opportunity within medical education to emphasize the intersection of prescribing and health care emissions as an added motivator for practice change. Toolkits, such as “Options for the Sustainable Prescriber,” and Appendix 1, available from CFPlus,† provide ideas on how to rethink prescribing habits.40
Finally, to ease burden of selecting the most sustainable medication for prescribers, carbon footprint grading systems can be used to clearly show emissions associated with individual medications. New tools, such as the Medicine Carbon Footprint Formulary, have been created to do this; the Medicine Carbon Footprint Formulary is a scalable and transparent database that classifies medications by carbon footprint.41
Limitations
The main limitation of our study was the difficulty in obtaining details on pharmaceutical companies’ production practices and emission data. A 2019 Health Care Without Harm study found the pharmaceutical industry discloses general data about sustainability and governance, but does not release detailed and specific information about pharmaceutical pollution and supplier facilities to the public.37 This report reflects our experience. Despite sources we consulted, obtaining details on production practices, distribution channels, total emissions, and waste was difficult and may not be possible without close ties to the industry. This is why we studied total distance travelled rather than carbon footprint. We did not know the origins or routes of the multiple excipients of the pill and have not fully included these in our distance calculations.
Given these limitations, the journey we depicted in Figure 2 is a global estimation, but there are potentially shorter supply chains to North America with suppliers in Mexico, Brazil, or even Europe. The pharmaceutical production markets in these locations have experienced growth in exports in recent years.42,43
Conclusion
The production of a clonazepam pill involves a complex global supply chain that is neither environmentally sustainable nor resilient to international disruptions. This journey is an example of the importance of health care manufacturers to prioritize a streamlined supply chain and to continue focusing on sustainable practices, and the importance of governments to demand these changes. Family physicians can promote change, join groups focusing on action or advocacy, and adopt more sustainable prescribing practices.
Acknowledgment
We thank Sara Rashighi for her design work in creating the original global journey figure, as well as Dr Sujane Kandasamy and Yusra Naqvi for their design and editing of the final map figures. We acknowledge Dr Greig Mordue for assisting lead author Harjas Kaur with her master’s thesis, which is the work this manuscript is based upon. We thank Salman Bawa and Richard Allen for providing advice and expertise during the conceptualization and initial research stages; Anish Kumar Bansal for supporting and guiding Harjas Kaur in her initial understanding of the pharmaceutical industry; and Liza Zvereva, Dr W. Scott Nash, and Dr Beth Henning for their editing support.
Footnotes
↵* There are several potential pathways that can be used to produce generic clonazepam and some of these pathways are likely more energy and resource efficient than the others.
↵† Appendix 1 is available from https://www.cfp.ca. Go to the full text of the article online and click on the CFPlus tab.
Contributors
Dr Myles Sergeant conceptualized the study framework and maps. Dr Sergeant, Harjas Kaur, and Dr Gail Krantzberg conceptualized the study approach and data collection process. All authors contributed to collecting, analyzing, and interpreting the data. Fiona Parascandalo, Harjas Kaur, Dr Sergeant, Dr Emma Ko, Dr Neha Mathur, Dr Krantzberg contributed to preparing the manuscript for submission. All authors provided critical feedback and helped shape the research, analysis, and manuscript.
Competing interests
None declared
This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
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