2.1. Goal and Scope Definition
The purpose of this study was to perform a comparative LCA to evaluate the cradle-to-use phase global warming potential (GWP) of a metered dose inhaler, specifically the Proventil®
HFA inhaler, relative to an electric nebulizer, specifically the DeVilbiss Pulmo-Aide®
nebulizer (both are pictured in Figure S1 in the Supplementary Data
). Both of the devices are used for the treatment of COPD via delivery of the inhalation aerosol drug albuterol sulfate.
The frequency of administration of bronchial dilation drugs (e.g., albuterol sulfate) to a patient varies between the inhaler and nebulizer methods of delivery based on the severity of asthma and the concentration of the drug that is delivered. Thus, to compare the environmental impacts of the inhaler and nebulizer, the functional unit in this study was defined as one dose of albuterol sulfate. A single inhaler can be used to supply 100 doses (2 puffs per dose). The nebulizer was modeled as being able to administer 2000 doses assuming 2–4 treatments per week and a 10 year average lifespan of the compressor [12
An inventory analysis of the manufacturing processes and materials used to produce the two drug delivery devices was conducted, and the inventories were then modeled using GaBi Product Sustainability software (v. 6) to calculate the products’ environmental impact quantified as GWP from cradle through use phase. Transportation and packaging were excluded from the analysis based on preliminary results, which demonstrated that they played insignificant roles in GWP impacts. When possible, pre-defined manufacturing processes included in the GaBi software were used to model the devices since these processes are typically well documented and vetted in terms of material and energy flows. Default process selections used U.S. data, while European process data was used when U.S. data was unavailable.
For consistency, the “US Electricity grid mix PE” GaBi process was used to model all of the electricity inputs. This electricity mix includes the U.S. national average mix of 0.4% geothermal, 0.3% wind, 6.4% hydro, 1.7% waste and biomass, 20% nuclear, 50.7% coal, 2.5% heavy fuel oil, and 20% natural and blast furnace gas energy sources.
2.2. Inventory Analysis: Metered Dose Inhaler
For each drug delivery device, the inventory was prepared by disassembling the device and determining the mass and major composition of each component, as shown for the metered dose inhaler in Table 1
. The Proventil®
HFA inhaler can be categorized into six major components: the active substance, propellant, surfactant, metering valve, actuator, and canister [13
]. The following sections describe the assumptions for the manufacture and assembly of each component used to model the device using manufacturing processes available in the GaBi Professional + Extension XVII database (as shown in the inventory flow diagram in Figure S2 in the Supplementary Data
). An inhaler assembly energy input of 1 MJ (0.001 MJ/dose) was estimated based on other manufacturing processes built into the GaBi database.
2.2.1. Active Substance
The active bronchodilator substance is albuterol sulfate, (C13
(also known as salbutamol sulfate, the WHO recommended name). Albuterol sulfate makes up 0.3% of the net weight of the drug [14
]. Detailed information about albuterol sulfate and its production is not publicly available. However, since the functional unit in this analysis was a single dose of the drug, an exact representation of the albuterol sulfate itself was not necessary in this comparative LCA since both devices use albuterol sulfate, and the device impacts were normalized to the functional unit of a single dose. Accordingly, a new GaBi process was developed to represent the active substance. A conservative placeholder, chlorodifluoromethane (CHF2
Cl, also known as HCFC-22 or R22), was used to model the active ingredient. HCFC-22 is commonly used as a propellant and is characterized by a high GWP (up to 1700× that of CO2
]); as such, it was anticipated to have greater negative GWP impacts than albuterol sulfate. If the GWP impacts of HCFC-22 were shown to be negligible in the model in comparison to other components, then negligible impacts from albuterol sulfate could also be assumed.
Microionizers using compressed air are used to convert the active drug into an ultra-fine powder [13
], so for production of the active substance, a compressed air manufacturing process was used in the GaBi model.
The inhaler relies on the propellant to forcefully deliver an aerosolized cloud of the drug (1% albuterol sulfate in saline solution combined with surfactant) to the user. The propellant in Proventil®
HFA is hydrofluoroalkane-134a (HFA-134a, or 1,1,1,2-tetrafluoroethane, C2
), which represents 99.7% of the net weight of the drug formulation [14
]. Production of the propellant was modeled in GaBi as a reaction between hydrogen fluoride (HF) and trichloroethylene (C2
) in a closed system [16
Based on stoichiometry, the chemical reaction to yield 1 kg of HFA-134a requires 0.784 kg of HF and 0.969 kg of C2HCl3. When the reactants are in vapor form, the temperature at which the reaction occurs is 380 °C; assuming room temperature initially, this would require 495 kJ of thermal energy input. The reaction also produces 2.14 kg of HCl, which was modeled as being recoverable for reuse for other purposes.
The surfactant allows the active substance and the propellant to mix together, creating the inhalation solution. For the aerosol drug in Proventil®
HFA, oleic acid and ethanol compose the surfactant [13
]. However, as mass of the surfactant is approximately 10% of the active substance (less than 0.01% of the total mass of the inhaler), the surfactant was considered negligible and was excluded from the model.
2.2.4. Metering Valve
The metering valve controls the dose of drug released in a single inhaler puff. It consists of the ferrule, ferrule gasket, valve stem, compression spring, tank, bottle emptier, diaphragm, and tank seal.
Stamping was used to model production of the aluminum ferrule in GaBi. The ferrule gasket was modeled as polyethylene composition manufactured by using injection molding. The valve stem, spring, tank, and bottle emptier were modeled as 316 stainless steel material. While valve stems can be manufactured using metal injection molding [17
], this process is not built into the GaBi database, so deep drawing was used instead. The compression spring is manufactured using an auto-coiling machine, which has a similar energy consumption to steel stamping and bending, as employed in the GaBi model. The tank and bottle emptier are manufactured via press forming, which was assumed to be similar to stamping and bending, as used in the GaBi model. Nitrile rubber is used to produce the diaphragm and tank seal. In GaBi, the rubber was modeled as a blend of 50% acrylonitrile and 50% butadiene (the acrylonitrile content in rubber typically ranges from 20–50%) [19
]. The polymerization process was condensed into a single phase and was assumed to have a similar energy consumption to the acrylonitrile-butadiene-styrene copolymer resin in GaBi [21
]. The mass of the tank seal was less than 0.01 g (<0.04% of the total mass of the inhaler), and was thus assumed to be negligible and was excluded in the model.
The actuator (which controls the inhaler movement) and actuator cap were modeled as polypropylene parts manufactured using plastic injection molding.
The canister containing the drug was modeled using aluminum deep drawing manufacturing. To prevent the albuterol sulfate and HFA-134a from reacting with the aluminum, the interior surface of the canister and valve components are coated with a thin dual-layer coating (<1 μm) consisting of a vapor-deposited inorganic layer and a fluorine layer [22
]. The mass of the coating in the device is negligible, and was thus excluded from the model.
2.2.7. Use Phase
During the inhaler’s use phase, the medicine canister is placed into the actuator and the device is primed by shaking before use. A single dose of the drug is administered in the form of two puffs of the inhaler. In the GaBi LCA model, the sole input for the use phase was the inhaler itself. All of the propellant associated with each puff was assumed to be released to the atmosphere (i.e., no absorption of the propellant itself in the body in this conservative model), with an associated GWP impact.
2.3. Inventory Analysis: Electric Nebulizer
An inventory of the components of the DeVilbiss Pulmo-Aide®
nebulizer was produced by disassembling the device and determining the mass and major composition of each component, as listed in Table 2
. The major components of the nebulizer were grouped into the active substance (as described previously), exterior shell, stator (including core, coils and cover), rotor (including squirrel cage, ball bearings, and central shaft), suction chamber, fan (including fan, fan housing, and cross brace), medicine delivery (including mouthpiece, medical tubing, and medicine chamber), and power cord.
Throughout the model, it was assumed that the DeVilbiss Pulmo-Aide® nebulizer was constructed out of lightweight, durable, and easily accessible materials to keep costs to a minimum. Additional assumptions for the manufacturing and assembly of each component were made to accommodate the LCA model by using the processes available in the GaBi database, as described in the following sections. An assembly energy of 0.1 MJ (0.0005 MJ/dose) was used to represent manufacturing based on other manufacturing processes built into GaBi.
2.3.1. Active Substance: Albuterol Inhalation Solution
A single dose of the albuterol sulfate inhalation solution used during device operation contains 0.003 g of albuterol sulfate, 3 g of sterile saline, and 0.000049 g of 96% sulfuric acid used to adjust the pH from 7 to 4. The saline solution was modeled using deionized water and sodium chloride. The solution production process included an input of 335 kJ thermal energy, as calculated to dissolve the sodium chloride using the specific heat of water and the required change in temperature from room temperature to boiling.
2.3.2. Exterior Shell
The outer shell of the nebulizer consists of three separate parts, all of which are composed of the same material, and was thus modeled as a single part. Acrylonitrile butadiene styrene (ABS) material was used to model the manufacture of the exterior shell via plastic injection molding.
2.3.3. Stator: Core, Coils and Cover
The motor’s core was manufactured using multiple steel sheets. The manufacturing process was simplified in the GaBi model by representing the mass of the steel in the core as 80% of the combined mass of the stator’s core and coils. The copper coils (remaining 20% of the combined mass) were modeled by using wire drawing manufacturing. The coils and core were coated with a laminate to improve the efficiency of the induction motor, but this coating was excluded from the model as its mass was negligible in comparison to the total mass. The cover was modeled as steel, which was bent, welded together, and press formed around the stator.
2.3.4. Rotor: Squirrel Cage and Ball Bearings & Central Drive Shaft
The rotor’s squirrel cage was assumed to be aluminum rather than copper composition because it would offer a less expensive option. Rotor manufacturing was modeled by using the common die casting process [23
]. The mass of the squirrel cage (electromagnets) was assumed to be 70% of the rotor’s mass, while the other 30% consisted of the ball bearings and the central drive shaft. The central drive shaft is inserted into the rotor squirrel cage when it is hot, which allows it to shrink onto the shaft and have a firm fit. The modeling assumption was that 0.1 MJ of electricity was input into the system to manufacture the ball bearings and the central shaft.
2.3.5. Suction Chamber
The suction chamber was simplified by assuming it was constructed using die casting with only aluminum materials. The rubber seal weighed less than 0.01 g (<0.0003% of device mass), and was thus assumed to be negligible in the model.
2.3.6. Fan: Fan, Fan Housing, and Cross Brace
The fan and housing for the fan were modeled using polyvinyl chloride (PVC) granulates to manufacture the parts using plastic injection molding. The cross brace was manufactured using steel and was modeled using a stamping and bending method.
2.3.7. Medicine Delivery: Mouthpiece, Medical Tubing, and Medicine Chamber
The materials used to model the mouthpiece, medical tubing, and medicine chamber were polypropylene, PVC, and polymethylmethacrylate (PMMA), respectively. The mouthpiece and medicine chamber manufacturing were modeled using plastic injection molding, while manufacturing of the medical tubing was modeled using extrusion.
2.3.8. Power Cord
The power cord was modeled as copper wire surrounded by PVC tubing, with the relative composition of the materials consisting of 70% PVC and 30% copper. In the model, the PVC tubing was manufactured by extrusion and the copper wiring was manufactured by wire drawing. The electricity required to manufacture the power cord was assumed to be 0.1 MJ based on other manufacturing processes in GaBi.
2.3.9. Use Phase
During the use phase of the nebulizer, the device was modeled as requiring 60 W of power for 15 min.
Unlike the inhaler, which cannot be reused after the drug is spent, a single nebulizer is used numerous times over its lifespan. The mouthpiece and medicine delivery components are cleaned between each use. In this study, two different approaches to cleaning were modeled as a part of the use phase: (1) using a dishwasher; and (2) hand cleaning. The model used a 1800 W dishwasher for one hour, requiring 15 L (4 gallons) of tap water. All of the tap water inputs were modeled as sourced from surface water, which is a more conservative source as it typically requires a higher degree of treatment than groundwater. A full-capacity dishwater was assumed to use 10 g of soap. In the GaBi model, the soap was modeled as glycerin, which is one of the products of saponification (the chemical process used to produce soap). The mouthpiece was assumed to take up 1% of the dishwasher volume, and materials and energy were allocated accordingly.
When the nebulizer mouthpiece was hand washed, it was assumed that 1 g of soap was used. Additionally, 7.6 L (2 gallons) of tap water was used per minute, and 1 min was assumed for device cleaning. After hand washing, the mouthpiece and medicine chamber are sterilized in a vinegar solution composed of one part acetic acid (5% acidity vinegar) to three parts water. In the model, the vinegar solution was composed of 100 g of vinegar and 300 g of tap water.