The ozone layer and metered dose inhalers

THE MONTREAL PROTOCOL In September 1997, the world celebrated the 10th anniversary of the Montreal Protocol on Substances That Deplete the Ozone Layer. The Montreal Protocol is an agreement, signed by more than 160 countries, to take “appropriate measures to protect human health and the environment against effects likely to result from human activities which modify or are likely to modify the ozone layer”. It is the first international agreement established to try to prevent a major environmental problem (1). In 1996, all developed countries agreed to stop production and banish importation of newly produced ozone-depleting substances, one class of which, the chlorofluorocarbons (CFCs), is widely used in metered dose inhalers (MDIs) for asthma and other respiratory diseases. The elimination of CFCs has led government authorities to establish transition strategies for a smooth phase-out of products that rely on CFCs. Along with dry powder inhalers and oral medications, the development of new propellants such as hydrofluoroalkanes (HFAs) has provided alternatives to CFCs, allowing

the continued use of MDIs in the future.However, these substitutes have many implications that will be discussed below.

THE OZONE LAYER AND POTENTIAL CONSEQUENCES OF OZONE DEPLETION
The stratospheric ozone layer is a protective natural band located between 15 and 35 km above the earth.It plays a crucial role in absorbing ultraviolet (UV) radiation and, in so doing, protects humans and the environment from the damage caused by this type of radiation (2).Ozone depletion allows increased penetration of the earth's atmosphere by type B UV rays (UVB), the most significant type of UV radiation with regard to health and environmental consequences (3).Increased exposure to UVB may increase the occurence of cataracts and skin cancer, particularly melanoma, diseases whose prevalence has markedly increased in the past decade, particularly in the southern hemisphere (4,5).It may also impair the immune defences of living organisms.UVB rays can also affect basic crops, such as soybeans, and destroy organisms placed at the first steps of the ocean food chain, such as phytoplankton and krill.

CAUSES OF OZONE DEPLETION
Ozone depletion, first hypothesized in 1974, was confirmed in 1985 by a British Antarctic survey team that found a marked thinning of the ozone layer over the South Pole.In 1989, the size of this 'ozone hole' was estimated to be 25 million km 2 , and it seems to be growing.It is now estimated to be approximately the size of North America.
The thickness of the ozone layer is affected by various natural factors, including volcanic eruptions, but one of the major depleting factors is the increasing quantity of substances such as CFCs in the atmosphere that destroy ozone by transforming it to chlorine monoxide and oxygen.More specifically, ozone-depleting substances include molecules such as hydrochlorofluorocarbons (HCFCs), methyl bromide, methylchloroform, carbon tetrachloride, various brominecontaining halons and many CFCs, including the frequently used CFC 11 and CFC 12. CFCs and halons are considered to be the main ozone layer depleters.
It is believed that one CFC molecule can destroy up to 100,000 ozone molecules.Furthermore, increased quantities of CFCs in the atmosphere appear to speed up the greenhouse effect.CFCs are entirely man-made substances that were invented in 1920.They have been the most widely used refrigeration agents in refrigerators and air-conditioners, and they are used for foaming plastic insulation, as propellants in MDIs, as extinguishing agents and for special cleaning purposes.In 1991, an estimated 1.1 million tonnes of CFCs were used, 6400 tonnes coming from a vareity of aerosol products.In 1991, MDIs accounted for about 1% of all CFCs used, but since the signing of the Montreal Protocol, this percentage has increased significantly as the use of CFCs for other purposes has declined.
Unfortunately, CFCs are projected to last 100 years or more in the atmosphere.Even with a complete cessation of CFC production, it will probably take many decades to re-store the thickness of the ozone layer to its pre-CFC condition.The potential for increased transmission of UV radiation will therefore exist for at least another century, and while little damage due to increased UV radiation seems to have occurred so far, the potential for long term problems is impressive.

INTERNATIONAL INITIATIVES TO PROTECT
THE OZONE LAYER In response to the projected consequences of ozone depletion, the 1985 Vienna Convention provided a framework for international restrictions on the production of ozonedepleting substances.This was followed in 1987 by the Montreal Protocol on Substances That Deplete the Ozone Layer.Since then, various amendments have been drawn up to establish deadlines for halting the production and use of CFCs.The use of CFCs has been banished with only two exceptions: for medical use, mostly for MDIs, and to meet some technical needs for space programs.The Montreal Protocol works under the auspices of the United Nations Environmental Program (UNEP), and relevant decisions are made at meetings of the countries that have ratified the Montreal Protocol.The Technical and Economic Assessment Panel (TEAP) is one of three expert advisory panels that provides information on how fast the world can reasonably expect to implement a reduction of ozone-depleting substances emissions and on the likely costs of such a phase-out.The TEAP coordinates the work of seven technical options committees (TOCs) that look at the different areas in which ozone-depleting substances are used.The TOCs are groups of experts who study the feasibility of phasing out in their own areas of expertise.They make recommendations, and the TEAP may endorse the recommendations.Transition strategies are the responsibility of individual countries, and they are implemented at the national level.
Responding to the decision to eliminate CFCs, the pharmaceutical industry has devoted major resources to developing replacement substances.At present, more than 1400 scientists in 90 laboratories in at least 10 countries are working to develop replacement products with new propellants.The pharmaceutical industry has already spent at least one billion dollars on this project, and they anticipate spending much more to complete it (6).

CFC-FREE MDIs
Alternatives to CFC-containing inhalers come in various forms.Several different dry powder inhalers are availaible, and some new asthma drugs have been developed in oral form (eg, leukotriene antagonists).However, MDIs still constitute 75% of all inhalers used in the treatment of diseases such as asthma, and the number of inhalers used has been increasing steadily over the past few years.In fact, the number is expected to continue to increase for several more years.More than 400 million inhalers are used around the world each year.
In March 1995, the first approval for a CFC-free MDI was granted in the United Kingdom to 3M's Airomir, an HFA-134a reformulated salbutamol (7).Airomir has been approved in Canada recently and is now available.Proventil-HFA, which is salbutamol with HFA-134a as a propellant, was approved by the United States Food and Drug Administration in August 1996.HFAs are nonflammable and chlorine-free, and they are believed to have no impact on the ozone layer.Toxicology studies have shown them to be safe for human use, and recent research demonstrated that the bronchodilating effects of HFA-salbutamol were similar to CFC-salbutamol (8).
Inhalers containing HFAs have been approved in more than 35 countries, and many pharmaceutical companies are about to introduce new CFC-free inhalers.The international pharmaceutical aerosol consortium (IPAC) recently predicted that by the end of 2000, there will be at least 36 CFCfree MDIs in the European Union, 11 in the United States and 33 in at least one other developed country.
The use of new HFA propellants has made it necessary to redesign not only MDI formulations but also the MDI hardware, a process that has led to interesting findings on the properties of these new devices.Indeed, it was determined that the inhalers' propellant was not the only thing that had to be changed but that different surfactants and new value design were also required because of the change in propellant.One of the features observed with the first HFAinhalers, such as Airomir, was that the doses produced were more consistent from the first to the last dose when used to exhaustion ('tail-off').They did not have the 'loss of dose' effect, a reduced dose for the first puff and enrichment of the second when actuated after storage.Furthermore, unlike CFC inhalers, they were minimally affected by cold temperatures.In addition, these new inhalers deliver a smaller volume of aerosol with each actuation than CFC-MDIs did, thus patients may note a comparatively 'softer puff' and less propellant sensation from the effect of cold freon (9).The particle size of the salbutamol aerosol was similar for that of CFC and HFA formulations, and the new inhalers deliver the same quantity of medication (10).

A NATIONAL STRATEGY TO ELIMINATE CFC
Canada and most other countries are developing phaseout strategies for metered dose inhalers containing CFCs and transition to the use of HFA inhalers.This transition strategy should ensure the safety and efficacy of the new therapeutic agents as well as patient acceptance and preservation of the patient-physician relationship.It should also address the cost concerns of the different parties involved.Particularly, physicians should be aware of the consequences of this phaseout and be able to transmit this information to their patients (9).In this regard, a recent survey conducted by the Canadian Lung Association has shown that patients' acceptance of new non-CFC inhalers depended primarily on the advice of their physician (11).
Among other elements to be considered when forming the transition strategy are access to the new non-CFC inhalers, their cost and pricing, and the competitiveness of the pharmaceutical industry.Of critical importance is the question of how the replacement of existing products will be accomplished effectively while ensuring patient safety.
It is essential that educational interventions be addressed not only to health care providers, but also to asthma patients to avoid misunderstandings and unreasonable fears.These efforts should be coordinated with the regional lung associations and other organizations involved in asthma education at both national and provincial levels.The time-frame of the phase-out is crucial; it should allow a smooth transition and therefore promote physicians' and patients' acceptance through effective dissemination of information, and it should reflect the spirit of the Montreal Protocol and encourage a rapid elimination of CFCs.
At the September 1997 meeting of the parties of the Montreal Protocol, the participants indicated that non-Article 5 countries (ie, developed countries such as Canada) should have ideally completed or almost completed the transition to non-CFC MDIs by the year 2000.More realisitically, as other countries, Canada should have achieved a substantial reduction of CFC-MDI by 2001 and a complete phaseout in 2005.Developing countries have until January 31, 1999 to have a transition strategy in place.
Various strategies have been suggested for dealing with the replacement of current CFC products.
• By category: When sufficient CFC-free alternatives to a drug category are available, the remaining CFC products in that category can be phased out.• By drug: At a given time after a reformulated CFC-free MDI has become available for one type of drug (eg, salbutamol, beclomethasone, etc) other CFCs-MDI containing the same substance can be withdrawn over a certain time period.• By brand: When a company produces a new CFC-free MDI, it can replace the existing product.A 'sunset date', indicating a specified date by which the quantity of CFC-free (or the number of CFC inhalers) is to be gradually reduced to zero, may also be added to the different options.A recent survey of the Canadian Thoracic Society Asthma Committee Members showed that the drug-by-drug option was generally the more popular option.
The decision regarding which of these approaches will be enforced is likely to have major consequences on patient acceptance.It may also affect the cost of treatment, although the industry has indicated that CFC-free inhalers will be sold at a competitive cost to the existing brand-name products.
Assessing the comparative effects of the new products against those of the old ones, particularly of inhaled corticosteroids, will require a major effort.Indeed, recent studies have suggested that the deposition of HFA-beclomethasone in the peripheral lung was increased compared with that of CFC-beclomethasone in asthma treatment; the increased deposition of HFA-beclomethasone leads to superior efficacy compared with its CFC counterpart (12).Of course, more studies will have to be completed on the different compounds using the new propellants to establish their comparative safety and efficacy profile.This will constitute a major task of regulatory agencies in the near future.Finally, because doctors have limited experience with the new inhalers, a postmarketing surveillance program will be required, looking at safety and efficacy, but at the acceptance of the new products by caregivers and patients.
All of these issues require harmonization of efforts by industry, government, licencing bodies, and patient and health professional organizations.Consultation meetings of stakeholders took place in July and December 1997 to voice opinions and allow discussions regarding the Canadian strategy for the phase-out of ozone-depleting substances.Further consultations are ongoing to complete this exercise and an education and awareness steering committee has been nominated to coordinate the education efforts aimed at health care professionals, patients and the general public.We should therefore hear more about new initiatives in the next few months.