Read the article in The Pharmaceutical Post The resurgence of certain respiratory diseases like asthma, which are linked to allergy factors, requires the prescription of inhaled treatments that are effective for patients of various types, as well as sustainable in terms of their carbon footprint.. Today, three major families make up the landscape of respiratory diseases – asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis – with allergic asthma at the top of the list, representing 70% of all forms of asthma. A major public health problem affecting 8 to 10% of the world’s population, this pathology is responsible for more than 250,000 deaths each year. Asthma and COPD are chronic diseases and both are characterized by inflammation of the airways leading to breathing difficulties. In the case of cystic fibrosis, there is an alteration in the secretion of the lungs which also leads to respiratory insufficiency. For all these pathologies, only the symptoms, and not the causes, are treated through the various treatments available on the market. The objective is to help patients to better bear the effects of their pathology and thus limit the loss of their respiratory capacities. Different treatments exist, most of which use the inhaled route. These include bronchodilators, corticosteroids, antibiotics and other anti-infectives, mucolytics, vasodilators and non-steroidal anti-inflammatory drugs. They act against the abnormal contraction of the muscles of the bronchial wall and allow the pulmonary alveoli to re-open. This allows the patient to regain optimal lung function. To target a local action of a drug, the inhaled route is the logical route to administer pulmonary treatments. Inhaled medications are deposited directly on the area to be treated without the need for absorption and/or transport. As the Aerosol Therapy Group (GAT) of the French Respiratory Society (SPLF) points out in its Recommendations on Aerosol Therapy Practices in Respiratory Medicine (1), the inhaled route is a highly technical route of administration: “(…) It is even the most technical route of administration. Inhalation devices (or aerosol generators) are used to turn the drug packaged as a solution, suspension or dry powder into an aerosol form that can be inhaled.” Inhaled or nebulized form Various forms of administration of these molecules are available, but the vast majority, if not the entirety, of treatments are administered by the inhaled or nebulized route. Among the delivery systems for the inhaled form, there are two types of devices: metered dose inhalers (MDIs) and dry powder inhalers (DPIs). MDIs can also be used with a spacer or chamber (spacer with a valve). The nebulized form or nebulization uses a compressor that transforms the liquid solution into a cloud of micro-droplets that the patient inhales through a mask. Therapeutic pros and cons of inhaled and nebulized forms The inhaled form accounts for 95% of the inhaled therapy prescribed in the respiratory market through two types of devices: metered dose inhalers (MDIs) and dry powder inhalers (DPIs) Metered-dose inhalers (MDIs) are the most widely used delivery system for the inhaled route. They are ready-to-use devices that require no preparation, and their portable (nomadic) form means they can be carried and used at any time. They deliver a calibrated dose to ensure the effectiveness of the treatment. However, the literature has repeatedly highlighted the misuse of these devices due to insufficient education of patients in their use. As indicated in the SPLF Scientific Dossier (1), 50 to 76% of patients would make at least one mistake when using this type of device. Requiring hand-mouth synchronization to ensure perfect dose delivery, they are not necessarily suitable for use by all types of patients. Indeed, coordinating a hand action to trigger the release of the dose at the same time as an inspiration can be a complicated gesture for the elderly and young children. In the absence of a perfect mastery of the inhalation technique, the guarantee of taking the right dose cannot be total to allow an optimal pulmonary deposit of medication and thus ensure the effectiveness of the treatment. Multidose, metered dose inhalers also contain preservatives to prolong the life of the medication. For several years now, preservatives have been scrutinized in the treatment of chronic diseases in the pulmonary, ophthalmic, or dermatological fields. Indeed, a daily use can generate problems of allergies, irritations and some preservatives were classified as endocrine disrupters. Overexposure of the body to this type of preservatives is not without consequences, especially for children. Dry powder inhalers represent only a small part of the treatment volumes of the inhaled form. They emerged in the late 1990s and early 2000s as an alternative to MDIs using CFCs (chlorofluorocarbons) as propellants, the production of which was halted by the Montreal Protocol on substances that deplete the ozone layer in 1987 and formalized by several industrialized countries in 1996. These devices disperse aerosolized powder particles into the patient’s inhalation air stream. The particles are suspended in the air by the patient’s inspiratory action. They are portable like metered dose inhalers and can be used at any time. Requiring a very deep exhalation from the patient, they are not suitable for asthmatic children or COPD patients. The disadvantages of this type of device include uneven particle dispersion and dose variability, which do not fully ensure the effectiveness of the treatment. The nebulized form represents the remaining 5% of the market for inhaled respiratory disease treatments. This form uses nebulizers operating from an energy source into which the drugs are introduced. Nebulizers, like all aerosol generators, turn the liquid or suspension medication into an aerosol form. They are cumbersome and are only useful in hospitals or at home. An electric source is required, and the patient or another person must introduce the medication into the nebulizer before treatment. Most nebulization treatments take between five and ten minutes. They offer the advantage of being able to administer many drugs, including antibiotics, which are not available in metered dose inhalers, and of delivering higher doses. This is the only inhalation device that does not require any special physical or respiratory skills. With a mouthpiece or a face mask, they are particularly suitable for children, including the very young, the elderly, and patients with severe respiratory distress. In comparison with powdered forms of DPIs, the liquid form allows for better dispersion and is less likely to cause irritation. In sterile single-dose (FFS) packaging, the treatment does not require preservatives for its conservation. With nebulization, micro- or even nanodroplets of medication are distributed gently and deeply into the respiratory tract, allowing the molecule to penetrate as much surface area as possible, ensuring greater effectiveness. At the end of the treatment session, we are sure that the patient has received the entire prescribed dose. Environmental impacts of inhaled and nebulized forms Due to the high priority given to drug safety (integrity, storage conditions, etc.), the pharmaceutical market is less advanced, when it comes to the environmental requirements of its packaging, than other consumer markets (food, cosmetics, etc.). Besides registering primary packaging inside the marketing authorization dossier, environmental protection is now an essential factor increasingly integrating into drug development. A 20 to 30 higher carbon footprint for MDIs A study published in November 2019 (2) demonstrated the impact on the carbon footprint of the choice of inhalers in asthma and COPD treatments. The authors recall that until the early 1990s, MDIs containing chlorofluorocarbons (CFCs) as propellants were the most common way to deliver inhaled therapy for asthma and COPD. As a result of the Montreal Protocol, they have been progressively replaced by DPIs that do not require propellants, MDIs using hydrofluorocarbons (HFCs) and nebulizers. Unlike CFCs, HFCs are not ozone-depleting substances, but they are greenhouse gases with a high global warming potential (GWP). The objective of this study was to compare the environmental impact of a DPI and an MDI based on the carbon footprint of each. The results showed a 20 to 30 times higher carbon footprint for an MDI compared to a DPI. The study took into account the entire life cycle of the device: the production of the pharmaceutical ingredients, the final product, its packaging, distribution and storage, its use and disposal at the end of its life. It appears that the major difference between the two carbon footprints is essentially related to the use phase of the MDI (use of HFCs) and its disposal at the end of its life, as this device has very few recyclable elements and generates a significant level of final waste. The risk of waste proliferation Due to the growing incidence of asthma, it is essential that medical authorities, as well as prescribers, consider the disposal options for the treatments prescribed to patients. Not only do MDIs have a higher carbon footprint than other devices, but in the context of asthma treatment, they must be renewed on average every 15 days. In terms of the development of new treatments that combine different molecules (up to three), it is difficult to see the possibility of prescribing three MDIs each containing three different molecules for the same treatment. From an environmental standpoint, this would be impossible to sustain. It will produce waste we don’t know how to deal with because it cannot be recycled. Unither Pharmaceuticals in the respiratory disease treatment market In the respiratory disease treatment market, Unither Pharmaceuticals is involved in the production and packaging of sterile single-dose BFS products for use with nebulizers for inhaled administration in nebulized form. This concerns 5% of the market for respiratory diseases treated by the inhaled route. More specifically, Unither Pharmaceuticals is targeting this market at patients with specific or severe pathologies in hospitals or at home, such as COPD or respiratory degeneration. Among the various inhaled treatments, only the nebulized form administered through a mask can be administered passively by the patient and does not require any hand-mouth coordination effort or very deep exhalation on the part of the patient to ensure the effectiveness of the treatment. Similarly, nebulized treatment of asthma, bronchiolitis and acute rhinitis is particularly indicated in young patients for the same reasons as mentioned above. In addition, with the use of a face mask, the nasal route is also used in conjunction with the oral route during inhalation sessions and it is much easier and more natural for a child to breathe through the nose and mouth. Buccal inhalation is definitely more effective in terms of drug dose deposited in the lungs than nasal inhalation, however the dose/Kg of drug deposited in the lungs is higher in children inhaling through the nose than in older patients inhaling through the mouth. Thus, it is probably similar to adults inhaling through their mouths. Unither Pharmaceuticals, the world’s leading manufacturer of BFS unit-doses Unither Pharmaceuticals was founded in 1993 following the acquisition of a Sanofi site in Amiens, France. Since its inception, the company has used Blow-Fill-Seal (BFS) technology to manufacture sterile single-dose products. World-renowned pharmaceutical contract manufacturer Unither Pharmaceuticals has operations in France, the United States, Brazil and China. The company has become the world’s leading manufacturer of BFS, with a 4 billion unit dose capacity at its four dedicated sites in France and the United States (Amiens, Coutances, Gannat and Rochester). With 29 years of experience, Unither Pharmaceuticals can legitimately claim to be a leading specialist in the manufacturing and packaging of sterile single-dose products, in particular using BFS technology, in various pharmaceutical markets such as physiological serum, ophthalmic products and respiratory disease treatments. All its French sites are inspected by the European authorities (EMA) in order to manufacture products for the European markets. The Coutances (France) and Rochester (USA) sites are inspected and accredited by the FDA (Food and Drug Administration) in order to supply the American market.