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Transitioning to CFCTransitioning to CFC--free Metered free Metered Dose InhalersDose Inhalers

Propellants and other components, Propellants and other components, regulatory input, regulatory input,

issues and opportunitiesissues and opportunities

Dr Tim Noakes(INEOS Fluor, UK)

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ContentContent1.1. Developing CFC and CFC MDI components supply Developing CFC and CFC MDI components supply

situation situation –– impact on MDI industryimpact on MDI industry2.2. CFC MDI availabilityCFC MDI availability3.3. Availability of Availability of HFAs HFAs & HFA MDI technology & HFA MDI technology ––

developing (A5) country focusdeveloping (A5) country focus4.4. Potential issues regarding supply of HFA Potential issues regarding supply of HFA MDIs MDIs to A5 to A5

countriescountries

For very useful background reading see ‘Ensuring Patient Care’ by IPAC (International Pharmaceutical Aerosols Consortium)http://unfccc.int/files/methods_and_science/other_methodological_issues/interactions_with_ozone_layer/application/pdf/ipacat2.pdf

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CFC propellant and components CFC propellant and components supply situationsupply situation

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MDI MDI –– key componentskey components

Valve

Can Propellant

(Actuator)

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CFC CFC MDIMDI’’s s –– the key the key componentscomponents

No issuesNo issuesActuatorsActuators

Generally no issuesGenerally no issuesDrugDrug

No issuesNo issuesCansCans

Common component (seal) to most Common component (seal) to most valves made by one company only. valves made by one company only. Exiting soon?Exiting soon?

ValvesValves

Tight regulatory control. Quality Tight regulatory control. Quality issues. Supply shortages.issues. Supply shortages.

Propellants (CFC 11,12)Propellants (CFC 11,12)

Supply situationSupply situationComponentComponent

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CFC propellant manufacturingCFC propellant manufacturing•• My company no longer manufactures CFCs, but we My company no longer manufactures CFCs, but we

qualify and trade in them for medical uses only qualify and trade in them for medical uses only –– as as part of an HFA bridging servicepart of an HFA bridging service..

•• Has given us a comprehensive viewpoint on the Has given us a comprehensive viewpoint on the practical travails of securing and supplying these practical travails of securing and supplying these products.products.

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CFC plants recently openCFC plants recently open

ExportingExports capped50 tes 2007

Closed/non medical

Limited exportsQuality issues

Closing 2007

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Propellant manufacture:Propellant manufacture:Swing plant Swing plant CFCs CFCs

Inputs:

HF

CCl4

•A batch picking regime•Extra analysis sometimes carried out

Applications:

RefrigerationAir ConditioningFoam blowingAerosolsMedical aerosols

CFCs 11,12

( CFCl3, CF2Cl2)Purification

CHCl3

CH2Cl2

CH3CCl3

22, 143a, 32 Low temprefrigerants

Reactor

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Swing plant campaigns Swing plant campaigns -- puritypurity

Medical specification

tonnes

impu

ritie

s

Good CFC campaign

start

Bad CFC campaign

start

Campaign variables: catalyst, CTC feedstock, frequency of campaigns …

End of campaignEnd of campaignStart of campaignStart of campaign

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Medical CFC specificationsMedical CFC specificationsWhich specification? Which specification? •• Old standard was BP (British Pharmacopoeia) 1988 Old standard was BP (British Pharmacopoeia) 1988 still still

used in most A5 countries.used in most A5 countries.•• Was inadequate but OK when developed Was inadequate but OK when developed –– CFC manufacture CFC manufacture

was predictable thenwas predictable then•• Now, in the exit, does not adequately control quality and is a Now, in the exit, does not adequately control quality and is a

potential danger to patients.potential danger to patients.

•• In most developed countries superseded by In most developed countries superseded by ‘‘FDA FDA guidance document 1998guidance document 1998’’ produced after product safety produced after product safety issuesissues

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Off Spec materialOff Spec material•• Risk of making off spec is increasing Risk of making off spec is increasing •• Until the end of 2006, CFC plants sank OOS medical Until the end of 2006, CFC plants sank OOS medical

material into nonmaterial into non--medical BDN applications for which medical BDN applications for which it was in spec.it was in spec.

•• January 2007 15% of baseline production ceiling for January 2007 15% of baseline production ceiling for BDNBDN

•• From 2007 onwards a From 2007 onwards a ‘‘badbad’’ campaign could so reduce a campaign could so reduce a plantplant’’s remaining BDN quota that medical CFCs cannot s remaining BDN quota that medical CFCs cannot be made later in year. Choice will be:be made later in year. Choice will be:

•• Destroy and remake (hugely expensive)Destroy and remake (hugely expensive)•• Under supplyUnder supply•• Use Use ‘‘badbad’’ CFC for CFC for MDIs MDIs exploiting inadequacy of BP 1988exploiting inadequacy of BP 1988

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Restricted CFC supply Restricted CFC supply --behaviour in A5 marketsbehaviour in A5 markets

In A5 countries where CFC MDI manufacture still exists, In A5 countries where CFC MDI manufacture still exists, range of behaviours:range of behaviours:

•• Medical & industrial uses compete for limited CFC Medical & industrial uses compete for limited CFC consumption rights consumption rights –– propellant manufacturers left to propellant manufacturers left to decidedecide

•• Erratic supply and manufacturing Erratic supply and manufacturing eg eg NovNov--Dec 06, IndiaDec 06, India

•• Some form of hypothecation of medical volume Some form of hypothecation of medical volume (usually where medical ~ total country needs)(usually where medical ~ total country needs)

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CFC MDI ValvesCFC MDI Valves•• Use specialised components (seals) that are becoming Use specialised components (seals) that are becoming

scarcescarce•• Manufacture is winding downManufacture is winding down•• CFC 11 used in manufacture of sealsCFC 11 used in manufacture of seals

•• Only one Only one ukuk supplier of seals to the world? supplier of seals to the world? (3M (3M NeotechnicNeotechnic, UK), UK)

•• Other valves (Other valves (eg eg modern HFA valves) cannot be modern HFA valves) cannot be substitutedsubstituted

Valves are often overlooked, but possibly the most likely Valves are often overlooked, but possibly the most likely nonnon--regulatory reason for the disappearance of the regulatory reason for the disappearance of the CFC MDICFC MDI

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CFC MDI availabilityCFC MDI availability

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Manufacturing locations supplying Manufacturing locations supplying developing world marketsdeveloping world markets

•• Europe (~ 10Europe (~ 10--15m units 2007)15m units 2007)•• India ( ~ 25India ( ~ 25--30 m)30 m)•• China (~ 20 m)China (~ 20 m)•• S America (~ 15m)S America (~ 15m)•• ROW (~ 15m) ROW (~ 15m)

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Future CFC MDI supply Future CFC MDI supply characteristicscharacteristics

•• Becoming erraticBecoming erratic•• Not all drugs available Not all drugs available –– some will transition sooner to some will transition sooner to

HFA replacementsHFA replacements•• CFC product will be channelled to most CFC product will be channelled to most ‘‘difficultdifficult’’ MDI MDI

markets:markets:•• Price caps (Price caps (eg eg 80 80 Rp SalbutamolRp Salbutamol in India)in India)•• Where HFA replacements are not yet fully approvedWhere HFA replacements are not yet fully approved

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HFAs HFAs & HFA MDI technology& HFA MDI technology

Article 5 country focus Article 5 country focus

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State of Development of State of Development of technologytechnology

•• HFA MDI technology is largely mature in the HFA MDI technology is largely mature in the developed world. developed world.

•• In the EU all HFA formulations are readily available, CFCs In the EU all HFA formulations are readily available, CFCs nearly off the market.nearly off the market.

•• In USA, main change will be over next 18 months.In USA, main change will be over next 18 months.

•• Technology is:Technology is:•• Different to CFCsDifferent to CFCs•• Very difficult unless close to existing developed HFA MDI Very difficult unless close to existing developed HFA MDI

modelsmodels•• All new componentsAll new components•• Surrounded by patentsSurrounded by patents•• Challenging for national Challenging for national pharma copharma co’’s s in developing countriesin developing countries

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Sources of HFA Sources of HFA MDIs MDIs into A5 into A5 countriescountries

•• Import from Global players Import from Global players (GSK, 3Ms, (GSK, 3Ms, BoehringerBoehringer))

•• Off the shelf, all drugsOff the shelf, all drugs•• Costly (Costly (Salbutamol Salbutamol ~ 4~ 4--5$)5$)

•• Local manufactureLocal manufacture•• Increasing options Increasing options •• Lower cost baseLower cost base•• Safe paths through the IP?Safe paths through the IP?•• ExportExport

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HFA MDI DC ManufactureHFA MDI DC Manufacture

Late 2007Late 20070.50.5UruguayUruguayHaymannHaymann

11

5577

55

11

0.10.1

0.30.344

6060

Unit M Unit M papa

Late 2007Late 2007TunisiaTunisiaBergBerg

from 2008/9from 2008/9IranIranSine Sine DarouDarouFrom 2008From 2008CubaCubaFarmacubaFarmacuba

from 2008/9from 2008/9EgyptEgyptArab Drug CoArab Drug Co

1010--15 planned15 plannedChinaChinaJinweiJinwei

10 planned10 plannedArgentinaArgentinaPablo Pablo CassaraCassara

3 planned3 plannedBangladeshBangladeshBeximcoBeximcoFurther increase plannedFurther increase plannedIndiaIndiaRanbaxyRanbaxy

Further major increase plannedFurther major increase plannedIndiaIndiaCIPLACIPLA

CommentsCommentsCountryCountryCompanyCompany

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Robustness of HFA MDI Robustness of HFA MDI component supplycomponent supply

•• All components are new:All components are new:•• Propellant / formulationPropellant / formulation•• ValvesValves•• CansCans•• ActuatorsActuators•• New filling equipment also neededNew filling equipment also needed

•• Driven by world demand growth there are several Driven by world demand growth there are several competitive suppliers for each component. Supplies are competitive suppliers for each component. Supplies are secure. Capacity is adequate and increasing.secure. Capacity is adequate and increasing.

•• Propellant: INEOS, Propellant: INEOS, SolvaySolvay, , DuPontDuPont•• Valves: Valves: ValoisValois, , BespakBespak, , CosterCoster, VARI, 3Ms, VARI, 3Ms•• Cans: Cans: PresspartPresspart, 3Ms, 3Ms•• Actuators Actuators –– freely availablefreely available

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Propellant Manufacture:Propellant Manufacture:HFAsHFAs

HFA ManufacturingPlants

Inputs:

HF

Cl2C:CHClOr

CF3CF=CF2

Applications:

RefrigerationFoam blowingAir conditioningFire fighting

HFA extra purification plantscGMP standard

Fully regulated, DMFs etcSpecialised analysis & handlingHFA 134a

And HFA 227ea

Medical propellants

Industrial

HFC 134a HFC 227ea

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HFA HFA MDIs MDIs to/in A5 countriesto/in A5 countries

Supply problems?Supply problems?

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PricesPrices•• New HFA components are expensive. Relative to CFC New HFA components are expensive. Relative to CFC

MDIsMDIs•• Propellants ~ +50% Propellants ~ +50% •• Valves up to + 100%Valves up to + 100%•• Cans parity to + 50%Cans parity to + 50%

•• Competition slowly forcing these prices downCompetition slowly forcing these prices down•• BUT in a number of markets, price caps on critical BUT in a number of markets, price caps on critical

medicationsmedications

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Price cap example: Price cap example: SalbutamolSalbutamol

This universal relief medication is capped in a number of This universal relief medication is capped in a number of markets, cap not adjusted for HFA change. markets, cap not adjusted for HFA change. ((egeg. India 80 . India 80 Rp Rp max retail price)max retail price)

•• MDI manufacturer faced with negative margin MDI manufacturer faced with negative margin business:business:

•• Cling onto CFCsCling onto CFCs•• Attempt to force component costs downAttempt to force component costs down•• Go for lower quality components?Go for lower quality components?•• Crunch coming?Crunch coming?

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Alcohol issuesAlcohol issuesTwo formulation routes to make HFA Two formulation routes to make HFA MDIsMDIs

•• HFA/ drugHFA/ drug•• HFA/alcohol/drug/HFA/alcohol/drug/……

•• Some drugs (Some drugs (salbutamolsalbutamol) can be done using either, ) can be done using either, some (especiallysome (especially preventers preventers like BDP) can only be done like BDP) can only be done with alcohol.with alcohol.

•• Generally alcohol technology is quicker, easier, Generally alcohol technology is quicker, easier, cheaper. cheaper. (Can have taste issues)(Can have taste issues)

•• BUT can cause problems in certain religious BUT can cause problems in certain religious environments environments ((eg eg Bangladesh)Bangladesh)

•• Could be some unexpected late adoption issuesCould be some unexpected late adoption issues

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Product ApprovalsProduct Approvals•• There are up to 15 different drugs/drug combinations There are up to 15 different drugs/drug combinations

that may need to be registered as their HFA that may need to be registered as their HFA replacements in each countryreplacements in each country

•• Some MDI manufacturers are still working on parts of Some MDI manufacturers are still working on parts of their rangetheir range

•• Approvals process typically takes 6Approvals process typically takes 6--12 months once 12 months once dossiers submitted to ministries of healthdossiers submitted to ministries of health

•• Uncertain when Uncertain when allall drugs and combinations will be drugs and combinations will be approved in approved in allall countriescountries

•• Could be post 2010Could be post 2010

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IP minefieldIP minefield•• There are over 150 different patent There are over 150 different patent familiesfamilies associated associated

with these changeswith these changes•• But most of the focus has been on EU/USABut most of the focus has been on EU/USA•• However, fear of IP has been a delaying factor in A5 However, fear of IP has been a delaying factor in A5

HFA MDI projects, mainly because it may forbid entry HFA MDI projects, mainly because it may forbid entry to lucrative western markets.to lucrative western markets.

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CFCs beyond 2010?CFCs beyond 2010?•• ““Was discussed in the recent SE Asia network meeting Was discussed in the recent SE Asia network meeting

in in ColumboColumbo•• Gas supply industry is very scepticalGas supply industry is very sceptical•• Could CFCs be made to Could CFCs be made to anyany sort of acceptable quality?sort of acceptable quality?•• Will other components be available?Will other components be available?•• IfIf this is required, storage of components and CFC for this is required, storage of components and CFC for

last years might be saferlast years might be safer