Nick Smalley- Vice President of Global Regulatory Affairs; Gareth Knowling- Global Sourcing and Procurement Manager, Kindeva Drug Delivery.
While sustainability has been the banner under which many topics have been debated, its focus here is on decreasing the ongoing negative environmental impacts of drug-delivery combination products without increasing patient risk. Much of the discussion herein is focused on inhalers due to the current state of evolving regulations, but analogous challenges can be found throughout the combination product ecosystem and, indeed, across virtually every industry. The drive to create greener products has been ongoing for quite some time. This journey, however, has been accelerated by recent concurrent legislative proposals in Europe aimed at reducing the use of fluorinated gases (F-gases) and eliminating ~10,000 per and polyfluoroalkyl substances (PFAS). Among the compounds included are ones popularly used as propellants in pressurized metered dose inhalers (pMDIs), necessitating a rapid leap ahead in the search for more environmentally friendly, or green, propellants.
At present, HFC-134a is the predominant propellant, in part because its large industrial footprint means it is cheap and readily available. Unfortunately, it also has significant global warming potential (GWP), a measure of the global warming contribution of one ton of gas compared to the same amount of CO2 , which has a GWP of 1. As measured by the United States Environmental Protection Agency (EPA), HFC-134a has a GWP of 1,430.1 For comparison, the GWP of HFC-134a is more than 11 times that of one likely replacement, HFC-152a. Given this and the fact that pMDIs alone account for around 3% of healthcare-related emissions from the National Health Service in the U.K., it is clear that we can, and indeed must, make adjustments to lessen the impact of pMDIs on the environment.2 It is, however, vital that this is not an endpoint in the conversation but is instead a waypoint on the path to truly greener therapies. So, while there has been a reflexive response toward demonizing pMDIs and championing dry powder inhalers (DPIs), the conversation must take into account a patient-centric, holistic view of all inhaled therapies for meaningful, responsible change to happen across the industry.
The Failure of One-Size-Fits-All
Suggestions for lessening the impact of inhaled therapies on the environment tend to center around two general ideas: 1) change propellants in pMDIs and 2) switch to a different device, such as a DPI. While both options should be considered as part of a larger patient-centric strategy, neither is a one-size-fits-all solution, and both are easier said than done. Given the ubiquity with which these solutions are offered, it is worth taking a moment to consider each more fully.
Changing Propellants
Like Kindeva, most CDMOs and other organizations working with inhaled therapies are continuously engaging in research to improve what is available and find what is next. This research, however, is not fast by design, which is something much of the current legislative processes fail to recognize. The pharmaceutical industry is highly regulated worldwide in order to ensure proper testing and appropriate measures are taken to protect patients. Additionally, were the act of discovery at will, modern life would likely be much different. Science, and particularly the science of human health, simply takes time. From determining the proper compound and formulation to testing and practical logistics, the pathway to meeting revised legislation is likely to require six to seven years. And it bears repeating that this is not a flaw in the system but is, in fact, a feature meant to safeguard patients.
While both HFC-152a and HFO-1234ze, which respectively have 90% and 99.9% lower GWP than the current greenest propellant, are both near commercialization at Kindeva, ensuring research anticipates legislation introduced years later is an impossibility. In the case of HFO-1234ze, which has the lowest GWP of the alternative propellants discussed thus far, it is currently within the scope of the ECHA draft PFAS legislation, illustrating that even when the discovery process seems to be on the right path, an unwelcome surprise could wait around the corner.
While changing propellants in pMDIs is absolutely an integral part of strategies to lessen the environmental impact of drug-delivery combination products, it is simply not something that can happen on demand. Patient safety must be at the fore of every decision we make as providers of needed therapies, so creating the safest, most effective product should always be the end goal. This means there is no wiggle room in adherence to timelines and procedures that ensure responsible formulation, development, and testing.
A Different Device
Given the necessary delay between the start of the discovery process and commercialization, the tactic of just switching patients to DPIs seems logical. As with the change in propellants though, it misses the fundamental necessity of putting the patient at the center of the discussion. While DPIs are accessible to many people, they are not suitable for all patients, including those who lack the capacity to create adequate inspiratory flow. The medical community also has ethical concerns around switching already stable patients, given the potential for short- and long-term harm.
If changing to a DPI were to adversely impact the effectiveness of the therapy or otherwise impair the ability of the patient to properly use the device, that can cascade into a sequence of events that will negatively impact the environment, including transportation to the doctor and hospitalization. While these may seem like secondary concerns, they further support the notion that the right device for the patient is the right device for the planet.
Proponents of a DPI switch are also missing the bigger picture of crafting a green therapy prior to patient use, overlooking the total footprint of devices in favor of focusing on a single portion of their design. While DPIs offer a lower GWP than pMDIs, they fail to exceed many of those same devices in other environmental measures, as will be discussed in the next section.
A Wide-Lens Look at Environmental Threats
With these two options in mind, it is important to determine how the needs of the patient and the needs of the planet can best align within the drug-delivery combination product marketplace. While there is a purpose within the industry to act incrementally, in part to allow for responsible timelines, there is also an opportunity to map out at least a partial path forward that would allow organizations to more accurately begin transitions prior to the proposal of requirements. This sort of preparation also provides a clearer view of the road toward truly greener therapies, ensuring the focus on individual compounds and components is not missing the bigger picture of a combination product’s environmental impact.
The pushes to change propellants and switch to DPIs both limit the ability of the industry to truly reach the goal. While there is value to transitioning in stages, an understanding of the overall challenges is the only way to responsibly pivot in the short term. Along with ensuring patients have access to devices that work for them, it is vital to make sure the device to which you are pivoting is not doing equal or greater damage in another area of environmental concern. To exemplify the holistic evaluation that must be performed, we will use data from a 2019 University of Manchester, U.K., evaluation of the life cycle impact on the environment of DPIs and pMDIs using HFC-134a, HFC-227ea, and HFC-152a.3
This study examined a range of environmental impacts, including GWP, fossil and metal depletion, and freshwater and marine eutrophication. While the DPI lived up to its promise in GWP measurement, coming in 2.4 times lower than the HFC-152a pMDI, it stumbled in other evaluations. In fossil depletion, for instance, the DPI was the worst option, with 75% higher depletion than the HFC-152a inhaler. Similarly, the DPI proved the worst choice based on impacts to both freshwater and marine eutrophication. In fact, for 10 out of 14 categories, the HFC-152a pMDI proved to have the least environmental impact, whereas the DPI had the most damaging impact in eight categories, in large part due to its componentry.
So, briefly removing patient use concerns from the discussion, the researchers found that switching entirely from pMDIs to DPIs would reduce the climate change impact of inhalers in the U.K. by 96%, but the environmental trade-off is a significant increase in human toxicity and other measured impacts. Alternatively, replacing high GWP propellants with HFC-152a would reduce climate change impact by 90-92% while decreasing most other impacts by 28-82%. While this suggests that a switch to HFC-152a is the correct choice, the re-inclusion of patient needs in the argument necessarily complicates matters. Patients are not a one-size behemoth. Each one thinks and acts differently than the other, and their reasons for needing an inhaler and their ability to use the different types are just as unique. For this reason, halting the use of DPIs would be just as problematic as doing the same with pMDIs. Wherever possible, we must ensure the availability of all therapies that successfully meet the needs of individuals, because helping every patient is ultimately the mission of this industry and each of us working within it.
Keeping Every Element in Focus
So, how can you balance regulatory proposals and all-or-nothing solutions with patient centricity and a wide-lens view of environmental impact? In part, the answer is in the question: A 40,000-foot view of the environmental impact of your therapy that includes components, compounds, and the manufacturing and shipping processes can help you stay a step ahead. While you will still encounter unexpected updates, evaluating your product holistically and being proactive about decreasing its environmental impact gives you time to make necessary adjustments while respecting the procedures meant to keep patients safe. Start with aspects you know are ripe for regulatory focus and anywhere you find yourself falling surprisingly short.
As discussed, current suggestions favoring a universal switch to DPIs are well-meaning but short-sighted. It is, in fact, important for the entire drug-delivery combination product industry to approach environmental concerns with a holistic view that places the patient at its center. This means acknowledging that the right device for condition management and adherence is the right device for the patient, whether that is a pMDI, a DPI, or something else entirely. In practicality, this means that there will be a need for most options (or versions thereof) currently on the market for the foreseeable future, which in turn indicates that the only way to create truly green therapies is to evaluate all environmental impacts of each therapy and make adjustments. Without a single, simple answer for protecting both patients and the environment, an all-of-the-above approach to improvements is the most realistic path to a marketplace of green therapies that meet individual needs.
References
- United States Environmental Protection Agency. Refrigerant Transition & Environmental Impacts. 2023. Available online: https://www.epa.gov/mvac/refrigerant-transition[1]environmental-impacts (accessed April 28, 2023).
- NHS England and NHS Improvement, Delivering a ‘Net Zero’ National Health Service (London: Skipton House, 2020).
- Jeswani, H. K., & Azapagic, A. (2019). Life cycle environmental impacts of inhalers. Journal of Cleaner Production, 237, [117733]. Available online: https://doi.org/10.1016/j. jclepro.2019.117733 (Accessed May 2, 2023).
Author Biographies
As Vice President of Global Regulatory Affairs, Nick Smalley leads Kindeva’s global regulatory affairs organization. Nicholas has held previous positions in regulatory at 3M Health Care, Perrigo, UCB, and Norton Healthcare Limited. He holds a BSc (Hons) in chemistry from Loughborough University.
As Global Sourcing and Procurement Manager, Gareth Knowling leads Kindeva’s global sourcing and procurement organization. Gareth has held previous positions in Quality, Supplier Management, and Process Engineering at 3M Health Care. He holds a BSc (hons) in Polymer Materials Science from the University of Manchester Institute of Science and Technology.
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