Next-Generation Pressurised Metered Dose Inhalers: a Holistic, Patient-Centred Approach to Sustainability

Kindeva

NEXT-GENERATION PRESSURISED METERED DOSE INHALERS: A HOLISTIC, PATIENT-CENTRED APPROACH TO SUSTAINABILITY

In this article, Mike Needham, Global Respiratory Product Development Manager, Phil Cocks, Product Design and Optimisation Lead, and Louise Righton, Global Strategic Marketing Leader, all of Kindeva Drug Delivery, discuss how sustainability should be a central theme of future innovation in inhalation drug delivery but must be balanced with the needs of the patient.

Mike Needham Kindeva Drug Delivery has a legacy of powder inhalers (DPIs) and soft mist Global Respiratory Product advancing the environmental sustainability inhalers (SMIs), are categorically superior to Development Manager of inhaled medicines. Formerly 3M Drug pMDIs, regardless of patient considerations. E: [email protected] Delivery Systems, Kindeva was a founding Kindeva believes that all inhaler types member of the International Pharmaceutical have a role to play in the management of Aerosol Consortium (IPAC), which was lung disease and no specific device should established to represent the industry in be singled out for replacement. It does not navigating the Montreal Protocol in the support blanket switching based on carbon late 1980s. footprint alone. Kindeva believes in a holistic Kindeva, a pioneer in hydrofluoroalkane approach to advancing sustainability in (HFA)-based formulations for pressurised the pharmaceutical industry that offers a metered dose inhalers (pMDIs), has developed longer-term view of environmental and the world’s first chlorofluorocarbon (CFC)- patient impact. This approach involves Phil Cocks Product Design and Optimisation Lead free pMDI (launched in 1995) and the empowering patient and physician choice E: [email protected] first CFC-free nasal pMDI (launched in to optimise overall disease management, 2012). These innovations were milestone innovation of novel propellants for pMDIs accomplishments that delivered step-change to reduce their carbon impact, and full life- improvements in the environmental impact cycle analysis and sustainable improvement of inhaled drugs. There is more work that of devices. Kindeva’s view is that we must needs to be done across the pharmaceutical simultaneously acknowledge the role of industry, and Kindeva remains at the pMDIs as a critical option for patients and forefront of environmental progress. seek to alleviate the environmental impact Today, there is renewed energy around of all inhalation therapies. the sustainability of inhaled therapies. Louise Righton At its core, this scrutiny is positive and Global Strategic Marketing Leader E: [email protected] will propel the industry forward. However, “There does not need to be much of the debate is narrowly focused on propellants and the comparative global a trade-off between patient Kindeva Drug Delivery warming potential (GWP) of different needs and sustainability; Charnwood Campus devices. As a result, advocacy too often 10 Bakewell Road these twin goals can be Loughborough LE11 5RB provides blanket recommendations that United Kingdom amount to “device switching” – the notion complementary.” that propellant-free devices, such as dry www.kindevadd.com

PATIENT-CENTRIC DECISIONS LEADING TO OPTIMISED DISEASE MANAGEMENT

As with any drug delivery development, an innovation that promotes sustainability must consider the needs of the patient. There does not need to be a trade-off between patient needs and sustainability; these twin goals can be complementary. Well-managed, stable patients have lower carbon footprints and less detrimental effects on the environment. They are less likely to be hospitalised and less likely to experience progression of their diseases, impacting their lifetime use of medication and devices. Therefore, a sustainability strategy that depends wholly on broad advocacy for device switching based solely on the relative GWP of different devices is unlikely to satisfy diverse patient needs and may be counterproductive to sustainability goals. There is no systematic evidence showing that DPIs are categorically more effective Figure 1: The Kindeva than pMDIs.1 Matching the patient with Intelligent Control Inhaler. the right inhaler is a complex decision, which must be judged by the clinician. Guidelines from the Global Initiative for lose satisfaction with their treatment; they Asthma (GINA) and the Global Initiative for can even lose trust in their doctor. Learning “Any alternative propellant Chronic Obstructive Lung Disease (GOLD), to handle a new device when the old one as well as current research, emphasise this. was working can lead to exacerbations and must be safe for patients If we limit the choice of devices for patients even hospitalisations. to use from a toxicology and practitioners, we risk reducing the Novel pMDI device design can also perspective and must be quality of care. Recent studies demonstrate support the overall management of lung that pMDIs are clinically equivalent or disease. The baseline rate of correct use of safe to manufacture.” even significantly more effective than DPIs, inhalers is low, with the literature suggesting indicating that pMDIs are a crucial option that up to 94% of DPI users and 74% of for physicians.2 In short, there’s no “one size pMDI users make mistakes.5 Beyond correct INNOVATION OF NOVEL fits all” inhaler; treatment must be tailored use, overall adherence to inhaled medicines PROPELLANTS FOR pMDIS from the plethora of options available and is low, with 60% of COPD patients and up patients should be engaged in the decision. to 70% of asthma patients non-adherent to There is a clear drive towards the use of An essential element of optimised disease their prescribed therapy.6,7,8 alternative propellants in pMDIs aligned management is the training and correct usage Kindeva’s Intelligent Control Inhaler to the desire to reduce their environmental of devices.3 If patients are using their devices (Figure 1), which is currently under impact. We need to remember that the use incorrectly, the medication will not work as development and not yet available for of hydrofluorocarbons (HFCs) in pMDIs intended. Incorrect usage can be particularly commercial sale, may provide a solution to represents less than 0.05% of all greenhouse problematic for patients who are prescribed both the correct usage and the adherence gas emissions. These emissions are a tiny multiple DPIs because it can be challenging challenge. Designed for easy and intuitive use, part of the global sustainability challenge. to train patients to use various DPI devices the Intelligent Control Inhaler provides flow Nevertheless, given the outsized importance – some incorporating reservoirs of powder, governance designed to optimise inhalation of the pMDI as the mainstay treatment others requiring single-use loading with a technique, and real-time feedback to aid in for asthma and COPD control, it is capsule, for example. proper inhaler technique. It also provides sensible to address environmental concerns Asthma and chronic obstructive reminders and scoring to promote adherence. related to propellants. pulmonary disease (COPD) patients with The industry should continue to invest in It is possible to make a significant stable disease should have continuity of innovation that will transform the way change in the carbon footprint of the pMDI. inhaler device.4 Suddenly asking the patient patients engage with their medicine. These By switching propellant from HFA227 to switch from a device that is working for solutions will systematically improve the or HFA134a to a lower GWP propellant, carbon-led reasons, not medical reasons, can management of respiratory diseases and such as HFA152a, a considerable reduction have negative consequences. Patients can ultimately lead to lower-cost, more sustainable in overall device carbon footprint can be lose confidence in their medicine; they can treatment over the patient’s lifetime. achieved (Figure 2). History tells us, however,

assessments, Kindeva has had small-scale, non-GMP manufacturing equipment installed, giving it the capability to manufacture cold-fill HFA152a safely. This equipment is adequate for most early- stage development projects and enables the company to perform small-scale feasibility assessments and short-term stability studies on future HFA152a opportunities. There are other developments in novel propellants with negligible carbon impacts that are perhaps even more future-proofed than HFA152a. For example, HFO1234ze is a commercially available propellant that has both technical and consumer applications. With very low GWP, HFO1234ze could offer a sustainability improvement for inhaled medicines. Figure 2: Global warming potential for different propellants.9 that it is not entirely straightforward to Finally, the cost and quality of any HOLISTIC DEVICE LIFECYCLE switch propellants. Kindeva learned this first alternative propellant must be acceptable from OPTIMISATION hand during the transition from CFCs to a supply chain perspective. GMP supplies HFAs following the establishment of the must be established and made available at an Propellants are only one part of the 1987 Montreal Protocol. When considering appropriate scale and at an acceptable cost story. We need a shared understanding any alternative, we must think seriously to meet future commercial needs. HFA152a of each product’s lifecycle and its total about many factors. does, however, initially appear to be a environmental impact to expand the Safety is the primary concern. Any highly suitable pMDI propellant candidate. discussion from a single focus on alternative propellant must be safe for Given the amount of research and investment propellants and GWP. A holistic approach patients to use from a toxicology perspective in this area, commercial manufacturing to sustainability will consider other raw and must be safe to manufacture. The capabilities are likely to be available soon materials used in the drug product or device, flammability of volatile propellant raises but a wide range of products in patients’ how they are sourced, how easily they some technological challenges with hands is still some years away. are recycled, and where they go after the HFA152a, which must be overcome. Kindeva has also completed several patient has finished using them. Formulation is another concern. A viable solubility studies on HFA152a. The current carbon-led switching propellant must have suitable physical Pharmaceutical product performance has discussion is based on only one element of and chemical properties to fully also been successfully demonstrated on the environmental issue: global warming. enable solution and suspension pMDI a range of formulations using a typical While climate change absolutely should formulations to meet the rigorous container-closure system. Following the drive policy when it comes to consumption pharmaceutical performance and completion of various flammability and of fluorinated gases, we must not overlook stability standards set for today’s Dangerous Substances and Explosive other environmental impacts such as human inhalation products. Atmospheres Regulations (DSEAR) toxicity, fossil depletion and marine water

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quality degradation caused by pollution leading to algae growth and damaging “Robust sustainability strategies require a holistic, end-to-end aquatic life. The excessive use of single-use plastics and the resultant burden on landfills view of the product design, lifecycle and patient impact.” are also key considerations in making inhalation therapy more sustainable. While a DPI has the lowest GWP, it is the least patient’s best interests. Patients deserve a 3. Usmani OS, “Choosing the right environmentally friendly option with respect thoughtful approach to treatment that is inhaler for your asthma or COPD to eight other impacts.9 We need to look designed to optimally treat their conditions. patient”. Ther Clin Risk Manag, holistically at sustainability and broaden Robust sustainability strategies require a 2019, Vol 15, pp 461–472. the avenues that we go down to come up holistic, end-to-end view of the product 4. Bjermer L, “The importance of with solutions. design, lifecycle and patient impact. By continuity in inhaler device choice At the forefront of sustainability thinking effectively optimising disease management for asthma and chronic obstructive at Kindeva is a reduction in the parts and preserving patient options, innovating pulmonary disease”. Respir, 2014, count of plastic devices. For example, the low GWP propellants, and sustainably Vol 88(4), pp 346–352. company is developing a new metal-free designing devices and components, pMDIs 5. Lavorini F et al, “Effect of incorrect dose counter with far fewer parts than has will continue to play a key role in lung use of dry powder inhalers on been available previously. This endeavour disease management. management of patients with asthma shows that there does not need to be a trade- and COPD”. Respir Med, 2008, off between performance and sustainability. ABOUT THE COMPANY Vol 102(4), pp 593–604. Kindeva believes this new dose counter 6. Laube BL et al, “What the pulmonary delivers benefits throughout the value chain Kindeva Drug Delivery is a contract specialist should know about the new – simplicity of assembly, compatibility development and manufacturing inhalation therapies”. Eur Respir J, with a broad range of actuators and valve organisation offering its partners 2011, Vol 37(6), pp 1308–1331. types, robust reset of dose counting – but integrated, end-to-end capabilities spanning 7. Lindsay JT, Heaney LG, also represents a marked sustainability formulation, product development, “Nonadherence in difficult asthma improvement by reducing plastic use. scale-up manufacturing and commercial – facts, myths, and a time to act”. Our industry must recognise that these manufacturing. Its full-service innovation Patient Prefer Adherence, 2013, improvements are possible through the offering covers: inhalation (pMDIs, DPIs, Vol 7, pp 329–336. regular cycles of innovation and to continue connectivity, nasal delivery); transdermal 8. Elliott RA, “Poor Adherence to to challenge ourselves on sustainability. delivery (drug-in-adhesive systems and Anti-inflammatory Medication in At one end of the product’s lifecycle is gel patches); and intradermal delivery Asthma: Reasons, Challenges, and the question of sourcing and manufacturing: (microneedles based on solid and hollow Strategies for Improved Disease what materials go into the product? At the microstructures). Kindeva Drug Delivery Management”. Dis Manag Health other end of the lifecycle is the question has locations in the US and the UK and Out, Vol 14(4), pp 223–233. of waste management: what happens at employs over 900 people. It was formed 9. Jeswani HA, Azapagic A, “Life cycle the end of patient use? Pharma companies in 2020 when 3M’s Drug Delivery environmental impacts of inhalers”. and device makers can and should be Systems business was acquired by Altaris J Clean Prod, 2019, Vol 237, influential in promoting the reusability Capital Partners for US$650 million Article ID 117733. and recyclability of devices. For example, (£503 million) and renamed Kindeva. Kindeva is developing new refillable devices that can help lessen the environmental REFERENCES ABOUT THE impact of its inhalers. The Intelligent Control Inhaler is designed with a reusable 1. Muraki M et al, “Which inhaled AUTHORS top element with a reduced number of corticosteroid and long-acting Mike Needham is a Global Respiratory disposable parts. 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Sustainability should be a central theme treated with inhaled corticosteroid/ of future innovation in inhalation drug long-acting β2-agonist via Louise Righton is a Global Strategic delivery but this must be balanced with the dry-powder inhalers and Marketing Leader for Inhalation needs of the patient. Sustainability strategies pressurized metered-dose inhalers”. Drug Delivery at Kindeva, based in that hinge solely on device switching for Int J Chron Obstruc Pulmon Dis, Loughborough. carbon reduction do not generally serve the 2019, Vol 14, pp 101–114.