HFA Market

1
Supply of HFA 227 and HFA 134a in MDIs - Past -
1980s Synthesis of HFA 134a and HFA 227 (134a
DuPont (1993), ICI (1991), Aussimont (1994),
Atofina (1993/5), Solvay (formerly Hoechst)
1994 (227ea Solvay (formerly Hoechst) 1996,
pilot plant since 1987, Great Lakes
(1993) 1990s Toxicological Testing of HFAs for
MDIs (IPACT-I for 134a ADIR (Institut de
Recherches Internationales Servier), Aeropharm
Technology, Inc., ASTA Medica AG, AstraZeneca
plc, Aventis Pharma Ltd., Boehringer Ingelheim
GmbH, Hoffmann-La Roche Inc., 3M, Norton
Healthcare Ltd, Novartis Pharma, Inc., and TAP
Holdings Inc.) (IPACT-II for 227 ASTA Medica AG,
AstraZeneca plc, Aventis Pharma, Ltd., Boehringer
Ingelheim GmbH, Glaxo Wellcome RD, Hoffmann-La
Roche Inc., 3M, Norton Healthcare Ltd., and
Schering-Plough Corp.) 1994/5 Safety Assessment
of HFAs for Use in MDIs by CPMP (134a July 1994
for IPACT-I Sept 1994 for Glaxo Inhalation
Grade) (227ea Sept 1995 for IPACT-II)
2
CFC Essential Use Exemptions Approved and
Actually Used (in metric tons) from 1997 to 1999
under the Montreal Protocol
CFCs approved

6000 4000 2000 0
6636
CFCs actually used or acquired

6592
5463
4656
4660
4429
4363
4168
3665
2644
2426
2255
1997
1997
1998
1999
1998
1999
EU
USA
Source April 2000 TE DAP Report
3
Use of HFA 227 and HFA 134a in MDIs - 134a
Present -
Active Product Company Beclometasone
QVAR (USA 09/00), UK 09/98)
3M BECLOJET (F 05/00)
Chiesi BECLAZONE (F, J 06/2000)
Norton Salbutamol AIROMIR (1995Japan
02/97) 3M VENTOLIN EVOHALER
Glaxo (D SULTANOL N 1997, UK 01/98)
Salmeterol SEREVENT , ARIAL
Glaxo Fluticasone FLIXOTIDE (D FLUTIDE
N 06/97) Glaxo Salmeterol SERETIDE
EVOHALER (UK 07/00) Glaxo Fluticasone
4
Use of HFA 227 and HFA 134a in MDIs - 227
Present -
Active Company Disodium
Cromoglycate INTAL Aerosol A (J
07/00) Aventis Pharma Ltd
(Eu 12/98)
(RoW 7/99) Nedocromil TILADE (Eu
1999, RoW 2000) Aventis Pharma Ltd Disodium
AARANE N (Ge 7/99) Aventis Pharma Ltd
Cromoglycate Reproperol Allergospasmin
N(Ge 10/99) Asta Medica AG

Product
HFA 227 products now launched in gt15 countries
5
Use of HFA 227 and HFA 134a in MDIs - Current -

• ? Propellant chosen by history rather
  than optimisation historical experiences and
  choices made by companies In mid 1990s
• price differential and availability of supply
• initial performance of delivery systems/valves
• IP web preventing free access to early
  formulations
• ? Product optimisation now available as
  properties and
• understanding has increased
• partnerships available for proven technologies
  and capabilities

6
Use of HFA 227 and HFA 134a in MDIs From
Past and Present- into the future

• Major technical challenge for entire industry
• ? Redevelopment of valves, mouthpieces and
  devices
• gt 10 yrs investment for most companies to reach
  new formula
• Major patent/IP web developed by most
  companies
• ? Major process and equipment development
• significant capital and human resource
  investment
• critical skills in developing and
  industrialising products
• competitive barrier to many competitors and high
  entry price
• ? Expanding use to partnerships with other
  companies
• access to know how, capability, IP and
  development-supply

7
Use of HFA 227 and HFA 134a in MDIs - Future -
Are HFAs going to be phased-out in MDIs ?
? Phase - out of CFCs in MDIs still Priority
Complete replacement by HFA in MDIs/ DPIs,
corresponds to a reduction in greenhouse gas
emissions of approx. 75 IPAC data 73
8
Use of HFA 227 and HFA 134a in MDIs - Future -
Are HFAs going to be phased-out in MDIs ?
? Phase - out of HFAs in MDIs would result in
? Almost no reduction of emissions (0.05
worldwide/ 0,13 EU) ? Highest cost per t CO2
saved gt100 to gt 500 / tonne CO2 equiv.,
with an average of 7 / tonne CO2 equiv. for 42
Mtonnes of CO2, better 1 - 2 / tonne CO2 equiv.
recommendation not to implement measures gt 30
/ tonne CO2 ? Longest duration for alternative
developments (8 - 12 years for new technology
10 - 20 years)
9
Use of HFA 227 and HFA 134a in MDIs - Future -
Are HFAs going to be phased-out in MDIs ?
? MDIs are reliable, cheap, convenient (EU
wide patients primarily rely on MDIs 85, DPIs
15) ? Certain patient groups depend on MDIs ?
Supply issue rather than legislation (year
2000 CFC MDIs in US 100, EU 75, HFA pharma
grade supply ensured over long-term period
(DuPont, ICI, Solvay)
10
Use of HFA 227 and HFA 134a in MDIs - Future -
Are HFAs going to be phased-out in MDIs ?
European Federation of Asthma Allergy
Associations EFA urges the national
governments, while developing policies to meet
the Kyoto protocol obligations not to take
measures against medical uses of HFC MDIs, EFA
Position Paper on the need for Metered Dose
Inhalers (MDIs) September 17, 2000
11
Use of HFA 227 and HFA 134a in MDIs - Future -
Use of pMDI/ DPI Technology for the Treatment
of ? Diabetes (e.g. insulin Pfizer/Aventis/
Inhale EliLilly/ Generex) ? Influenza (e.g.
neuraminidase inhibitor, zanamivir, Relenza
Glaxo) ? Osteoporosis ? Cancers ? Septic Shock ?
Viral Diseases etc.
12

• Process optimised for each product
• eg INTAL high dose hygroscopic drug
• Fully enclosed process to give product/operator
  protection
• Much reduced emissions and cleaning with
  aqueous system to improve environmental impact
• Lab (1-10kg) pilot (100kg)-production
  scale(1000kg) for solution and suspension aerosol
  using identical equipment
• Aventis patented formulations and exclusive
  Optimised valve for HFA 227

For further details contact Dr Mike
Dey Director, Respiratory Technology, Aventis
Pharma London Road, Holmes Chapel, Cheshire CW4
8BE Tel [phone] email
Mike.Dey_at_aventis.com