The broader considerations associated with the HFA MDI project in Mexico. David Howlett

Transcription

1 The broader considerations associated with the HFA MDI project in Mexico David Howlett

2 Background Wrote the project document for Mexico/ UNIDO and prepared the national strategy document. Prepared the arguments for the MLF to get the $$$$$$ Outlined preliminary Terms of reference. Similar inputs or technical advice in other projects including Egypt, Iran, Uruguay, India, Bangladesh, Pakistan, Cuba and Russia.

3 How Much? At a cost of over $1 billion, the pharmaceutical industry is now bringing a wide range of pressurised MDIs to patients around the world. The cost for each of the 2 HFA safety programs was $15 20 million.

4 What about the MLF funded programs MLF funding approved by the Executive Committee of the Montreal Protocol for MDI projects is USD 52.2 million. These may still, in some cases, take a few more years to complete. UNEP 2010 REPORT OF THE MEDICAL TECHNICAL OPTIONS COMMITTEE 2010 ASSESSMENT REPORT

5 HFA MDIs are implicated in Global warming What are the alternatives?

6 Dry Powder Inhalers are not a replacement for MDIs Although we often hear. Wouldn t they be better, they don t use any propellants! There seem to be so many of them. They are low cost.

7 Somewhat misguided Dry powder inhalers provide a suitable technical alternative to MDIs for almost all patients. DPIs fall into two categories, single dose and multi-dose inhalers. Single-dose DPIs, which have been in use world-wide for more than 40 years, utilise a single capsule that is inserted into the device. They are inexpensive but may not have the dose-to-dose reliability of more recent multidose DPIs. Multi-dose inhalers typically contain at least enough doses for 1 month s treatment, and have also been in use for more than 20 years.

8 Yes there are Myhaler Dr Reddys Redihaler Lupin Transhaler Kopran Easehaler Lupin Lupihaler Cipla Rotahaler Respihaler Zydus Cadilla

9 Somewhat misguided Dry powder inhalers provide a suitable technical alternative to MDIs for almost all patients. DPIs fall into two categories, single dose and multi-dose inhalers. Single-dose DPIs, which have been in use world-wide for more than 40 years, utilise a single capsule that is inserted into the device. They are inexpensive but may not have the dose-to-dose reliability of more recent multidose DPIs. Multi-dose inhalers typically contain at least enough doses for 1 month s treatment, and have also been in use for more than 20 years.

10 Pressure drop kpa Diskus at 30 l/min Turbuhaler at 60 l/min 12 % Capable of Age achieving PIFR Plot of pressure 93.3 drop vs flow rate for various DPIs % Capable of Age achieving PIFR Next Aerolizer Turbuhaler Diskus Novolizer 4mm orifice 5mm orifice Flow rate l/min Ability of preschool children to use dry powder inhalers as evaluated by In-Check Meter. Pediatr Int. 2006; 48(1):62-5 (ISSN: ) Adachi YS ; Adachi Y ; Itazawa T ; Yamamoto J ; Murakami G ; Miyawaki T

11 Rest In Peace

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13 Compilation of guidelines

14 Totally incorrect. Older reservoir DPIs can suffer from water ingress in high humidity environments, leading to clumping of the powder formulation and reduced dosing (also seen with some HFC MDIs). DPIs are easier to use for the patient as the drug delivery is effected by the patient s inhalation. Multi-dose DPIs from multinational pharmaceutical companies have generally been priced at the same level as the same company's MDIs, but remain more expensive than domestically manufactured MDIs in developing countries. In some parts of Europe, multi-dose DPIs now account for more than 90% of inhaled therapy, and in India single dose DPIs now account for more than 50% of inhaled therapy. There is no reason in principle (when manufactured in moderate volumes) that a multi-dose DPI should not be priced comparably to an HFC MDI. In addition, newer multi-dose DPIs function equally well in areas of high humidity, such as seen in many developing countries.

15 British Thoracic Society comment on compliance The proportion of patients making no mistakes with an inhaler in one well conducted study was 23-43% for pmdi, 53-59% for dry powder inhaler (DPI) and 55-57% for pmdi + spacer. When technique was assessed as number of steps correct out of the total number of steps, pmdi + spacer was slightly better than DPI. 352

16 generally been priced at the same level!!! Source BNF June 2010

17 Affordability Taken From: Bulletin of the World Health Organization Print version ISSN

18 The Cost

19 An on-going burden If one assumes a hypothetical switch for the most widely used inhaled medicine (salbutamol) from HFC MDIs to DPI, the projected recurring annual costs would be on the order of US$ 1.7 billion with an effective mitigation cost of between US$/tCO2-eq.

20 In the context of the MLF projects Development time 6 to 10 years Development costs (device/ formulation) $3 4 million Manufacturing for a 15 component device (5 million per annum) $7-8 million.

21 Liquid inhalers may not be the answer either.

22 SMIs/ MDLIs hold promise but! Cost and limited products.

23 The V.A.R.I & Co. approach Less HFA (Metering valve and ethanol) Less aluminum (thinner wall cans) Less energy (baking linings, units per minute) Represents an annualised reduction in excess of 100 tonnes CO 2 equivalent, when compared to other HFA MDIs.

24 Most important is to manage the expectations of the patient!!!

25 Resources and communication

26 Frequently Asked Questions (and some answers)

27 Q: Why are albuterol CFC inhalers being phased out? A: The phase out of albuterol CFC inhalers is due to an international agreement called the Montreal Protocol on Substances that Deplete the Ozone Layer at CFCs are harmful to the environment because they decrease the protective ozone layer above the Earth.

28 Q: Will the new HFA inhaler work as well as my old one? A: Yes. The medication in the HFA inhaler is the same as what you were using, only the propellant has changed.

29 Q: How are albuterol HFA inhalers the same as albuterol CFC inhalers? A: Albuterol HFA inhalers are used in the same way as albuterol CFC inhalers and give the same dose of albuterol as the CFC inhalers. Albuterol HFA inhalers are safe and effective for the same FDA approved uses: treatment or prevention of bronchospasm in patients with reversible obstructive airway disease, including asthma and chronic obstructive pulmonary disease (COPD).

30 Q: How are albuterol HFA inhalers different from albuterol CFC inhalers? A: CFCs are used as propellants (spray) to move the albuterol medicine out of the inhaler so patients can breathe the medicine into their lungs. HFAs are a different type of propellant (spray). The albuterol and levalbuterol HFA inhalers have a different propellant called hydrofluoroalkane (HFA). Albuterol HFA and albuterol CFC inhalers may taste and feel different. The force of the spray may feel softer from albuterol HFA than from albuterol CFC inhalers. Each of the HFA inhalers is different (see table). Albuterol HFA inhalers have to be cleaned and primed to work in the right way and give the right dose of medicine. Each HFA inhaler has different instructions for cleaning and priming. The patient information that comes with each inhaler tells you how to clean and prime your inhaler.

31 The table

32 Q:What should I do if I have problems with my albuterol HFA inhaler? A: First, remember that the force of the spray from the albuterol HFA may feel different. Make sure you wash, dry, and prime the inhaler as described in the directions that come in each package. If you have problems using your albuterol HFA inhaler, talk to your health care professional as a different product may be right for you.

33 Q: Can I get drunk on the alcohol in my inhaler. A: = 2,000 *

34 FACT: Regulatory expectations are always evolving

35 Expanding influence of the The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

36 Submissions in C.T.D Format now a requirement India as of January 2011 China September 2010 The Association of South East Asian Nations (ASEAN) (Brunei Darussalam, Cambodia, Indonesia, Lao PDR (Laos), Malaysia, Myanmar, Philippines, Singapore, Thailand and Vietnam) - ASEAN Common Technical Dossier (ACTD) World Health Organization:

37 Pharmacopeial Working Group (PWG) of the Pan American Network for Drug Regulatory Harmonization Taken from Review of the Pharmacopeial Processes in the Americas: Argentina, Brazil, Mexico, and the United States

38 Mexican Pharmacopoeia (translated) Extractable substances. Since aerosols and pressurized inhalers are usually formulated with organic solvents, such as the propellant or the carrier, the leaching of removable material from the plastic and elastomeric components in the formulation poses a serious problem. Therefore the formulation and material quality used for the manufacture of the valve parts must be carefully selected and controlled. Its compatibility with the components of the formulation must be well established in order to prevent valve parts fault and minimize the changes in the medicine spray. The extractable material in a representative sample of each plastic or elastomeric component of the valve must be evaluated under specific conditions and must be consistent with the drug or placebo extractable profile in order to guarantee the reliable quality of the medicine. The extractable substances, including polynuclear aromatic compounds, nitrosamines, vulcanization catalysers, antioxidants, plasticisers, monomers, etc. must be identified and minimised as much as possible.

39 Spot the difference USP <1151> Extractable Substances Since pressurized inhalers and aerosols are normally formulated with organic solvents as the propellant or the vehicle, leaching of extractables from the elastomeric and plastic components into the formulation is a potentially serious problem. Thus, the composition and the quality of materials used in the manufacture of the valve components (e.g., stem, gaskets, housing, etc.) must be carefully selected and controlled. Their compatibility with formulation components should be well established so as to prevent distortion of the valve components and to minimize changes in the medication delivery, leak rate, and impurity profile of the drug product over time. The extractable profiles of a representative sample of each of the elastomeric and plastic components of the valve should be established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Extractables, which may include polynuclear aromatics, nitrosamines, vulcanization accelerators, antioxidants, plasticizers, monomers, etc., should be identified and minimized wherever possible. Specifications and limits for individual and total extractables from different valve components may require the use of different analytical methods. In addition, the standard USP biological testing (see the general test chapters Biological Reactivity Tests, In Vitro 87 and Biological Reactivity Tests, In Vivo 88) as well as other safety data may be needed.

40 Argentinian Pharmacopoeia Sustancias extraibles - La composición y la calidad de los materiales empleados en la elaboración de los componentes de las válvulas (como por ej. vástago, juntas, etc.) deben seleccionarse con cuidado debido a que en la formulación de aerosoles se emplean solventes orgánicos como propelentes o vehículos que pueden extraer materiales de los componentes elastoméricos y plásticos a la formulación. Las sustancias extraibles, entre las cuales se pueden incluir hidrocarburos aromáticos, nitrosaminas, aceleradores de vulcanización, antioxidantes, plastificantes, monómeros, etc., deben identificarse y minimizarse en lo posible.

41 Far more emphasis on the performance of the aerosol

42 42

43 Stability without the need for overwrapping

44 A significant undertaking

45 Beclametasone dipropionate (BDP) some unique challenges

46 There are no BDP HFA MDI suspensions! If ethanol is not used there are typically stability issues. If ethanol is used it has to be a solution.

47 Reference HFA formulations for BDP Global approvals Incl, USA, UK, Japan, China, Eu Incl, UK, Eu Incl, UK, Eu M Approach IVAX Approach Chiesi Approach Cipla Approach

48 Essential Medicines Lists Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the individual and the community can afford. The WHO Model List is a guide for the development of national and institutional essential medicine lists. It was not designed as a global standard. However, for the past 30 years the WHO Model List has led to a global acceptance of the concept of essential medicines as a powerful means to promote health equity. Most countries have national lists and some have provincial or state lists as well. National lists of essential medicines usually relate closely to national guidelines for clinical health care practice which are used for the training and supervision of health workers. Source :

49 WHO Model List of Essential Medicines for Adults 17 th Edition effective March 2011

50 QVAR BDP The active component of QVAR 40 mcg Inhalation Aerosol and QVAR 80 mcg Inhalation Aerosol is beclomethasone dipropionate, USP Appearance: white or almost white, crystalline powder. Solubility: practically insoluble in water, freely soluble in acetone, sparingly soluble in ethanol (96 per cent).

51 The target is typically the smaller conducting airways

52 Gamma scintigraphic lung images of the nine study volunteers after inhalation of radiolabeled HFA- BDP (top), CFC-FP (middle), and CFC-BDP (bottom). Leach C. L. et.al. Chest 2002;122: by American College of Chest Physicians

53 C.L. Leach, P.J. Davidson, R.J. Boudreau Eur Respir J 1998; 12:

54 Improved deposition Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone*: a cross-over study in healthy volunteers. Chest. 2002;122:

55 More effective In a clinical dose-response trial, Bogston et al. Showed that the efficiency of HFA-BDP is equivalent to a dose 2.6 times higher of CFC-BDP when the forced expiratory volume in one second (FEV1) was assessed, and to a dose of 3.2 times smaller of HFA-BDP when the maximal midexpiratory flow rate was analyzed (FEF25-75). Dolovich MB, Fink JB. Aerosols and devices. Respir Care Clin N Am. 2001;7:

56 HYDROFLUOROALKANE-134A BECLOMETHASONE DIPROPIONATE IS MORE EFFECTIVE THAN DOUBLE DOSE CHLOROFLUOROCARBON BECLOMETHASONE DIPROPIONATE FOR THE TREATMENT OF SEVERE ASTHMA RESULTS: Switching from CFC-BDP to HFA-BDP significantly improved pulmonary function including predicted FEV1 (from 71.7% to 81.2%), predicted MMF (from 47.0% to 61.0%), predicted V50 (from 39.1% to 50.3%) and predicted V25 (from 38.2% to 48.1%). CONCLUSION: These data suggest HFA-BDP may improve small airway of patients with severe asthma. Hideto Obata, MD* and Kenji Ikeda, MD CHEST/128/ October 2006 supplement

57 QVAR provides similar control of asthma symptoms with no decrease in plasma cortisol compared to Fluticasone propionate. Results from a 6-week, multicenter, double-blind, double-dummy, parallel-group, comparative study demonstrating the clinical equivalence of QVAR (400 μg/day) and fluticasone (400 μg/day) in 172 symptomatic asthma patients.

58 What about other MDI products?

59 Safety concerns with salmeterol (LABA) It is therefore of great significance that the US Food and Drug Administration (FDA) has issued advice about longacting beta agonists that states 'these medicines may increase the chance of severe asthma episodes, and death when those episodes occur'. Those on salmeterol appeared to have a three times greater risk of death. There was one death for every 650 patient years of salmeterol treatment. As there were only 14 asthma-related deaths in the 16-week study, the difference between salmeterol and salbutamol was not statistically significant.

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61 Intal Inhaler discontinued August 04, 2009 King Pharmaceuticals has decided to discontinue the manufacturing of Intal Inhaler (cromolyn sodium inhalation aerosol). This decision is based on King's inability to identify a qualified manufacturer for chlorofluorocarbon propellant inhalers and to reformulate Intal to a chlorofluorocarbon-free or hydrofluoroalkane (HFA) propellant formulation. Intal Inhaler will remain available through pharmacies and wholesalers until current supplies are depleted. Healthcare professionals are being notified to transition patients currently using Intal to alternative therapies

62 Thank You!