1. Choosing the right deviceThe case for DPIsDavid HarrisDrug Delivery to the Lungs 22, 8th December 2011Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 1 www.team-consulting.com

2. Choosing the right device the case for DPIsWhere did it all begin? Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 2 www.team-consulting.com 3. Choosing the right device the case for DPIs First capsule DPI First multi-unit dose DPI - Spinhaler (Fisons)Serevent Accuhaler (GSK)First DPI Aerohalor(Abbott)The first DPI patent -Inhaling Apparatus High performance multi-unit First DPI with a breath-triggered dose DPI Starhaler (Sun first Reservoir DPI actuation mechanism Novolizer Turbuhaler (Astra)(Sofotec Almirall) Pharma) 18641948 1967 1987 1995 2001 2011 Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 3www.team-consulting.com 4. Choosing the right device the case for DPIsThe story behind the Spinhaler is inspiring Invented by Roger Altounyan, a long-sufferingasthmatic and medical doctor former RAF Spitfire pilot and instructor, who sawthe potential to use a propeller in an inhaler todeliver dry powder effectively He spent half a year experimenting withprototypes in his living room laboratory It still didnt work. The powder impacted onthe inside of the tube, rather than forming anacceptable aerosol However Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 4 www.team-consulting.com 5. Choosing the right device the case for DPIsOne day he noticed that when he sucked one of the models it vibrated and buzzed like a dentists drill, presumably because the bearing was poor and rattled. Then he wondered if this shaking might prevent the powder from impacting. He tried it with some powder, and at last it produced a steady and efficient inhalation. Ironically, it was the very fault in the eccentric action of the slightly imperfect bearing that made the little machine work.Rodney Dingle, Biography of Roger Altounyan Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 5 www.team-consulting.com 6. Choosing the right device the case for DPIsThe most exciting phrase to hear in science, the one that heralds new discoveries, is not Eureka! (I found it!) but Thats funny ...Isaac Asimov Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 6 www.team-consulting.com 7. Choosing the right device the case for DPIsWhy are DPIs difficult to get right? Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 7 www.team-consulting.com 8. Choosing the right device the case for DPIsRespirable particles are very small The diameter of an average human hairis ~50 times that of a respirable drugparticle Its extremely difficult to transfer energyto disperse such fine particles efficiently They can easily become trapped influidic boundary layers shielded fromaerodynamic drag forces Large surface area to volume ratiomeans that they are susceptible toacquiring high specific charge(electrostatic charge to mass ratio) Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 8 www.team-consulting.com 9. Choosing the right device the case for DPIsI asked a fluid dynamics expert, James Tibbatts (Concept Flow Ltd) how well he could simulatean aeroplane in order to optimise efficiency and he replied with -Youd be able to get lift and drag coefficients to within a few percent but youd need a lot of computing power.In contrast, I posed the same question about optimising the airway of a dry powder inhalerand his reply was -Quantitatively, you cant get any discernible accuracy at all. Because the physics isnt well understood you can throw all the computing power in the world at it and not get a meaningful solution. Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 9www.team-consulting.com 10. Choosing the right device the case for DPIsIt can be done Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 10 www.team-consulting.com 11. Choosing the right device the case for DPIs Sun Pharma (with CambridgeConsultants & Design Directions) 8 dimensional reduced order numericalmodel of DPI airway based upon CFD, empirical andtheoretical inputs successfully mapped out design space enabled performance optimisation +high independence of flowrate future proof easy to fine tune Conix 1 Disposable single-dose 3Ms Conix DPI family are all based uponone single aerosolisation engineConix 2Reloadable single-dose three different inhaler products all have the same performanceConix 3Pre-metered multi-dose Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 11 www.team-consulting.com 12. Choosing the right device the case for DPIsRemember that all models are wrong; the practical question is how wrong do they have to be to not be useful George E. P. Box, 1987 Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 12 www.team-consulting.com 13. Choosing the right device the case for DPIsAn exciting future! ? Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 13 www.team-consulting.com 14. Choosing the right device the case for DPIsSemiotics the study of signs and symbols1234 56 How is this relevant to DPIs ? Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 14 www.team-consulting.com 15. Choosing the right device the case for DPIs Huge diversity of scientific / technologicalapproach to inhaler design but does this have to be presented as diversity ofuser interactions? There may be an opportunity to agree acommon symbol for a key inhaler use step e.g. load dose There is certainly an opportunity to agree acommon approach to instructions for useThe nice thing about standards is that you have so many to choose from. Andrew S. Tanenbaum Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 15 www.team-consulting.com 16. Choosing the right device the case for DPIs The MannKind Corporation pursuing the delivery of inhaledinsulin - DPI product Afrezza which is undergoing late stageclinical studies Successful treatment of diabetesCricketsTM - disposablethrough the systemic delivery ofinhaled insulin would be a majorbreakthrough potentially opening the route formany forms of the therapeuticdelivery of new molecules pain management vaccinationWhat therapies will DPIs ofDreamBoatsTM reusablethe future deliver? Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 16www.team-consulting.com 17. AcknowledgementsMany thanks to:- Mark Sanders, Inhalatorium for kindly providing the images of Aerohalor and Spinhaler John Bell, Stewart Erl Associates, for sharing his extensive insights about the early development ofthe Spinhaler Robert N Slinn, who worked on the synthesis of analogues of cromoglycate at Fisons, for sendingme a copy of Roger Altounyans biography Hans Lundback, Astra Zeneca, for the kind provision of images of early Turbuhaler images David Blakey & The Device Technology Group, GSK, for kindly providing images of the originalSerevent Accuhaler Prashant Kane, Sun Pharma, for permission to use images of the Starhaler(developed in collaboration with Cambridge Consultants and Design Directions) Jag Shur, University of Bath, for providing excellent SEMs of Salbutamol on a human hair James Tibbatts, Concept Flow, for the quotations and informative discussion around CFD andreduced order numerical modelling Georgina Fradley, 3M, for kindly providing images of the three Conix DPI platforms Chad Smutney, MannKind Corporation, for the great images of their Cricket and Dreamboatranges of DPIs Julian Dixon, Team Consulting, for his input on the usability of DPIs Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 17www.team-consulting.com 18. Confidential Team Consulting 2011: Presentation_DDL22_v1-0 slide 18 www.team-consulting.com