PATIENT CARE ISSUES IN HFC EMISSIONS POLICY

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1 PATIENT CARE ISSUES IN HFC EMISSIONS POLICY Dr. Paul Wright, Astra Formulation Manager (Pharmaceutical Sciences Department) Bakewell Road, Loughborough Leicestershire, LE11 ORH England Paper presented at the Joint IPCC/TEAP Expert Meeting on Options for the Limitation of Emissions of HFCs and PFCs (26-28 May 1999, Petten, The Netherlands) ABSTRACT The presentation describes the role of medical aerosols in treating patients with respiratory disease, the transition from CFCs to HFCs as propellants in metered-dose inhalers (MDIs), and potential alternative therapies for the future. 1. INTRODUCTION For approximately forty years, MDIs have used chlorofluorocarbons (CFCs) as propellants. Due to environmental concerns regarding CFCs and their subsequent phaseout, some pharmaceutical firms are reformulating and introducing MDIs with hydrofluorocarbons (HFCs). HFC 134a and HFC 227 are the only known suitable alternatives to CFC propellants for MDIs. No other compounds are proven to meet the stringent criteria required for a propellant which is inhaled by patients on a daily basis. The challenging but worthwhile progression away from CFC-propelled medications to HFC MDIs will involve millions of patients and their healthcare providers in over 100 countries around the world. 2. RESPIRATORY DISEASE MDIs are currently used by patients mainly for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Asthma Asthma is a chronic and debilitating respiratory disease with sudden, unpredictable and potentially life-threatening effects. Factors that may trigger asthma attacks include air pollutants, smoke, airborne molds, pollens, dust, tiny scales from animal skin, exercise, cold air, household and industrial products, scents, and stress. 1 The impact of asthma on children is particularly severe. 2 Asthma is a serious health problem in both developed and developing countries. Worldwide rates of asthma are, on average, rising by 50% every decade. 3 The alarming increase in asthma's prevalence, morbidity, and mortality over the past decade has triggered serious concern among pulmonary care physicians and scientists. 4 An estimated 300 million people worldwide are asthma sufferers. 5

2 The major factors contributing to asthma morbidity and mortality are under-diagnosis and inappropriate treatment. Most exacerbations can be prevented if treatment of the disease is comprehensive and ongoing. 6 Chronic Obstructive Pulmonary Disease COPD, such as emphysema and chronic bronchitis, produce inflammation, swelling and mucus in the human airway and gradually destroy the surface area of the lung. COPD is inexorably progressive and generally irreversible. Although COPD has a public health importance similar to asthma, it has previously received much less attention. 7 COPD is the fifth leading cause of death worldwide, with an estimated 600 million cases and 2.8 million deaths in The mortality rate for COPD is 14 times greater than for asthma. 8 In the European Union, COPD and asthma rank together with pneumonia as the third most common cause of death. 9 Inhalation Delivery Systems 3. RESPIRATORY THERAPY In respiratory treatment, inhaled therapies are preferred over non-inhaled therapies because they are targeted, that is, they deliver the active ingredient directly to the lungs. 10 By this method, the patient is able to obtain relief within one or two minutes after inhalation. Another important benefit of inhaled therapy is the much lower dose of medication that is used to achieve the same clinical result, compared to oral administration. 11 Inhaled therapy avoids metabolism of the drug substance by the liver before the medication reaches the rest of the body, allowing effective treatment at lower dose levels. 12 This method greatly minimises the risk of adverse side effects. Three types of inhaled drug delivery systems are currently available: metered does inhalers (MDIs), nebulisers, and dry powder inhalers (DPIs). These devices are described below. Metered Dose Inhalers The MDI is a pocket-sized, hand-held, pressurised multiple-dose delivery system that delivers small, measured, therapeutic doses directly to the patient's lungs and produces rapid onset of therapeutic relief. MDIs are the mainstay of respiratory therapy worldwide. Recent data from the world's fifteen largest populations of patients receiving respiratory medication indicate that MDIs account for 77% of all inhalation therapy. 13 This same data indicates that DPIs constitute 18% of the market, and nebulisers, 5%. Nebulisers Using either ultrasonic or air-jet technologies, nebulisers transform an aqueous solution in which drug particles are dissolved or suspended into an aerosol cloud for inhalation by the patient. The most significant drawbacks of nebulisers are the length of time

3 needed for delivery of the medication, the complexity of assembling the device and filling it with nebuliser solution, and the amount of energy required for operation. Many nebulisers require an independent power source. The mechanics of set-up and administration can consume minutes, a period that may be too long for a patient in severe respiratory distress. Use of nebulisers is generally restricted to hospitals and to home care of severely incapacitated patients and young children. 14 Dry Powder Inhalers Like MDIs, dry powder inhalers are small, portable delivery systems that deliver low doses of medication directly to the lungs. DPIs require the patient to provide the energy needed to deagglomerate the powder and move the drug into the lungs. Thus, the patient's inspiratory effort may affect the quantity of drug that reaches the lungs from a DPI. 15 Preservation of Therapy Options Each of the inhalation delivery systems described above has an important role in the treatment of respiratory disease. These delivery systems are not equally suitable for all patients. 16 Preservation of the entire range of delivery systems is critically important, as it increases the likelihood that physicians will be able to prescribe appropriate medication in the optimum format for each patient. 17 The characteristics of the three delivery systems are summarised below: Characteristics of Inhalation Delivery Systems Nebulisers MDIs DPIs Energy Source for Drug Delivery Provided by an external source Provided by the device Provided by patient inspiration Consistency of Dose Released Dose dependent on type of nebuliser used and duration of therapy Dose independent of patient inhalation Dose dependent on inspiratory effort of patient Device Operation Varies from one product to the next Similar for all products, provided that the same type of actuator is used Varies from one product to the next Co-ordination Do not need to co-ordinate inspiration with actuation Must be able to co-ordinate inspiration with actuation, except when using a breathactuated device or a spacer Do not need to co-ordinate inspiration with actuation Protection from Humidity Aqueous medium; protection not required Good High for unit dose; Low for reservoir devices Paediatric Use Accepted practice Accepted practice (with spacer) Limited Availability Widely available Widely available Not widely available 2

4 4. THE SELECTION OF HFCs AS REPLACEMENTS FOR CFCs IN MDIs For over forty years, MDIs have used CFCs as propellants. In response to the knowledge that CFC emissions contribute to the depletion of stratospheric ozone, the international community agreed -- through the Montreal Protocol -- to phase out CFC production for nearly all uses in the developed world by January Recognising that CFC alternatives would not be available by that date for certain important products, the Parties established a process for exempting "essential uses" from the phaseout. A use is considered essential if it "is necessary for health, safety or is critical for the functioning of society and there are no technically and economically feasible alternatives or substitutes that are acceptable from the standpoint of environment and health. 18 The Parties to the Protocol have confirmed, on an annual basis, the essentiality of the MDI. The pharmaceutical industry began an intensive search in the mid-1980s for alternatives to the CFC-propelled MDI. Three major initiatives resulted: testing of alternative propellants and reformulation of MDIs with these propellants; acceleration of programmes to improve existing non-propellant delivery systems, such as nebulisers and dry powder inhalers; and expansion of efforts to develop new, innovative delivery systems. Criteria for an MDI Propellant Compounds identified as potential substitutes for CFCs must meet particularly strict requirements in order to be considered for use in MDIs. 19 The principal criteria for MDI propellants are now well established. 20 An MDI propellant must: be a liquefied gas; have very low toxicity; be chemically stable; be acceptable to patients (in terms of taste and smell); have appropriate solvency characteristics; and have appropriate density. The relative significance of these criteria may vary from one product or formulation to another. The Choice of HFCs The search for CFC alternatives required extensive research into toxicological and environmental effects of promising substitutes. After extensive investigation, only two compounds emerged as acceptable substitutes for CFC propellants in MDIs: HFCs 134a and 227. Consideration of two or three of the necessary criteria for MDI propellants quickly eliminated many compounds from consideration. For example, a survey of 15,000 compounds 3

5 listed in the Handbook of Chemistry and Physics shows that fewer than 200 have boiling points in the required range. 21 Stability concerns also eliminated many possible propellants. A relatively unstable compound may deteriorate over time and lose its essential properties, react with the other agents in a formula, or cause container corrosion. Degradation can be dangerous, as it leads to breakdown products with unknown toxicity. In seeking a class of compounds that would provide the best possible mix of characteristics, and after review of other potential alternatives to CFCs, the chemical producers eventually began to focus on hydrofluorocarbons and hydrochlorofluorocarbons (HCFCs). HCFCs have some ozone depletion potential (though less than CFCs); thus, they are not attractive as long-term CFC replacements. HFCs 134a and 227 fit the criteria for an MDI replacement propellant far better than any other known compound. These propellants are non-flammable and have been shown to be safe for human inhalation through extensive toxicity testing, which has been to the same detailed level as a new drug. 22 Each has a vapour pressure suitable for MDI usage, and each are essentially biologically inert. Neither HFC 134a nor HFC 227 has any ozone-depleting potential. Moreover, these HFCs have shorter atmospheric lifetimes and lower global warming potentials than the CFCs which they replace. The chart below demonstrates the differences between these compounds. Propellant COMPARISON OF CFCS AND HFCS USED IN MDIS Ozone Depletion Potential (CFC 11 = 1) Atmospheric Life (years) Direct Global Warming Potential (CO 2 = 1) 23 CFC ,000 CFC ,500 CFC ,300 HFC 134a ,300 HFC ,900 The Transition to HFC MDIs The development of HFC MDIs is one of the most complex endeavors in product development undertaken by pharmaceutical companies. 24 Once the HFC propellants were identified, the components and formulations used in CFC MDIs had to be modified. Intensive testing and research to identify and develop formulations and materials that are compatible with HFCs is well underway, and in some cases completed. Potential formulations must also undergo toxicology, stability, and clinical testing. The patients themselves will make perhaps the most remarkable effort in this transitional period. The progression away from CFC MDIs will involve millions of patients and their health care providers around the world. Those who suffer from respiratory disease are extremely sensitive to even the smallest changes in medication. Comprehensive education 4

6 programmes to teach doctors and patients about the new products will be of the utmost importance. Several HFC MDI products are now available to patients in many countries around the world. Many more products are now awaiting regulatory approval and will be introduced over the next several years. This global transition process is likely to continue well into the first decade of the 21st century. 5. POTENTIAL FUTURE TECHNOLOGIES Pharmaceutical companies are committed to innovation to improve patient treatment. The development of the HFC MDI is only one element of the pharmaceutical industry s efforts to develop new delivery systems. The industry is actively engaged in research on alternative technologies for delivering medication to the lungs which do not use propellants. Several examples of technology under development which utilise liquid formulation are as follows: A drug containing solution can be forced through a nozzle with two small channels, resulting in two beams of liquids, which generate the aerosol by impaction. 25 For example, one of these delivery systems is a multidose inhaler, which releases a soft mist aerosol of medication. Promising results for this type of soft mist inhaler have been reported for beta agonists, anticholinergics, inhaled corticosteroids and combination bronchodilators. 26 Piezoelectric materials change their shape in response to an alternating electric current. The movement of the piezoelectric material may be transmitted to a liquid, causing droplets to be thrown off the surface of the liquid. Piezoelectric devices are now used in nebulisers to generate a fine droplet mix by means of a rapidly vibrating crystal. 27 A delivery device might force liquid through a break-up plate, mesh cap, or open-cell foam, resulting in droplets slightly larger than the size of the holes. 28 An ultrasonic horn might be used to generate an aerosol cloud by capillary wave action. 29 Other possible future initiatives include use of microelectronics in breath actuated devices to improve accuracy and allow compliance monitoring; use of reusable delivery systems to diminish the waste stream; and development of strategies for reduction of droplet coalescence. 30 Some of the technologies described above are under active development. It is important to recognise that new products are developed on a drug-by-drug and indication-byindication basis. 5

7 Many years will be required to demonstrate acceptable in vitro and in vivo performance, gain regulatory approval, and achieve patient acceptance for each new product. MDI products are subject to extensive regulation by national health authorities to ensure product safety, product efficacy, and manufacturing quality. 31 Additional time is required for registration on a country-by-country basis. Once a new product is approved, significant time is required for uptake and evaluation by physicians and patients. Post-market experience will ultimately demonstrate to what extent a new product can meet the needs of patient populations and subpopulations. The pharmaceutical industry is highly regulated, with standards significantly different to food or consumer products. For example the specification recently released by the United States Food and Drug Administration for HFC 134a contains 38 named impurities to be analysed with the majority being controlled to below 5 ppm. Small volumes of drug in HFC suspension must be accurately metered ( microlitres) from the MDI valve, and here as in any other pressurized system the rubber seals' performance is vital. However extractives and leachables must be minimized, e.g. typically PNAs < 5 ppm or nitrosamines < 5 ppb, and hence normal additives such as antioxidants, lubricants and carbon black cannot be added. It is impossible to predict to what extent new technologies might replace current delivery systems. The MDI is a nearly universal device, applicable to virtually all asthma medications. There is no guarantee that any new technology would have universal application over the full spectrum of active ingredients and patient populations around the world. Inhalation products based on new delivery systems would likely add to the mix of treatment options rather than leading to a wholesale substitution. Asthma, once thought of as a simple hypersensitive reaction, is now known to be a complex condition with a probable spectrum of causes and contributing factors, with airway inflammation as its central attribute. There has been a recent explosion of research on asthma, and in the future, a better understanding of the disease process could also lead to improved therapies. 32 Preliminary Emissions Projections 6. HFC EMISSIONS FROM MDIs In response to recent inquiries from climate change officials, IPAC is currently conducting a comprehensive HFC emission projection survey of MDI companies. This survey will generate information required to most accurately calculate projected emissions from MDIs worldwide and in several individual Parties. [See 15 July 1999 Submission to UNFCCC Secretariat, Preliminary Projected Emissions from HFC Metered Dose Inhalers (MDIs). ] Steps to Minimise Emissions IPAC companies are committed to best practices for controlling emissions. MDI companies understand the need for compliance with guidelines regarding good housekeeping practices, sound manufacturing operations, and responsible disposal and/or recycling of manufacturing waste. Examples of waste minimisation practices employed include 33 : Use of a vapour return hose 6

8 Trucks and canisters dedicated to a single material Installation of permanent, hard piping Detection and prevention of pump failure Detection and prevention of leaks Minimisation of mixing vessel waste material Minimisation of leaks during blending Replacement of rubber elastomers in MDIs Special gassing adapters Destruction or reclamation of reject canisters In addition, as referenced above in the table comparing CFCs and HFCs used in MDIs, the industry is significantly reducing greenhouse gas emissions by transitioning from CFCpropelled devices to HFC ones. 7. CLOSING MDIs are critically important to public health. Understanding the vital role that HFC MDIs play in treating serious medical conditions worldwide is essential to the development of sound emissions policy. 7

9 ENDNOTES 1 American Lung Association, Lung Disease Data 1996, at 3. 2 Global Initiative for Asthma, Global Strategy for Asthma Management and Prevention: NHLBI/WHO Workshop Report, NHLBI Pub No (Jan. 1995), at World Health Organization Press Release (7 Dec. 1998). 4 National Heart, Lung, and Blood Institute, National Institutes of Health, International Consensus Report on Diagnosis and Treatment of Asthma, U.S. Dept. of Health and Human Svcs. Pub No , vii (June 1992)(hereinafter International Consensus Report ). 5 March 1996 Report of the Technology and Economic Assessment Panel, at International Consensus Report at xi. 7 L. Fabbri, G. Caramori, et al., "COPD International Guidelines," 4 Pulmonary Medicine (1998). 8 M.W. Higgins & T. Thorn, "Incidence, Prevalence and Mortality: Intra and Intercountry Differences" in Clinical Epidemiology of Chronic Obstructive Pulmonary Disease at (M.J. Hensley & N.A. Saunders, eds. 1989). 9 N.M. Siafakas et al., Optimal assessment and management of chronic obstructive pulmonary disease (COPD), Consensus Statement of the European Respiratory Society (ERS), 8 Eur. Respir. J. 1398, 1398 (1995). 10 International Consensus Report at J.H. Toogood, J. Baskerville, et al., "Bioequivalent Doses of Budesonide and Prednisone in Moderate and Severe Asthma," 84 J. of Allergy and Clinical Immunology 688 (Nov. 1989). 12 Inhalation therapy is not limited to asthma and COPD. This form of therapy may be used in other respiratory disorders, including cystic fibrosis, bronchietasis and airway irritability. It is also employed in the treatment of non-respiratory disorders, e.g., for the delivery of medications whose oral bioavailability is extremely low, such as peptides. 13 International Pharmaceutical Aerosol Consortium, "Ensuring Patient Care" 14 (Peer-reviewed publication, 1997). 14 Id. 15 Id. at International Consensus Report at Id. 18 Decision IV/25 of the Fourth Meeting of the Parties to the Montreal Protocol. 19 Metered Dose Inhaler Technology (Tol S. Purewal & David J.W. Grant, eds., 1998). 20 International Pharmaceutical Aerosol Consortium, "Ensuring Patient Care" The Handbook of Chemistry and Physics (67th ed ). The required boiling point range is -100 to + 30 C). 8

10 22 In response to a joint request by the U.S. EPA, the U.S. Department of Defense, the U.S. Food and Drug Administration, and interested industry, the TNO Food and Nutrition Institute in the Netherlands recently conducted clinical safety studies on HFCs 134a and 227 in healthy volunteers. The clinical phase of the studies was completed in late June No treatment related effects were observed in the TNO studies, and these results are entirely consistent with the extensive pre-existing body of safety data on HFC 134a and HFC A 100 year time horizon is assumed. 24 Metered Dose Inhaler Technology, supra, at BWJ Freund, B. Zierenberg, et al.,...a New Approach to Inhalation Therapy, 10 J. Aerosol Med. 246 (1997). 26 FPV Maesen, JJ Smeets, et al., A Pilot Study to Compare the Efficacy and Safety of Ipratropium Bromide Administered from an MDI with a Metered Dose Solution from a Novel Device, Ann. Cong. of the European Respiratory Society (ERS) (Barcelona, Sept. 1995), 8 Eur. Respir. J. (Suppl. 19) 426S (1995). See also, SP Newman, J. Brown, et al., Lung Deposition of Fenoterol and Flunisolide Delivered Using a Novel Device for Inhaled Medicines, 113(4) Chest (1998); SP Newman, J. Brown, et al. Lung Deposition of Fenoterol... a Novel Inhaler Device for Pulmonary Drug Delivery, 10 J Aerosol Med. 268 (1997); P. Iacono, E. Guemas, et al., Cumulative Dose Response Study Comparing a New Soft Mist Inhaler with a Conventional Metered Dose Inhaler (MDI) for Delivery of Ipratropium Bromide in Patients with COPD, 1998 Int. Conf. of the American Thoracic Society (Chicago, April 1998), Am. J. Respir. Crit. Care Med. 157 (3, Part 2), A800 (1998); and J. Goldberg, E. Freund, et al, Combination Fenoterol/Ipratropium Bromide Delivered Via a New Soft Mist Inhaler, 1998 Int. Conf. of the American Thoracic Society (Chicago, April 1998), Am. J. Respir. Crit. Care Med. 157 (3, Part 2), A401 (1998). 27 See, e.g., 28 See, e.g., 29 See Alec MacAndrew et al., "Alternative Technologies for Portable Inhalers," Management Forum Conference of Portable Inhalers, London (1 Dec. 1994). 30 Id. 31 P. Grapel & D.J. Alexander, CFC Replacements: Safety Testing, Approval for Use in Metered Dose Inhalers, 4 J. Aerosol Med (1991). 32 ALA Lung Disease Data 1997, at 7. Now under intensive study are: the chemical reactions that take place in the asthmatic process; the nature of cell-cell communications; the way information is conveyed from one cell or type of cell to another; and the role of the tissue lining of the airways. 33 Based on a 1999 survey of IPAC member companies. 9