Communication from the Commission to the Council and the European Parliament - Strategy for the phaseout of CFCs in metered dose inhalers
Date: 1998-10-23
Institutions: European Commission
Subjects: medical device, medical research, medicinal product, public awareness campaign, stratospheric pollutant

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Communication  from  the  Commission  to  the  Council  and  the  European  Parliament:  Strategy
for  the  phaseout  of  CFCs  in  metered(cid:220)dose  inhalers

(98/C  355/02)

COM(1998)  603  final

CHAPTER  1

INTRODUCTION

1.1.(cid:218)(cid:217)Decision  IX/19  of  the  Parties  to  the  Montreal
Protocol  requires  Parties  requesting  essential  use  nomi(cid:220)
nations  for  chlorofluorocarbons  CFCs  for  metered(cid:220)dose
inhalers  (MDI)  to  present  to  the  Ozone  Secretariat  an
initial  national  or  regional  transition  strategy  if  possible
by  31  January  1998,  and  in  any  case  by  31  January  1999.
The  European  Community  is  a  Party  to  the  Montreal
Protocol,  and  this  document  is  its  transition  strategy
prepared 
in  accordance  with  decision  IX/19  of  the
Parties.  The  European  Community  believes  that  a  tran(cid:220)
sition  strategy  is  necessary  to  set  out  how  the  transition
out  of  CFCs  in  MDIs  is  to  be  managed  such  that  the
CFCs  can  be  phased  out  as  quickly  as  possible  without
putting  in  jeopardy  supplies  of  necessary  medicines  to
patients  in  need.

1.2.(cid:218)(cid:217)The  European  Community,  on  behalf  of  the
Member  States,  submits  a  joint  request  every  year  to  the
Parties  for  the  continued  use  of  CFCs  to  manufacture
MDIs.  Under  Regulation 
(EC)  No  3093/94  on
Substances  that  Deplete  the  Ozone  Layer,  the  European
Commission,  with 
the  assistance  of  a  Management
Committee  of  Member  States,  determines  every  year:

-(cid:217)the  essential  uses  which  shall  be  permitted  in  the

Community

-(cid:217)the  users  who  may  take  advantage  of  these  essential

uses

-(cid:217)the  quantities  of  CFCs  which  may  be  used  for

essential  uses

should 

also  be  managed  on 

Given  that  the  supply  of  CFCs  for  MDIs  is  managed  on
a  Community(cid:220)wide  basis,  the  transition  away  from  the
a
use  of  CFCs 
Community(cid:220)wide  basis.  As  far  as  possible,  the  approval
and  introduction  of  CFC(cid:220)free  products  and  the  with(cid:220)
drawal  of  CFCs  from  the  manufacture  of  MDIs  should
be  coordinated  across  the  Community.  This  will  prevent
any  part  of  the  Community  remaining  dependent  on
obsolete  CFC(cid:220)containing  medicines  long  after  the  rest  of
the  Community  has  moved  over  to  the  new  CFC(cid:220)free
products.

1.3.(cid:218)(cid:217)This  transition  strategy  draft  has  been  prepared
by  the  European  Commission  with  the  assistance  of  an
ad  hoc  working  group  comprising  representatives  of  the
Community’s  pharmaceutical  and  ozone  management
the
committees,  Member  State  Health  Authorities, 
European  Federation  of  Pharmaceutical 
Industries’
Associations  (EFPIA),  the  International  Pharmaceutical
Aerosols  Consortium  (IPAC),  the  Standing  Committee
of  European  Doctors, 
the  European  Federation  of
Asthma  and  Allergy  Associations  (EFA),  the  European
Chemical  Industry  Council  (CEFIC)  and  other  experts  in
the  field.  Detailed  comments  have  also  been  received  and
incorporated 
including
representatives  of  Nurses,  Pharmacists,  Asthma  Patients,
Doctors,  and  the  manufacturers  of  asthma  medicines
is  most  grateful  for  the
The  European  Commission 
invaluable  help  and  co(cid:220)operation  of  these  individuals  and
organisations  in  preparing  this  strategy.

from  many 

organisations 

CHAPTER  2

EXECUTIVE  SUMMARY

for 

strategy 

is  the  European  Community’s
2.1.(cid:218)(cid:217)This  document 
transition 
in
the  phaseout  of  CFCs 
metered(cid:220)dose  inhalers  (MDIs).  It  is  to  be  submitted  to
the  Parties  to  the  Montreal  Protocol  in  accordance  with
is  to
Decision  IX/19.  The  purpose  of  the  strategy 
describe  how  the  phaseout  of  CFC(cid:220)containing  MDIs  and
their  replacement  by  CFC(cid:220)free  MDIs  is  to  be  managed
in  the  Community.

in  MDIs 

2.2.(cid:218)(cid:217)The  phaseout  of  CFCs 
is  necessary
because,  under  the  Montreal  Protocol  on  substances  that
deplete  the  ozone  layer,  the  production  and  consumption
of  CFCs  is  now  banned  in  the  European  Community  and
throughout  the  developed  world.  Developing  countries
have  a  grace  period  under  which  the  production  and
consumption  of  CFCs  may  continue  to  meet  their  basic
domestic  needs.  Developing  countries  will  phase  out
these  substances  in  2010.

2.3.(cid:218)(cid:217)CFCs  are  still  currently  available  in  Europe  for
the  manufacture  of  MDIs  through  the  essential  uses
exemption.  This  permits  the  continued  production  and
use  of  CFCs  for  agreed  essential  uses  where  technical

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and  economically  feasible  alternatives  are  not  available.
treatment  of  asthma  and  chronic  obstructive
The 
pulmonary  disease  (COPD)  by  metered(cid:220)dose 
inhalers
containing  CFCs  has  been  acknowledged  as  an  essential
use  by  the  Parties  to  the  Montreal  Protocol.  Some
10(cid:216)000  tonnes  per  year  of  CFCs  are  used  world(cid:220)wide  to
manufacture  around  500  million  MDIs.

acceptable  alternatives  is  available.  The  number  of  alter(cid:220)
natives  required  before  CFCs  can  be  phased  out  varies
from  product  to  product  and  from  category  to  category,
depending  on  the  extent  and  pattern  of  use.

the 

the 

rules  of 

throughout 

2.4.(cid:218)(cid:217)Alternatives  to  CFC(cid:220)containing  MDIs  are  now
European
available 
becoming 
Community.  Suitable  alternatives 
include  dry  powder
inhalers  (DPIs)  and  MDIs  with  HFC  instead  of  CFC
propellant.  Under 
the  essential  uses
exemption,  CFCs  will  no 
longer  be  authorised  for
products  where  acceptable  alternatives  are  available.  In
some  parts  of  the  European  Community,  a  majority  of
patients  are  already  treated  with  DPIs  rather  than  MDIs.
Throughout  the  entire  Community,  CFC(cid:220)free  MDIs  are
now  being  introduced  such  that,  by  the  year  2003,  there
should  be  no  further  need  for  CFC(cid:220)containing  MDIs  in
the  Community.

authorisation 

the  proposed  alternative  product 

2.5.(cid:218)(cid:217)Before  CFC(cid:220)free  MDIs  can  be  prescribed  to
patients,  they  need  to  receive  marketing  authorisation
from  the  competent  authorities.  Such  authorisation  is
only  granted  when  the  competent  authority  is  satisfied
is  safe  and
that 
effective.  Obtaining  marketing 
for
CFC(cid:220)free  MDIs  across  the  entire  European  Community
is  currently  a  lengthy  process,  because  each  Member
State  conducts 
review  and  authorisation
procedures.  This  strategy  proposed  a  means  whereby
Member  States,  the  Commission  and  the  manufacturers
can  cooperate  to  streamline  the  approvals  procedure.  An
efficient,  streamlined  procedure  for  approving  CFC(cid:220)free
products  across  the  Community  is  an  important  and
necessary  part  of  the  strategy  to  phaseout  CFCs 
in
MDIs:  Competent  authorities  should  no 
longer  give
new  CFC(cid:220)containing
marketing 
inhalers.

authorisation 

its  own 

for 

2.6.(cid:218)(cid:217)While  the  early  phaseout  of  CFCs  is  important,  so
too  is  the  health  of  the  millions  of  patients,  including
children  and  the  elderly,  who  currently  depend  on  their
CFC  inhaler.  CFCs  should  only  be  withdrawn  once  these
patients  have  access  to  a  satisfactory  alternative.  This
strategy  confirms  the  commitment  of  the  European
Commission  to  safeguard  supplies  of  necessary  medicines
and  the  health  and  safety  of  patients  during  the  tran(cid:220)
sition.  This  is  to  be  done  by  ensuring  that  CFCs  will  only
be  withdrawn 
from  particular  CFC  products  or
categories  of  product  when  a  sufficient  number  of

2.7.(cid:218)(cid:217)The  strategy  recognises  that  there  are  differences
between  Member  States  regarding  the  CFC  products
prescribed,  the  balance  between  DPIs  and  MDIs,  and
the  number  of  products  which  will  require  alternatives.
Nevertheless,  there  are  important  similarities  for  some  of
the  most  widely(cid:220)prescribed  products,  and  it  is  likely  that
the  transition  out  of  CFC(cid:220)MDIs  will  occur  quickly
across 
the  entire  Community  once  alternatives  are
available  for  the  main  types  of  inhaler.  Where  particular
problems  persist,  small  quantities  of  CFCs  for  specific
MDI  products  may  be  authorised  as  part  of  the  annual
Commission  decision  in  essential  uses  in  the  Community.

2.8.(cid:218)(cid:217)The  European  Community  is  a  major  exporter  of
CFC(cid:220)containing  MDIs  to  both  developed  and  developing
countries.  These  exports  will  need  to  continue  even  after
the  transition  has  been  accomplished  in  the  Community
in  order  to  ensure  that  patients,  especially  in  developing
countries,  are  not  deprived  of  essential  medicines.  MDI
manufacturers  based  in  the  European  Community  are
expected  to  help  promote  the  transition  away  from
CFC(cid:220)containing  MDIs  in  their  export  markets.  They
should  ensure  that,  wherever  possible,  patients  relying  on
MDIs  produced  in  Europe  are  given  access  to  CFC(cid:220)free
inhalers  and  thereby  benefit  from  the  experience  of  tran(cid:220)
sition  in  Europe.

inhaler  given  sufficient 

2.9.(cid:218)(cid:217)Patients  are  at  the  centre  of  the  transition  and
need  to  be  fully  aware  of  the  issues  involved.  Most  if  not
all  patients  will  successfully  switch  from  a  CFC  inhaler
to  a  CFC(cid:220)free 
information,
advice  and  help.  Information  needs  to  be  coordinated  to
ensure 
that  doctors,  other  health  professionals  and
patients’  associations  provide  accurate,  coherent  and
useful  information  to  patients  before,  during  and  after
transition.  Wherever  possible,  new  patients  should  be
started  on  CFC(cid:220)free  inhalers,  and  manufacturers  should
no  longer  develop  and  market  new  inhalers  containing
CFCs.

2.10.(cid:218)(cid:217)The  Community’s  annual  essential  use  nomi(cid:220)
nation  for  CFCs  to  UNEP  will  be  based  on  the  best
available  forecasts  of  the  future  availability  of  alter(cid:220)
natives  -  the  so(cid:220)called  "targets  and  timetables’  approach.
Through  its  decision  on  essential  uses  each  year,  the

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Commission  will  ensure  that  CFCs  remain  available  for
those  products  where  they  are  still  required,  but  are  not
authorised  for  products  where  acceptable  alternatives  are
available.  In  this  way,  and  with  the  co(cid:220)operation  and
involvement  of  Member  States,  MDI  manufacturers,
patients  and  health  professionals,  the  phaseout  of  CFCs
in  MDIs  in  the  European  Community  can  take  place
quickly  and  smoothly  while  safeguarding  the  health  and
safety  of  patients.

CHAPTER  3

CFCS  AND  MDIs

incidence  of  asthma 

is  around  5(cid:220)8(cid:216)%  of 

3.1.(cid:218)(cid:217)CFC(cid:220)containing  MDIs  have  proved 
to  be  a
low(cid:220)cost,  effective  and  reliable  means  to  respiratory
such  as  asthma  and  chronic  obstructive
diseases 
(COPD).  These  medicines  are
pulmonary  disease 
in  developed
important  as  the 
countries 
the  population  and
increasing  at  an  average  rate  of  around  5(cid:216)%  per  year.
On  average  throughout  the  European  Community,  some
80(cid:216)%  of  inhaled  medicines  are  delivered  by  MDIs,  with
the  rest  delivered  by  dry  powder  inhalers  (DPIs)  and
nebulisers.  There  are  currently  some  500  million  MDIs
used  annually  worldwide,  resulting 
the  use  and
emission  of  around  10(cid:216)000  tonnes  CFCs  per  year.  In
general,  CFC  12  is  used  as  a  propellant  in  the  MDIs,  and
CFC  11  or  CFC  114  is  used  to  dissolve  or  suspend  the
drug  being  delivered  to  the  patient.

in 

3.2.(cid:218)(cid:217)CFCs  released  to  the  atmosphere  eventually  find
their  way  up  to  the  stratosphere  where  they  destroy  the
ozone 
layer  which  protects  the  earth’s  surface  from
harmful  ultra(cid:220)violet  radiation.  During  the  last  few  years,
the  ozone  layer  has  been  severely  depleted,  both  over  the
Antarctic  region  where  the  "ozone  hole’  now  appears
annually,  but  also  over  the  northern  hemisphere.  Ozone
depletion  up  to  40(cid:216)%  has  been  recorded  in  each  of  the
last  three  years  over  Northern  Europe.

3.3.(cid:218)(cid:217)In  order  to  prevent  the  destruction  of  the  earth’s
ozone  layer,  the  international  community  has  agreed  a
Convention 
(the  Vienna  Convention,  1985)  and  a
Protocol  (the  Montreal  Protocol,  1987).  The  Montreal
Protocol 
the
production  and  consumption  of  substances  which  destroy
the  ozone  layer.  It  is  therefore  vital  for  those  industries
which  use  CFCs  to  find  alternatives  as  quickly  as
possible.

the  progressive  phaseout  of 

requires 

3.4.(cid:218)(cid:217)Under  the  Montreal  Protocol,  the  production  and
in  developed
consumption  of  CFCs  was  phased  out 

countries  from  1  January  1996.  This  phaseout  occurred
one  year  earlier  in  the  European  Community.  However,
under  the  Montreal  Protocol,  temporary  exceptions  to
the  phaseout  can  be  made  under  the  "essential  uses’
procedure.  This  procedure  provides  that  a  particular  use
of  CFCs  may  be  declared  "essential’  where:

(a)(cid:217)it  is  necessary  for  the  health,  safety  or  is  crucial  for
the  functioning  of  society  (encompassing  cultural
and  intellectual  aspects);  and

(b) there  are  no  available  technically  and  economically
feasible  alternatives  or  substitutes  that  are  acceptable
from  the  standpoint  of  environment  and  health

Further,  the  production  and  consumption  of  CFCs  for
essential  uses  may  be  permitted  only  if:

(a)(cid:217)all  economically  feasible  steps  have  been  taken  to
the  essential  use  and  any  associated

minimise 
emissions  of  the  controlled  substance;  and

(b) the  controlled  substance  is  not  available  in  sufficient
quantity  and  quality  from  existing  stocks  of  banked
or  recycled  controlled  substances,  also  bearing  in
mind  the  developing  countries’  need  for  controlled
substances  (Decision  IV/25  of  the  Parties  to  the
Montreal  Protocol).

3.5.(cid:218)(cid:217)The  use  of  CFCs  for  the  manufacture  of  MDIs
has  qualified  for  essential  use  status  since  the  initial
is  because  the  provision  of
phaseout  of  CFCs.  This 
asthma  medication  is  clearly  necessary  to  the  health  of
society,  and,  at  least  until  recently,  no  technically  and
economically  feasible  alternatives  or  substitutes  to  CFCs
have  been  available.  The  following  quantities  of  CFCs
have  been  approved  by  the  Parties  for  the  manufacture
of  MDIs  in  the  European  Community:

Year  of  use

Tonnes  of  CFCs
approved  by  the  Parties

1996
1997
1998
1999

7(cid:216)546
6(cid:216)635
5(cid:216)610
5(cid:216)000

pharmaceutical 

3.6.(cid:218)(cid:217)Since  the  phaseout  of  CFCs  was  first  agreed,  the
international 
been
researching  into  alternative  substances  to  use  in  MDIs.
is  that  some  technically  an  economically
The  result 
feasible  alternatives  to  CFCs  now  exist  and  are  becoming
increasingly  available  for  the  successful  treatment  of
some  types  of  asthma  and  COPD.  The  increased  avail(cid:220)

industry 

has 

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alternatives  will  mean 

technically  and  econ(cid:220)
ability  of  clinically  effective, 
omically 
that,
feasible 
progressively,  CFCs  will  no  longer  meet  the  essential  use
criteria  under  the  Montreal  Protocol  and  will  therefore
no  longer  be  authorised  for  the  manufacture  of  those
types  of  MDI  for  which  alternatives  exist.

of 

to  phasing  out 

committed 
consumption 

3.7.(cid:218)(cid:217)All  the  signatories  to  the  Montreal  Protocol,
the  European
including  all 
the  Member  States  of 
Community,  are 
the
ozone(cid:220)depleting
production 
and 
this
substances  as  quickly  as  possible.  Part  of 
commitment  includes  minimising  exemptions  from  the
Protocol  under  the  essential  uses  procedures.  Therefore,
the  European  Commission  and  Member  States  will  be
seeking  early  opportunities  to  reduce  the  quantities  of
CFCs  approved  for  use  in  the  manufacture  of  MDIs  in
the  European  Community.  Equally,  however,  all  those
involved  recognise  an  equally  important  obligation  to
ensure  that  asthma  and  COPD  patients  continue  to
receive 
the
following  principles  have  been  agreed  to  guide  the  phase
out  of  CFCs  in  MDIs:

they  require.  Therefore, 

the  medicines 

Principle  1:  That  all  those  involved  will  promote  the
transition  to  non(cid:220)CFC  alternatives

Principle  2:  That  the  health  and  safety  of  patients  during
the  transition  will  be  safeguarded

Principle  3:  That  the  nomination,  approvals  and  licensing
systems  will  be  operated  with  efficiency,  consistency  and
transparency.

3.8.(cid:218)(cid:217)This  draft  strategy  sets  out  a  policy  for  the
management  of  the  transition  out  of  CFC(cid:220)containing
inhalers  based  on  these  three  principles.  In  particular,  the
strategy;

-(cid:217)reviews  current  and  future  demand  for  asthma  and

COPD  therapy  in  the  European  Community

-(cid:217)summarises  current  progress  in  the  development  of
alternatives  to  CFC  inhalers,  including  forecasts  of
the  rate  of  introduction  of  alternatives

-(cid:217)sets  out  a  policy  to  facilitate  the  efficient  and  fast
review  and  approval  of  non(cid:220)CFC  alternatives
throughout  the  European  Community  as  a  whole

-(cid:217)sets  out  an  aproach  to  pharmacovigilance  and  safety
monitoring  of  the  new  products  to  ensure  that  patient
safety  is  maintained

-(cid:217)sets  out  a  procedure  by  which  CFCs  can  be
progressively  phased  out  as  alternative  medicines  and
treatments  become  available

-(cid:217)makes  recommendations  to  raise  the  awareness  of
doctors  and  patients  and  to  promote  the  rapid  and
successful  acceptance  of  CFC(cid:220)free  medicines

-(cid:217)considers  how  to  treat  MIDs  manufactured  in  the
European  Community  for  export,  particularly 
to
developing  countries

-(cid:217)reviews  the  continued  production  and  supply  of

CFCs  in  the  EC  during  the  transition

3.9.(cid:218)(cid:217)The  European  Community  is  the  world’s  largest
manufacturer  of  MDI 
inhalers,  25(cid:216)%  of  which  are
exported.  This  means  that  we  have  a  particular  responsi(cid:220)
bility 
to  develop  and  promote  environmentally  safe
inhalers  while,  at  the  same  time,  meeting  the  needs  of
patients  throughout  the  world  who  depend  on  our
products.  This  strategy  puts  forward  a  means  through
which  both  these  responsibilities  can  be  met,  and  the
transition  away  from  CFCs  be  successfully  managed
the  European
across  all 
Community.

the  Member  States  of 

CHAPTER  4

PATIENT  NEEDS

is 

4.1.(cid:218)(cid:217)The  prevalence  of  asthma  and  chronic  obtructive
pulmonary  disease  (COPD) 
increasing  world(cid:220)wide.
There  are  at  least  25  million  people  with  asthma  in
Europe.  The  prevalence  of  asthma  has  risen  over  the  last
20  years,  especially  amongst  children  where 
it  now
approaches  15(cid:216)% 
in  Western  Europe.  Asthma  has
enormous  health  and  economic  costs  and  is  probably
responsible  for  16(cid:216)000  deaths  per  year  in  Europe.  The
incidence  of  COPD  is  related  to  tobacco  smoking,  and
affects  20(cid:220)30  million  adults  in  Europe.  While  levels  are
relatively  static 
in  females
following  the  increase  in  smoking  in  European  women.
It  is  estimated  that  COPD  accounts  for  over  5(cid:216)%  of  all
deaths  in  Europe.

in  men,  they  are  rising 

4.2.(cid:218)(cid:217)It  is  likely  that  the  prevalence  and  diagnosis  of
asthma  and  COPD  will  continue  growing  in  the  EC  over
the  next  decade.  In  addition,  there 
is  considerable
potential  for  increased  prescription  of  inhaled  therapy
for  both  conditions  in  a  number  of  Member  States  as
international  treatment  guidelines  are  implemented  more
widely  than  at  present.  For  these  reasons,  IPAC  has
forecast  that  annual  usage  of  MDIs  in  the  European
Community  may  increase  by  5(cid:216)%  per  year  between  now
and  2010.  This  growth  rate  assumes  that  there  will  be
increased  usage  of  DPIs  and  other  new 
types  of
non(cid:220)MDI  inhalers,  as  well  as  a  potential  increase  in  the
use  of  newer  oral  therapies  for  some  patients.

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4.3.(cid:218)(cid:217)There  is  international  (WHO/GINA)  consensus
that  the  primary  treatment  of  these  diseases  should  be  by
the  inhaled  route.  This  permits  treatment  to  be  delivered
quickly  and  efficiently  to  the  airways,  with  minimal  risk
regular
of  adverse 
treatment,  often  with  more  than  one  medicine.  Inhaled
therapy  is  delivered  mainly  by  Metered(cid:220)dose  inhalers
(MDIs)  or  Dry  Powder  Inhalers 
less
commonly  by  nebulisers.

reactions.  Therapy  necessitates 

(DPIs)  and 

Categories  of  drugs  used  for  asthma/COPD

4.4.(cid:218)(cid:217)It  is  possible  to  recognise  the  following  categories
treatment  of
of  drugs 
asthma/COPD:

currently  used 

the 

for 

Scandinavia  and  the  Netherlands,  there  is  far  greater  use
of  DPIs  (up  to  85(cid:216)%).  MDIs  are  an  inexpensive,  reliable
and  effective  therapy  for  respiratory  diseases.  Currently,
some  500  million  MDIs  are  used  annually  world(cid:220)wide,
mainly  in  developed  countries.  Of  these  approximately
200  million  are  made  in  Europe  requiring  during  1997
the  use  of  some  6(cid:216)635  tonnes  of  CFCs.

4.7.(cid:218)(cid:217)CFC(cid:220)containing  MDIs  have  a  forty  year  record
of  safety  and  efficacy.  They  are  designed  to  deliver  drugs
in  an  appropriate  particle  size  to  target  the  lung  airways.
Reproducing 
in  reliable,  safe  and
effective  MDIs  without  CFCs  has  proved  to  be  a  tough
technical  challenge.

the  particle  size 

Category  A:  Short  acting  beta  agonist  bronchodilators,
such  as  salbutamol,  terbutaline,  fenoterol

Alternatives  to  MDIs

Category  B:  Inhaled  Steroids,  such  as  beclomethasone,
budesonide,  fluticasone,

Category  C:  Non  Steroidal  anti(cid:220)inflammatories,  such  as
cromoglycate,  nedocromil

Category  D:  Anticholinergic  bronchodilators,  such  as
ipratropium,  oxytropium

Category  E:  Long  acting  beta  agonists  bronchodilators;
salmeterol,  formoterol

Category  F:  Combination  products  containing  two  or
more  different  active  substances

4.5.(cid:218)(cid:217)It  is  important  to  realise  that  categories  A  and  B
combined  account 
for  approximately  80(cid:216)%  of  CFC
MDIs  currently  used  in  Europe.  For  these  categories  A
and  B,  there  are  several  different  active  substances  and
alternative  brands  available 
the  most  widely
prescribed  products,  but  in  other  categories  there  may  be
no  more  than  one  or  two  brands  or  products  which
require  substitution  by  a  non(cid:220)CFC  product.

for 

MDIs

4.6.(cid:218)(cid:217)The  predominant  form  of  inhaled  therapy  in  most
of  Europe  is  the  MDI  which  accounts  for  approximately
80(cid:216)%  of  prescribed  inhalers.  The  remaining  20(cid:216)%  are
mainly  DPIs,  together  with  a  much  smaller  proportion  of
nebulised  drugs.  However  in  some  countries,  especially

Inhalers 

inhaled  therapy 

(DPIs):  Although 

the
4.8.(cid:218)(cid:217)Dry  Powder 
is  traditionally
European  market  for 
dominated  by  MDIs,  almost  all  active  substances  are  also
available  in  DPI  formulations.  The  impending  ban  on
CFCs  in  the  1980’s  led  to  considerable  innovation  in  DPI
technology  and,  in  particular,  to  the  transition  from
systems.  These
single(cid:220)dose  DPIs 
new(cid:220)generation  multidose  DPIs  can,  like  MDIs,  deliver
up  to  200  doses.  Multidose  DPIs  are  now  quite  widely
available  (as  Turbuhaler,  Easyhaler  and  Accuhaler,  for
example),  and  can 
in  many  respects  be  considered
equivalent  to  MDIs.

to  multidose 

4.9.(cid:218)(cid:217)As  a  result  of  developments  such  as  these,  DPI
use  has  increased,  but  since  the  overall  use  of  inhaled
therapy  has  increased  further,  the  greater  use  of  DPIs
has  not  reduced  the  sales  of  MDIs.  Penetration  of  DPIs
into  a  market  depends  on  their  acceptance  by  health
professionals  and  patients  and  also  on  their  cost.  In  some
countries,  especially  Scandinavian  countries  where  action
has  been  taken  by  governments  to  support  the  transition
from  MDIs  to  DPIs,  the  DPIs  dominate  the  market.  In
other  countries,  DPIs  can  often  be  considerably  more
expensive 
than  cheaper  generic  MDIs.  A  complete
change  from  MDIs  to  DPIs  in  such  countries  would
increase  the  costs  of  inhaled  medicines.  New  DPIs  are
likely  to  be  introduced  over  the  next  few  years  which
may  be  cheaper  and  will  increase  patient  choice.  DPIs
may  become  an  increasingly  appropriate  and  accepted
alternative 
for  new  patients,
although,  they  are  not  suitable  for  all  patients  (for
example  some  very  young  children  may  experience  diffi(cid:220)
culties).  Nevertheless,  the  wide  range  of  available  DPIs
provides  a  safety  back(cid:220)up  during  transition  to  CFC(cid:220)free
MDIs  and  provides  additional  options  for  patients.

for  MDIs,  especially 

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4.10.(cid:218)(cid:217)As  far  as  DPIs  are  concerned,  products  are
already  available  in  each  category  such  as  the  following:

Category  A:  Salbutamol  (DiskhalerTM,  DiskusTM,  Rota(cid:220)
halerTM,  EasyhalerTM);  terbutaline  (TurbuhalerTM)

Category  B:  Beclomethasone 
Easyhaler); 
(Diskhaler)

budesonide 

(Rotahaler,  Diskhaler,
fluticasone

(Turbuhaler); 

Category  C:  Cromoglycate  (Spinhaler)

Category  D:  Ipratropium  (Aerohaler)

Category  E:  Salmeterol  (Diskhaler,  Diskus,  formoterol
(Turbuhaler,  Aerolizer)

This  suggests  that,  subject  to  greater  acceptance  by
doctors  and  patients,  and  given  sufficient  manufacturing
capacity,  there  may  be  scope  for  an  increase  in  the
numbers  of  patients  treated  by  DPIs  rather  than  by
MDIs.  This  of  itself  would  contribute  to  reducing  the
current  use  of  CFCs  in  the  treatment  of  asthma  and
COPD.

4.11.(cid:218)(cid:217)Nebulisers:  These  devices  produce  aerosols  by
agitation  of  solutions,  and  account  for  1(cid:220)2(cid:216)%  of  the
market.  They  are  generally  reserved  for  patients  with
special  needs,  such  as  very  young  babies  or  patients  with
severe  disease,  who  need  much  higher  doses  of  active
substance.  They  are  currently  an  expensive  form  of
inhaled  therapy,  but  new  devices  may  make  this  a  more
viable  option  in  the  future.

4.12.(cid:218)(cid:217)New  Oral  Therapy:  A  novel  tablet  (leukotriene
modifier)  for  the  treatment  of  asthma  is  currently  under
regulatory  review  in  Europe.  This  type  of  oral  therapy
may  be  of  value  to  some  asthma  patients,  but  is  highly
unlikely  to  become  a  significant  substitute  for  the  current
inhaled  preventative  therapy.  The  mainstay  of  therapy
for  asthma/COPD  is  likely  to  remain  that  administered
by  the  inhaled  route.

MDIs  Reformulated  Without  CFCs

4.13.(cid:218)(cid:217)As  a  result  of  a  major  research  and  development
effort,  pharmaceutical  companies  have  made  good
progress  in  developing  CFC(cid:220)free  MDIs.  In  March  1995,
Europe’s  first  approval  for  a  CFC(cid:220)free  MDI  was  granted
to  3M  in  the  UK  for  its  product  "Airomir’,  a  salbutamol
product  reformulated  with  HFC(cid:220)134a  propellant.  By
September  1997,  this  product  had  been  approved  for  use
in  over  40  countries  and  in  nearly  all  the  Member  States
the  European  Community.  Glaxo  Wellcome  has
of 

recently 
"Ventolin’
launched  CFC(cid:220)free  versions  of 
(salbutamol)  and  the  first  reformulated  inhaled  steroid
"Flixotide’  (fluticasone)  in  some  Member  States.  Other
companies  have  also  submitted  applications  to  market
CFC(cid:220)free  inhalers,  and  further  approvals  are  anticipated
during  1998  and  beyond.  It  is  therefore  expected  that,
during  the  course  of  1998,  two  salbutamol  CFC(cid:220)free
MDIs  will  become  available  in  a  number  of  countries,
including  a  number  of  EC  Member  States.

launched  by  the  year  2000.  It 

(International  Pharmaceutical  Aerosols
4.14.(cid:218)(cid:217)IPAC 
Consortium)  predicted  in  January  1997  that,  in  Europe,
between  36  and  42  HFC  MDI 
"entities’  (individual
individual  brands)  would  be
dosage  formulations  of 
reformulated  and 
is
anticipated  that  at  least  two  salbutamol  CFC(cid:220)free  MDIs
could  be  available  throughout  the  EC  by  the  end  of
1998.  Since  salbutamol  MDIs  are  estimated  to  comprise
half  the  total  use  of  MDIs,  the  potential  exists  for  a
significant  reduction  in  consumption  of  CFCs  in  1999.
This  is  dependent  on  regulatory  and  pricing  approval,
good  acceptance  and  uptake  by  patients  and  physicians,
and  the  consequent  timely  phaseout  of  CFC  inhalers.  In
addition,  two  or  more  CFC(cid:220)free  inhaled  steroids  should
be  available  in  some  Member  States  by  1998.  Reformu(cid:220)
lation  efforts  for  most  of  the  remaining  inhaled  medi(cid:220)
cations  are  well  advanced,  using 
the  propellants
HFC(cid:220)134a  and  HFC(cid:220)227.  Alternative  technologies  such
as  portable  hand(cid:220)held  nebulisers  are  also  being  evaluated.

Experience  to  date

into 

salbutamol 

in  Germany  with  a 

than  unbranded  CFC 

4.15.(cid:218)(cid:217)Almost  two  years  after  the  introduction  of  the
first  CFC(cid:220)free  salbutamol  MDI 
the  European
Community,  it  had  only  reached  1,5(cid:216)%  market  share.
Factors  influencing  the  slow  uptake  of  this  CFC(cid:220)free
product  might  include  lack  of  incremental  benefit  to
patients,  apathy  of  physicians  to  environmental  benefits,
continued  easy  availability  of  CFC(cid:220)products  and  higher
cost 
products.
Experience 
second  CFC(cid:220)free
salbutamol  product  is  more  encouraging.  Three  months
after  the  launch  it  has  achieved  considerable  success,  but
to  maintain  the  growth  in  uptake,  the  manufacturer
intends  voluntarily 
the  CFC  version.
to  withdraw 
However,  it  is  unlikely  that  voluntary  action  by  manu(cid:220)
facturers  and  education  programmes  alone  will  produce
a  significant  switch  away  from  CFC  products  in  the
absence  of  a  clearly  defined  and  properly  implemented
transition  policy.  This  needs  to  be  accompanied  by  a
clear  message 
health
physicians 
professionals  that  the  transition  is  not  optional.  Where  a
CFC(cid:220)free  alternative  is  available  and  suitable,  it  should
be  prescribed  in  favour  of  the  CFC  product  unless  this
would  compromise  patient  treatment.

other 

and 

to 

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Considerations  in  devising  a  transition  strategy

4.16.(cid:218)(cid:217)A  number  of  factors  have  been  considered  when
developing  a  European  transition  strategy.  In  particular,
before  the  use  of  CFCs  can  be  phased  out  in  the  manu(cid:220)
facture  of  MDIs:

-(cid:217)a  sufficient  number  of  clinically  effective,  technically
and  economically 
(including
DPIs)  needs  to  be  available  to  ensure  an  uninter(cid:220)
rupted  supply  of  medication.

feasible  alternatives 

5.3.(cid:218)(cid:217)The  first  step  in  this  reseach  was  to  identify
propellants  which  could  be  substitutes  for  CFCs.  The
principal  criteria  for  successful  MDI  propellants  are  the
following:

-(cid:217)a  liquefied  gas  of  very  low  toxicity,  non(cid:220)flammable

and  chemically  stable,

-(cid:217)acceptable  to  patients  in  terms  of  taste  and  smell,

-(cid:217)possessing  appropriate  solvent  characteristics  and  a

suitable  density.

-(cid:217)a  sufficient  period  of  post(cid:220)marketing  surveillance  of
the  reformulated  products  has  to  be  carried  out.

-(cid:217)there  needs  to  be  sufficient  choice  of  alternatives
available  to  meet  the  needs  of  different  patient
sub(cid:220)groups.

Other  considerations  include  sufficient  commercial  avail(cid:220)
ability  of  the  proposed  propellant,  whether  it  can  be
made  sufficiently  pure  for  pharmaceutical  use,  and  its
continued  future  availability  in  quantities  sufficient  to
meet  patient  needs.  It  has  been  extremely  difficult  to
identify  a  single  compound  which  meets  all  of  these
criteria.

CHAPTER  5

DEVELOPING  ALTERNATIVES
TO  CFC(cid:220)CONTAINING  MDIs

Current 
nebulisers

treatment  by 

inhalation:  MDIs,  DPIs  and

5.1.(cid:218)(cid:217)The  three  main  types  of  inhaled  treatment  for
respiratory  disease  include  MDIs,  DPIs  and  nebulisers.
Each  type  presents  certain  advantages  and  disadvantages.
Efforts  are  being  made  to  overcome  disadvantages,  for
example  by 
in  DPIs  to
improving  powder  delivery 
facilitate  their  use  by  small  children  and  the  elderly.
However,  nebulisers  and  DPIs  are  not  interchangeable
with  MDIs  for  all  patients.  It 
is  vital  to  develop
CFC(cid:220)free  MDIs  with  the  same  advantages  for  patients  as
the  current  CFC(cid:220)containing  MDIs  but  without  the  disad(cid:220)
vantage  of  depleting  the  ozone  layer.

Developing  non(cid:220)CFC  MDIs

5.2.(cid:218)(cid:217)The  pharmaceutical  industry  has  put  significant
resources 
into  researching  and  developing  CFC(cid:220)free
MDIs.  More  than  70  separate  programmes,  involving
1(cid:216)400  scientists  and  90 
in  10  countries
around  the  world,  have  been  involved  in  reformulating
MDIs  with  alternative  propellants.  Investment  to  date  in
this  task  by  the  pharmaceutical 
industry  world(cid:220)wide
exceeds  1  billion  ECUs.

laboratories 

extensive 

research(cid:216)(˛)  HFC(cid:220)134a 

and
5.4.(cid:218)(cid:217)After 
HFC(cid:220)227  have  been  identified  as  the  only  real  alter(cid:220)
natives  to  CFCs  for  MDI  use.  They  are  non(cid:220)flammable,
safe  for  human  inhalation  and  have  the  required  vapour
pressure  and  density  for  MDI  usage.  HFCs  have  zero
ozone(cid:220)depleting  potential,  but  both  HFC(cid:220)134a  and
HFC(cid:220)227  are  greenhouse  gases  and  part  of  the  basket  of
gases  whose  emissions  must  be  reduced  under  the  Kyoto
Climate  Change  Protocol.  However,  both  these  HFCs
have  a  lower  global  warming  potential  (GWP)  than  the
CFCs  which  they  replace.  For  example,  HFC(cid:220)134a,  the
most  frequently  chosen  replacement  propellant,  has  a
GWP  of  1(cid:216)300,  compared  with  CFC  12  which  has  a
GWP  of  8(cid:216)500.  Note  that,  as  a  point  of  reference,  the
GWP  of  CO2  (cid:216)is  1.  Therefore,  a  change  from  CFCs  to
HFCs  as  propellants  in  MDIs  will  contribute  to  reducing
both  ozone  depletion  and  greenhouse  gas  emissions  in
the  future.  Nevertheless,  there  remains  scope  to  continue
research  into  products  which  have  even  less  environ(cid:220)
mental  impact.

5.5.(cid:218)(cid:217)Once  identified  as  possible  CFC  substitutes  on  the
their  chemical  characteristics,  HFCs  were
basis  of 
subjected  to  extensive  research  and  testing.  In  January
1989, 
its  own
consortium  (ultimately  known  as  IPAC),  and  began  toxi(cid:220)
cology  testing  of  propellants  for  pharmaceutical  usage.

the  pharmaceutical 

industry  set  up 

(˛)(cid:217)Studies  have  been  carried  out  to  determine  whether  any
compounds  other  than  HFCs  could  be  substituted  for  CFCs
in  MDI  usage.  Some  15(cid:216)000  compounds  have  been  reviewed
in  light  of  the  various  criteria  set  out  above  but  none  of
them,  with 
to  be  a
promising  CFC  substitute.

the  exception  of  HFCs,  appears 

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These  testing  programmes,  designed  to  meet  world(cid:220)wide
regulatory  requirements,  including  those  of  the  US,  the
EC  and  Japan,  were  substantially  completed  by  the  end
of  1995,  and  concluded 
that  both  HFC(cid:220)134a  and
HFC(cid:220)227  were  safe  for  use  in  MDIs.  The  Committee  on
Proprietary  Medicinal  Products 
the
European  Community  assessed  both  propellants  as
suitable  alternatives 
for
for  CFCs 
HFC(cid:220)134a  and  in  September  1995  for  HFC(cid:220)227),  subject
to  completion  of  additional 
the
medicinal  products  concerned.

(CPMP)  of 

studies  on 

July  1994 

safety 

(in 

to 

reformulate 

their  MDIs  using 

5.6.(cid:218)(cid:217)Having  identified  HFCs  as  the  best  alternative  to
CFCs  and  shown  that  they  have  no  adverse  toxicological
effects,  the  second  step  was  for  the  pharmaceutical
these
industry 
propellants.  In  the  EC,  the  European  Commission  has
published  guidelines  on  the  replacement  of  CFCs 
in
medicinal  products(cid:216)(˛).  These  identify  the  questions  of
product  efficacy,  safety  and  quality  which  must  be  taken
they  prepare
into 
submissions 
for  marketing  authorisation  of  products
containing  alternative  propellants.  A  guideline  on  post(cid:220)
marketing 
prepared
has 
(CPMP/180/95).

companies  when 

account  by 

surveillance 

been 

also 

formulations  have 

involved  several
5.7.(cid:218)(cid:217)The  reformulation  effort  has 
steps  in  order  to  fulfill  the  regulatory  guidelines  and
create  replacement  products  which  are  comparable  in  all
respects  to  the  existing  ones.  First,  there  is  intensive
research  and  testing  to  identify  and  develop  new  formu(cid:220)
lations  of  the  active  anti(cid:220)asthmatic  drugs  with  the  new
HFC  propellants.  Such 
to  meet
rigorous  quality  criteria,  for  example,  with  respect  to
accurate  dose  reproducibility  throughout  the  life  of  an
MDI,  and  maintenance  of  a  consistent  particle  size
distribution  in  the  spray.  Next,  the  components  of  the
primary  packaging  (metal  cans,  valves,  elastomers  and
actuators)  have  to  be  redeveloped  to  be  compatible  with
the  new  propellant  and 
formulation.  Toxicological
studies  are  carried  out  on  the  final  formulation  (which
possibly  contains  new  inactive  ingredients)  before,  or  in
parallel  with,  stability  testing  of  the  new  MDI.  The  latter
is  undertaken  to  ensure  that  quality  is  maintained  over
the  entire  shelf(cid:220)life  of  the  new  product.  Finally,  clinical
studies  are  carried  out  on  the  new  product,  over  a
treatment  period  of  up  to  one  year,  to  demonstrate  that
it  is  as  safe  and  effective  as  the  CFC  product.

Difficulties  encountered  in  reformulating  MDIs

5.8.(cid:218)(cid:217)The  reformulation  of  CFC  MDIs  has  proved  to
be  much  more 
than  originally
technically  difficult 
envisaged.  In  addition  to  the  complexity  of  identifying
and  testing  alternative  propellants,  the  pharmaceutical
industry  has  encountered  a  number  of  other  challenges
its  reformulation  efforts.  For  example,  the  usual
in 
in  CFC  MDIs  are  generally  not
surfactants  used 
compatible  with  HFCs.  New  surfactants, 
lubricating
agents  and  co(cid:220)solvents  had  to  be  identified.  Some  valve
elastomers  are  affected  by  HFCs  and  do  not  function
with  sufficient  reliability  so  new  elastomers  had  to  be
developed.  In  some  cases  actuators  had  to  be  redesigned
together  with  the  manufacturing  process  to  accom(cid:220)
modate  the  more  volatile  HFC  propellants,  sometimes
facilities  and
involving  building  new  manufacturing 
finding  new  manufacturers  of  components.

5.9.(cid:218)(cid:217)It  is  only  after  reformulation  and  clinical  testing
have  been  successfully  completed  that  the  regulatory
review  phase  can  begin,  encompassing  pharmaceutical
safety  and  efficiency  assessments  of  the  data  submitted
by  companies  against  the  guidelines  described  earlier.  A
new  marketing  authorisation  would  be  required  from  the
appropriate  regulatory  authorities,  where  the  MDI  is
fundamentally  altered  by  the  change  in  propellant  and
the  formulation  and  manufacturing
modifications 
to 
fundamental;  a
the  change 
process.  Where 
national  variation  procedure  may  be  used.  Efforts  are
ongoing  to  enable  CFC(cid:220)free  MDIs  to  be  approved  as
rapidly  as  possible  by  all  the  Member  States  of  the  EC
(see  Chapter  6).  Regulatory  authorities  must  also  review
pricing  and  reimbursement  of  CFC(cid:220)free  MDIs,  as  price
differentials  can  significantly 
influence  acceptance  by
patients  and  prescribers.

is  not 

Prioritizing  reformulation  efforts

in  respect  of  each  of 

5.10.(cid:218)(cid:217)Although  the  decision  to  reformulate  a  specific
MDI  product  is  taken  by  each  individual  pharmaceutical
its  CFC  MDIs,  the
company 
the 
priorities  are  common 
industry.  In
throughout 
general,  each  company  has  focused 
its  reformulation
efforts  on  the  MDI  products  which  are  the  most
commonly  prescribed  and  which  use  the  most  CFCs.
Products  which  are  used  less  frequently  are  the  second
priority,  even  though  these  MDIs  may  be  important  for
certain  patient  sub(cid:220)groups.

(˛)(cid:217)Note  for  Guidance  Replacement  of  Chlorofluorocarbons
(CFCs)  in  metered(cid:220)dose  inhalation  products  (III/5378/93  -
final).  CPMP  Cover  note  -  Matters  relating 
the
replacement  of  CFCs  in  medicinal  products  (III/5462/93  -
final  rev.  1).

to 

5.11.(cid:218)(cid:217)In  addition  to  the  above  considerations,  the
pharmaceutical  industry  is  limited  by  the  technical  feasi(cid:220)

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bility  of 
reformulating  MDIs.  Particular  molecules
and/or  dosage  strengths  may  be  more  difficult  than
others  to  reformulate.  Failure  to  satisfy  product  quality
criteria  fully  could  necessitate  multiple  attempts  at  refor(cid:220)
mulation  and  testing.  Important  products  which  are
given  a  high  priority  could  therefore  still  take  time  to
come  through  the  development  pipeline.

CFC(cid:220)free.  CFC(cid:220)free  products  should  also 
include  a
leaflet  to  explain  about  the  new  propellant  and  the
reasons  for  change.  This  differentiation  is  vital  to  post(cid:220)
marketing  safety  monitoring  so  that  any  reported  adverse
effects  can  correctly  be  attributed  to  the  type  of  product
concerned.

Strategy/risk  analysis  for  products  which  are  not  refor(cid:220)
mulated

5.12.(cid:218)(cid:217)Some  products  may  not  be  reformulated  for
economic  reasons  while  others  may  ultimately  prove
impossible  to  reformulate  for  technical  reasons.  It 
is
important  to  note  that  Decision  VIII/10  of  the  Parties  to
the  Montreal  Protocol  requires  that  companies  applying
for  continued  essential  use  of  CFCs  for  MDIs  should
"demonstrate  ongoing  research  and  development  of  alter(cid:220)
natives  with  all  due  diligence  and/or  collaborate  with
other  companies  in  such  efforts.’  Therefore,  CFCs  will
not  continue  to  be  available  to  MDI  companies  which
are  not  actively  engaged  in  developing  and  marketing
CFC(cid:220)free  alternatives.  After  the  bulk  of  the  transition  to
non(cid:220)CFC  MDIs  is  accomplished,  the  Commission  and
to  assess  whether  any
Member  States  will  need 
remaining  CFC(cid:220)containing  inhalers  are  still  essential,  for
example  because  there  is  no  other  way  to  meet  the
medical  requirements  of  particular  patients.  Where  they
are  not  essential,  physicians  and  patients  will  have  to
switch  to  an  alternative  treatment  within  a  reasonable
time(cid:220)frame.  Where  they  are  essential,  a  mechanism  for
further,  but  temporary,  supply  will  need  to  be  found.
Note  that  there  can  be  no  long(cid:220)term  dependency  on
CFCs  as  both  the  propellant  and  the  products  will
progressively  disappear  from  the  market.

Naming,  packaging  and  identifying  the  alternatives

5.13.(cid:218)(cid:217)Decision  VIII/10  (3)  of  the  Parties  to  the
Montreal  Protocol  states  that  the  CFC  and  non(cid:220)CFC
products  must  be  differentiated  in  terms  of  packaging
and  marketing.  To  ensure  a  smooth  transition  from
for
CFC(cid:220)containing  MDIs 
that
maximum 
from
CFC(cid:220)free 
CFC(cid:220)containing  ones.  This  should  be  done  by  changing
the  brand  name  or  by  adding  a  logo  or  "flash’  to  the
existing  packaging  to  indicate  clearly  that  the  product  is

to  CFC(cid:220)free  MDIs  and 
it  has  been  agreed 

transparency, 
products  will 

differentiated 

be 

sets  out 

5.14.(cid:218)(cid:217)Directive  92/27/EEC 
the  normal
procedure  whereby  the  proposed  labeling  for  medicinal
products  is  submitted  to  the  appropriate  regulatory  auth(cid:220)
orities  with  the  application  for  marketing  authorisation.
Pharmaceutical  companies  will  decide  whether  they  wish
to  retain  the  existing  brand  name  and  adapt  its  existing
labeling,  including  the  addition  of  the  term  "CFC(cid:220)free’  or
introduce  a  completely  new  brand  name  for  the
to 
non(cid:220)CFC  MDI.  These  provisions  should  ensure  that
CFC(cid:220)free  MDIs  are  appropriately  and  adequately  differ(cid:220)
entiated  from  CFC(cid:220)containing  MDIs.  It  would  also  be
useful  for  the  name  and  characteristics  of  the  propellant
used  to  be  written  on  the  container.

Forecasts  of  future  availability  of  alternatives

launched  on 

5.15.(cid:218)(cid:217)It  is  difficult  to  forecast  with  any  certainty  the
dates  by  which  CFC(cid:220)free  versions  of  particular  products
will  be  available  on  the  Community  market.  At  the
beginning  of  1996,  IPAC  forecast  that  there  would  be
between  36  and  42  HFC  MDIs 
the
European  market  by  the  year  2000.  However,  that
forecast  has  since  been  revised  downwards  in  light  of
technical  problems  some  companies  have  encountered
with  reformulations  and  unanticipated  delays 
in  the
granting  of  market  authorisations.  To  try  to  obtain  some
more  recent  information,  the  Commission  recently  asked
MDI  manufacturers  in  the  Community  to  forecast  when
they  planned  to  submit  applications  for  marketing  auth(cid:220)
orisation  for  CFC(cid:220)free  versions  of  their  current  CFC
inhalers.  The  results  indicate  that,  by  the  year  2000  we
can  expect  companies  to  have  submitted  applications  for
marketing  authorisation  for  CFC(cid:220)free  versions  of  over  30
different  MDI  products.  This  does  not  include  different
strengths  or  dosage  versions  of 
same  active
substance.

the 

A  summary  of  planned  dates  reported  by  companies  for
the  European
filing  of  marketing  authorisation 
Community  for  selected  active  substances 
is  shown
below.  Not  all  the  details  can  be  given  for  reasons  of
commercial  confidentiality.

in 

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Active  Substance

First  mentioned  filing
date

Last  mentioned  filing
date

When  product  is  likely  to
lose  essential  use  status(cid:216)(*)

Salbutamol
Terbutaline
Fenoterol
Beclomethasone
Budesonide
Cromoglicic  Acid
Ipratropium  Bromide

1994
2000
1998
1996
2000
1998
1999

2001
2004
2002
2002
2002
1999
2000

1998(cid:220)1999
2001(cid:220)2002
1999(cid:220)2000
1999(cid:220)2000
2001(cid:220)2002
1999(cid:220)2000
2000(cid:220)2001

(*)(cid:217)period  during  which  CFCs  for  a  particular  product  are  likely  to  lose  their  essential  use  status  in  some  or  all  of  the
Member  States  under  the  provisions  of  this  strategy  if  the  granting  of  marketing  authorisations  for  the  CFC(cid:220)free
alternatives  is  not  unduly  delayed.

5.16.(cid:218)(cid:217)The  survey  indicates  that  some  companies  are
expecting  to  file  applications  after  a  CFC  product  is
likely  to  have  lost  its  essential  use  status.  For  example,
Salbutamol 
likely  to  be  available  throughout  the
is 
in  CFC(cid:220)free  versions  by  the  year  2000.
Community 
CFCs  for  the  manufacture  of  salbutamol  would  not  then
meet  the  essential  uses  criteria  in  2000  and  none  would
be  approved.  This  may  pose  problems  for  the  few
companies  which  except  to  submit  their  application  for
marketing  authorisation  of  the  CFC(cid:220)free  alternative  in
2001.

5.17.(cid:218)(cid:217)It  should  be  emphasized  that  even  with  ques(cid:220)
tionnaire  surveys  like  this,  it  is  not  possible  to  predict
with  any  certainty  how  quickly  the  alternatives  will
become  available  and  therefore  how  quickly  the  demand
for  CFCs  will  fall.  Much  depends  on  how  quickly  and
efficiently  Member  States  grant  marketing  authorisation
for  the  alternatives.  When  taking  decisions  on  quantities
of  CFCs  to  approve,  it  will  remain  a  priority  to  ensure
that  patients  continue  to  have  access  to  the  medicines
they  need.

CHAPTER  6

APPROVAL  OF  NEW  PRODUCTS  AND
POST(cid:220)AUTHORISATION  SURVEILLANCE

should  not  be  delayed  by  slow,  repetitive  procedures  for
obtaining  marketing  and  pricing  authorisation 
inde(cid:220)
pendently  in  each  Member  State  of  the  Community.

Co(cid:220)operation  between  Member  States

the 

6.2.(cid:218)(cid:217)Recognising 
large  number  of  CFC(cid:220)free
products  which  may  be  submitted  to  Regulatory  Auth(cid:220)
orities  over  a  relatively  short  time  period,  it  is  in  the
general  interest  of  Member  States  to  co(cid:220)operate  and
share  the  workload  of  review.  Procedures  for  reviewing
replacements  for  existing  CFC  products  and  approving
new  CFC(cid:220)free  products  should 
least  the
following  elements:

include  at 

-(cid:217)that  companies  should  submit  applications  across  the

whole  of  the  Community  simultaneously,

-(cid:217)that  competent  authorities 

should  co(cid:220)operate 

in

sharing  out  the  work  and  its  results,

-(cid:217)that  CFC(cid:220)free  products  should  be  authorised  for  use
without  delays  and,  as  far  as  possible,  simultaneously
across  the  Member  States.

6.1.(cid:218)(cid:217)At  their  November  1996  meeting  in  Costa  Rica,
the  Parties  to  the  Montreal  Protocol  agreed  "to  request
national  authorities  to  expedite  review  of  marketing/
licensing/pricing  applications  of  CFC(cid:220)free  treatments  of
asthma  and  COPD,  provided  that  such  expedited  review
does  not  compromise  patient  health  and  safety’  (Decision
VIII/11).  A  clear  statement  of  how  this  decision  is  to  be
implemented  in  the  EC  is  an  important  part  of  this
phaseout  strategy.  In  particular,  the  strategy  identifies
marketing  authorisation  procedures  which  will  ensure
the  earliest  possible  introduction  of  CFC(cid:220)free  MDIs.  The
availability  of  CFC(cid:220)free  products  to  patients  in  the  EC

to 

In  addition,  Member  States  should  ensure  that  their
procedures  for  agreeing  pricing  and  reimbursement  do
the  availability  of
not  cause  unnecessary  delays 
CFC(cid:220)free  medical 
inhalers  on  the  European  market.
Decision  VIII/11  of  the  Parties  to  the  Montreal  Protocol
requests  national  authorities  "to  review  the  terms  for
public  MDI  procurement  and  reimbursement  so  that
purchasing  policies  do  not  discriminate  against  non(cid:220)CFC
alternatives’.  Manufacturers  of  alternatives  can  assist  this
process  by  pricing  their  CFC(cid:220)free  products  at  similar
levels  to  the  CFC  products  they  are  intended  to  replace.

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6.3.(cid:218)(cid:217)Although  it  is  important  to  ensure  that  CFC(cid:220)free
products  are  brought  to  the  market  quickly,  this  should
not  compromise  patient  safety.  The  prime  objective  of
the  review  and  approval  procedures  is  to  ensure  that
products  submitted  for  approval  meet  all  the  necessary
standards  of  quality,  safety  and  efficacy.

6.4.(cid:218)(cid:217)There  are  a  number  of  possible  routes  to  obtain
marketing  authorisation  in  the  European  Community  for
CFC(cid:220)free  MDIs.  Further  details  are  shown  on  Figure  1.

-(cid:217)A  referral  under  Article  12  of  Council  Directive
75/319/EEC:  this  is  the  preferred  route  in  order  to
gain  access  to  the  entire  Community  market.  The
Commission  considers  the  rapid  and  safe  replacement
of  CFCs  in  MDIs  to  be  a  matter  of  Community
interest.  Therefore,  if  other  procedures  fail  to  operate
successfully,  the  Commission  reserves  the  right  to  use
the  Article  12  referral  mechanism  as  a  means  to
expedite  the  evaluation  of  marketing  authorisations
for  reformulated  CFC(cid:220)free  MDIs.

to 

the  EMEA 

the  application 

-(cid:217)a  Centralised  Procedure,  as  set  out  in  Council  Regu(cid:220)
lation  (EEC)  No  2309/93:  this  includes  submission
of 
(European
Medicines  Evaluation  Agency),  scientific  evaluation
and  opinion  by 
(Committee  of
Proprietary  Medicinal  Products),  and  a  Commission
Decision  granting  a  marketing  authorisation  valid  for
the  entire  Community  market.  CFC(cid:220)free  MDIs
containing  new  active  substances  are  eligible  for
evaluation  under  this  centralised  procedure  only  if
they  comply  with  part  A  or  part  B  of  the  annex  to
the  Regulation.

the  CPMP 

this 

-(cid:217)a  Mutual  Recognition  Procedure: 

involves
submissions  to  all  Member  States  which  need  to  place
the  CFC(cid:220)free  MDI  on  their  market.  One  Member
State  prepares  a  scientific  evaluation  and  grants
marketing  authorisation  for  its  own  territory.  The
other  Member  States  recognise  the  decision  and
grant  their  own  national  marketing  authorisation.

-(cid:217)an  ad(cid:220)hoc  co(cid:220)operation  mechanism  agreed  between
the  Commission  and  Member  States:  this  will  enable
a  series  of  national  marketing  authorisations  to  be
granted  quickly  by  promoting  the  mutual  sharing  of
information  and  work  among  Member  States.

6.5.(cid:218)(cid:217)From  1  January  1998,  the  mutual  recognition
procedures  applies  for  new  applications  for  the  same
medicinal  product  in  more  than  one  Member  State.  For
"stand(cid:220)alone’  applications  (i.e.  those  made  in  accordance
ii  of  Council  Directive
with  Articles  4.8  or  4.8(a) 

the  mutual 

65/65/EEC  as  amended), 
recognition
procedure  is  mandatory.  Even  when  a  company  does  not
request  mutual 
recognition,  Member  States  will
recognise  decisions  of  other  Member  States  for  the  same
is
medicinal  product  where 
submitted  in  all  Member  States  concerned.

same  application 

the 

6.6.(cid:218)(cid:217)Where 
used,  two  situations  can  apply:

the  ad(cid:220)hoc  co(cid:220)operationmechanism 

is

(a)(cid:217)where  the  company  wishes  to  use  a  different  brand
name  or  to  introduce  a  second  product  which  is
CFC(cid:220)free.  Under  these  circumstances,  an  abridged
application 
4.8(a)(i)  of  Directive
65/65/EEC)  should  be  submitted.

(cf.  Article 

(b) where  the  company  wishes  to  retain  the  same  brand
name  with  the  addition  of  a  flash  "CFC(cid:220)free’.  Under
these  circumstances,  a  submission  in  the  form  of  a
national  variation  should  be  submitted.

Note  that  if  reformulation  results  in  changes  to  the
content  per  actuation  or  dosing  schedule  or  includes  a
quantitative  change  in  the  active  substance  or  a  change
in  bioavailability,  then  the  application  could  not  be
classified  as  a  variation  but  should  be  submitted  as  an
abridged  application  (cf.  Annex  II  of  Commission  Regu(cid:220)
lation  on  Variations  to  the  terms  of  a  marketing  author(cid:220)
isation,  (EC)  No  541/95).

6.7.(cid:218)(cid:217)Whether  or  not  the  submission  is  made  as  an
abridged  application  (a)  or  national  variation  (b),  the
agreed  procedures  are  very  similar.

The  applicant:

(a)(cid:217)provides  a  list  of  the  Member  States  in  which  the
same  abridged  application  or  variation  has  been
submitted  or  will  be  submitted  in  parallel  and,  in  the
latter  case,  the  dates  at  which  the  applications  are
planned  to  be  submitted.  Note  that  companies  should
simultaneously  submit  the 
information  to  all  the
Member  States  where  authorisation  is  going  to  be
required.

(b) includes  a  commitment  that  he  has  submitted  or  will
submit  exactly  the  same  data  package  to  each
Member  State.

(c) provides  copies  of  the  current  and  proposed  new
labelling  to  allow  review  of  the  information  to  be

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provided  on  the  replacement  and  to  ensure  that
patients  will  receive  sufficient  detailed  information.

Post  Authorisation  surveillance  and  safety  studies

(d) provides  a  draft  Summaries  of  Product  Charac(cid:220)
teristics  (SPC)  of  the  CFC(cid:220)free  product  consistent
with  SPC  of  the  CFC(cid:220)containing  product 
is
intended  to  replace,  including  all  relevant  details  of
the  replacement  so  that  health  professionals  will
receive  complete  information.

it 

6.8.(cid:218)(cid:217)The  legal  framework  for  pharmacovigilance  of
medicinal  products  for  human  use  in  the  Community  is
given 
in  Council  Directive  75/319/EEC.  Detailed
guidelines  on  pharmacovigilance  are  included  in  Volume
9  of  the  rules  governing  medicinal  products  for  human
use  in  the  European  Community.

The  Member  States:

Safety  Issues  relating  to  new  products

(a)(cid:217)One  Member  State  prepares  an  assessment  report  on

the  abridged  application  or  the  variation.

(b) As  soon  as  the  assessment  is  completed,  the  Member
to  other

State  circulates 
Member  States  listed  in  the  applicant’s  dossier.

the  assessment  report 

(c) Based  on 

their  own  assessment  or  assessment
report(s)  circulated  by  other  Member  States,  they
will  grant  the  authorisation  or  variation  and  issue  the
marketing  authorisation  within  a  period  of  180  days.
To  expedite  this  process,  all  usual  forms  of  contact
between  Member  States  will  have 
to  be  used,
including  phone  calls,  ancillary  information  requests
on  the  assessment  report,  answers  to  requests  etc.

(d) They  inform  other  Member  States  of  the  date  at
which  the  variation  to  the  terms  of  the  marketing
authorisation  has  been  granted.

(e) They  prepare  a 

for 

schedule 

the
CFC(cid:220)containing  product  by  the  CFC(cid:220)free  product.
This  substitution  process  should  not  exceed  twelve
months,  which  allows  adequate 
for  post(cid:220)
marketing  surveillance  of  the  CFC(cid:220)free  product.

substituting 

time 

6.9.(cid:218)(cid:217)When  products  are  marketed,  their  use  may
include  patient  groups  which  differ  in  various  respects
from  those  represented  in  clinical  trials  performed  prior
to 
issuing  or  varying  of  a  MA.  How  products  are
prescribed  and  how  patients  use  them  will  also  differ
from  the  clinical  trial  situation.  Clinical  trials  designed  to
demonstrate  efficacy  of  the  new  products  for  author(cid:220)
isation  are  frequently  not  large  enough  to  detect  rare
side  effects.  For  these  reasons 
intensive  post(cid:220)author(cid:220)
isation  surveillance  is  critical  in  confirming  the  safety  of
new  CFC(cid:220)free  products.

to 

the 

from 

6.10.(cid:218)(cid:217)Safety 
intro(cid:220)
issues  possibly  relevant 
duction  of  CFC(cid:220)free  products  include  paradoxical  bron(cid:220)
the  new
chospasm  and  rare  adverse  effects 
recipients.  New  formulations  may  result  in  altered  lung
deposition  and  hence  biovailability.  For  this  reason  the
occurrence  of  significant  systemic  adverse  reactions  to
the  reformulated  products  may  differ  considerably  from
the  equivalent  CFC(cid:220)containing  product.  In  addition,
changing  from  CFC(cid:220)containing  to  CFC(cid:220)free  products
could  result  in  short(cid:220)term  deterioration  in  disease  control
for  some  patients.  Long(cid:220)term  use  of  CFC(cid:220)free  inhaler
devices  will  occur 
their
performance  will  need  to  be  established.

following  marketing  and 

(f) They  keep  the  Commission  and  the  EMEA  informed
by  sending  details  on  the  approvals  granted,  active
substance  by  active  substance,  and  on  the  progress  of
substituting  CFC(cid:220)containing  products  by  CFC(cid:220)free
products  in  their  territories.

The  European  Commission

For  both  abridged  applications  and  national  variations,
to  facilitate  the  centralisation  of  data  for  the  Community
as  a  whole,  the  Commission  requests  the  EMEA  to  keep
an  up  to  date 
list  of  the  submissions  received  and
approved  for  each  active  substance  in  each  Member
State;  and 
substituting
CFC(cid:220)containing  products  by  CFC(cid:220)free  products  in  each
Member  State.

rate  of  progress  of 

the 

6.11.(cid:218)(cid:217)Intensive  post(cid:220)authorisation  surveillance  will  be
needed,  with  regulatory  authorities  and  MA  holders
working  in  close  partnership.  Doctors  and  pharmacists
can  also  play  a  useful  role  in  evaluating  the  success  and
safety  of  CFC(cid:220)free  inhalers  as  their  use  increases.

Phase  Out  Time  of  CFC(cid:220)Containing  Products

6.12.(cid:218)(cid:217)CFC(cid:220)containing  products  should  be  phased  out
quickly,  so  the  time  that  a  CFC(cid:220)free  product  and  its
equivalent  CFC(cid:220)containing  product  will  be  available
limited.  Sufficient  time  needs  to  be
concurrently 
available  for  data  collection.  It  has  been  agreed  that,
normally,  the  CFC  product  could  remain  available  in  the
market  for  up  to  twelve  months  following  launch  of  the

is 

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replacement  product.  During  that  time,  MA  holders  and
pharmacies  will  run  down  stocks  of  the  CFC  product  as
take(cid:220)up  of  the  replacement  product  increases.  Any  safety
issues  with  the  CFC(cid:220)free  products  will  need  to  be  rapidly
identified,  evaluated  and  acted  on  so  that  they  are
resolved  before  the  equivalent  CFC(cid:220)containing  product  is
finally  withdrawn.  MA  holders  should  prepare  plans  so
that,  if  important  safety  concerns  arise  relating  to  their
CFC(cid:220)free  product,  they  will  be  able  to  supply  patients
with  an  equivalent  CFC(cid:220)containing  product.

Spontaneous  Adverse  Drug  Reaction  Reporting

6.13.(cid:218)(cid:217)The  requirements  for  MA  holders  to  report
spontaneous  adverse  drug  reactions  are  set  out 
in
Directive  75/319/EEC.  No  change  in  these  requirements
is  necessary  for  CFC(cid:220)free  products.

Post(cid:220)Authorisation  Studies

6.14.(cid:218)(cid:217)A  guideline  for  post(cid:220)marketing  surveillance  of
inhalers  has  been  prepared(cid:216)(˛).  MA
new  CFC(cid:220)free 
holders  are  encouraged  to  perform  large  safety  studies  of
CFC(cid:220)free  products.  These  studies  will  usually  include
comparisons  of  CFC(cid:220)free  and  CFC(cid:220)containing  inhalers
following  a  randomised  clinical  trial,  or  observational
cohort  design.  The  use  of  single(cid:220)dose  studies  should  also
be  considered.  The  trials  should  be  set  up  in  such  a  way
that  it  is  clear  that  the  patients  who  complete  them  are
representative  of  the  whole  patient  population,  including
study  design  may
children  and 
encompass  an  assessment  of  the  changeover  from  the
original  CFC(cid:220)containing  product 
the  CFC(cid:220)free
product.

the  elderly.  The 

to 

haematological 
6.15.(cid:218)(cid:217)Adverse 
biochemical  monitoring  should  be  undertaken 

event 

and 

and
in  all

(˛)(cid:217)EEC/180/95.

studies, 

together  with 

safety 
specific  assessments,
pertinent  to  the  drug  substance,  to  look  for  local  and
systemic  effects  which  might  not  necessarily  be  recorded
as,  or  manifest  themselves  as,  adverse  events  (e.g.  adrenal
suppression  with  inhaled  corticosteroids).

6.16.(cid:218)(cid:217)MA  holders  will  submit  proposals  to  the  regu(cid:220)
latory  authority  to  monitor  the 
introduction  of  the
CFC(cid:220)free  products  in  order  to  identify  rare  and  unex(cid:220)
pected  adverse  effects.  A  method  such  as  the  use  of
record  linkage  schemes  should  be  considered,  as  this
could  provide  a  means  for  monitoring  the  CFC(cid:220)free
products  against  historical  data  relating  to  the  products
using  CFC  propellants.  Careful  observation  of  patients
and  a  specific  assessment  of  cough,  wheezing  and  bron(cid:220)
chospasm  on  first  administration  of  the  product,  paying
particular  attention  to  the  time  to  onset  of  any  effect,
would  be  useful.  Specific  questioning  and  assessment  of
in
paradoxical  bronchospasm  would  be  appropriate 
single(cid:220)dose  studies  and  after  the  first  dose  of  each  limb
in  crossover  studies.

Liaison  with  regulatory  authorities

6.17.(cid:218)(cid:217)Companies  proposing  to  perform  a  post(cid:220)author(cid:220)
isation  safety  study  are  advised  to  discuss  the  draft
protocol  with  the  relevant  regulatory  authorities  when
is  made.
the  application 
Particular  consideration  should  be  given 
to  specific
safety  issues  which  may  require  investigation.  National
legislative  requirements  or  guidelines  should  be  taken
into  account  in  those  Member  States  where  these  exist.

for  an  MA  or  variation 

6.18.(cid:218)(cid:217)A  final  report  on  the  study  should  be  sent  to  the
relevant 
regulatory  authorities  within  1  month  of
follow(cid:220)up  being  completed.  Ideally  this  should  be  a  full
report  but  a  preliminary  report  within  1  month,  followed
by  a  full  report  within  3  months  of  completion  of  the
study  would  normally  be  acceptable.  The  findings  of  the
study  should  be  submitted  for  publication.

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Figure  1

POSSIBLE  ROUTES  TO  APPROVAL

Route(cid:217)1:(cid:217)Referral  under  Article  12  of  Directive  75/319/EEC

Route(cid:217)2:(cid:217)Referral  under  the  centralised  procedure  of  Regulation  (EEC)  No  2039/93

Either  Route  3  or  Route  4  depending  on  whether  or  not  the  brand  name  changes

(Route 3)

unchanged

BRAND NAME

(Route 4)

changed

(a)

(b)

purely national
procedures

in one
Member State

in more than one
Member State

procedures for variations to
national MA or abridged
application

MA national 
procedure

proposed ad-hoc 
procedure

in future, 
provisions of 
Chapter III 
of Directive 75/319/EEC 
applicable if product is to be
marketed in other 
Member States

mutual
recognition
procedure
Article 9, Directive
75/319/EEC
Article 7a, Directive
65/65/EEC

harmonised MA
decentralised
procedure

national
MA

MA
decentralised
procedure

In  practice,  the  approval  procedures  in  route  4a  and  4b  rely  on  the  initial  dossiers  (pseudo(cid:220)
abridged  application)  with  two  conditions:  a)  all  the  initial  dossiers  have  to  be  identical  and
updated  b)  initial  dossier  to  be  completed,  where  necessary,  with  additional  information
including  (Directive  75/318/EEC)  parts  II  and/or  III  and/or  IV  (in  particular  biodisponi(cid:220)
bility).

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CHAPTER  7

-(cid:217)companies  manufacturing  CFC  products  must  be

committed  to  reformulation

PHASING  OUT  CFCs

Possible  approaches  to  the  CFC  phaseout

-(cid:217)the  strategy  should  be  consistent  with  the  relevant
legal  and  economic  framework  covering  such  things
as  approval,  registration  and  pricing  of  medicines.

7.1.(cid:218)(cid:217)The  essential  use  exemption  for  CFCs  in  MDIs
cannot  continue  indefinitely.  As  alternative  propellants
become  available,  together  with  alternative  methods  of
treating  asthma  and  COPD,  CFCs  will  progressively  be
withdrawn.  Based  on  the  expected  rate  of  development
and  timely  approval  of  alternatives,  it  is  likely  that  many
metered  dose  inhalers  used  in  the  European  Community
will  be  CFC(cid:220)free  by  2000.

it 

this 

is  vital 

transition  period 

7.2.(cid:218)(cid:217)During 
that
patients  continue  to  have  access  to  the  medicines  they
require.  At  the  same  time,  it  is  necessary  to  ensure  that
the  production  and  use  of  CFC(cid:220)containing  MDIs
declines  at  a  rate  consistent  with  the  introduction  of
alternatives.  Balancing  these  two  imperatives  requires  a
clear  strategy.  This  strategy  sets  out  the  circumstances
and  procedures  under  which  any  new  CFC(cid:220)free  inhaler
will  be  determined  to  be  a  technically  and  economically
feasible  alternative  or  substitute  for  one  or  more  existing
CFC(cid:220)containing  products.  The  strategy  also  specifies  the
mechanism  and  timetable  for  the  withdrawal  of  CFCs
from  the  manufacturing  process  once  satisfactory  alter(cid:220)
natives  are  available  and  advice  on  how  to  deal  at  that
stage  with  stocks  of  CFCs  and  CFC(cid:220)containing  inhalers.

7.3.(cid:218)(cid:217)Some  useful 
information  on  CFC  phaseout
strategies  has  been  provided  by  the  Aerosols,  Sterilants,
Miscellaneous  Uses  and  Carbon  Tetrachloride  Techncial
Options  Committee  of  the  Montreal  Protocol  in  their
April  1997  report.  The  committee  notes 
the
following  points  should  be  considered  when  developing  a
CFC  phaseout  strategy:

that 

-(cid:217)there  should  be  sufficient 

technically  and  econ(cid:220)
omically  feasible  alternatives  available  to  assure  an
uninterrupted  supply  of  medication

-(cid:217)one  or  more  separate  formulations  of  the  same  thera(cid:220)

peutic  substances  need  to  be  available

-(cid:217)there  should  be  sufficient  post  marketing  surveillance

of  the  reformulated  products

-(cid:217)there  should  be  sufficient  choice  of  alternatives  to

meet  the  needs  of  different  patient  sub(cid:220)groups

-(cid:217)sufficient  time  and  resources  should  be  available  for

educating  health  professionals  and  patients

7.4.(cid:218)(cid:217)In  addition  to  these  general  points,  the  Technical
four  possible
Options  Committee 
approaches  to  designing  a  strategy  for  the  phaseout  of
CFCs  in  metered  dose  inhalers.  These  include:

sets  out 

report 

(1) Phasing  out  CFCs  brand  by  brand:  With 

this
approach,  when  a  company  produces  a  new  or  refor(cid:220)
mulated  product  which  replaces  its  CFC  product,  it
would  be  required  to  introduce  the  new  product  and
phase  out  the  old  over  a  given  timescale.  The
timescale  would  be  consistent  with  the  company’s
production  and  distribution  capacity  and  reasonable
post(cid:220)marketing  surveillance.

a 

particular 

(2) Phasing  out  CFCs  active  substance  by  active  substance:
this  approach,  once  a  CFC(cid:220)free  MDI
With 
containing 
(eg
salbutamol)  had  been  launched  and  satifactory  post(cid:220)
marketing  surveillance  data  obtained,  CFCs  would
be  withdrawn  for  all  MDIs  containing  that  particular
active  substance  and,  after  a  given  period,  licenses
for  the  further  sale  of  the  CFC  product  would  be
withdrawn.

substance 

active 

(3) Phasing  out  CFCs  category  by  category:  With  this
approach,  existing  CFC  products  are  grouped  into
categories  according  to  the  type  of  disease  being
treated  or  the  way  the  active  substance  operates.  The
categories  are  as  follows:

Category  A:  short(cid:220)acting  beta  agonist  broncho(cid:220)
dilators  (eg  salbutamol)

Category  B:  inhaled  steroids  (eg  beclomethasone)

Category  C:  non(cid:220)steroidal  anti(cid:220)inflammatories  (eg
cromoglycate)

Category  D:  anticholinergic  bronchodilators 
ipratopium)

(eg

Category  E: 
dilators  (eg  salmeterol)

long(cid:220)acting  beta  agonist  broncho(cid:220)

Category  F:  combinations

For  each  of  the  categories  (A)  to  (F),  when  sufficient
CFC(cid:220)free  alternatives  become  available 
that
category,  all  the  remaining  CFC(cid:220)containing  products
in  that  category  can  be  phased  out.  What  is  defined
as  a  "sufficient’  number  of  CFC(cid:220)free  products  will
vary  from  category  to  category  according  to  the
importance  and  extent  of  use  of 
the  products
concerned.

in 

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(4) Phasing  out  CFCs  according  to  targets  and  timetables:
With  this  approach,  the  strategy  would  set  targets
for  CFC  reduction  to  zero  over  a  given  time  period,
in  line  with  the  expected  availability  of  CFC(cid:220)free
alternative  products  or  treatments.  The  timetable
could  be  reviewed  regularly  and  amended  in  the
light  of  actual  progress 
in  the  development  and
launch  of  alternatives.  Under  another  variant  of  this
approach,  the  strategy  might  simply  plan  to  reduce
the  availability  of  CFCs  by  a  given  percentage  each
year  (e.g.  20(cid:216)%  cut  each  year  to  zero  over  5  years),
leaving  manufacturers,  doctors  and  patients  to  find
ways  to  work  successfully  within  these  limits.

7.5.(cid:218)(cid:217)Among  these  different  options,  different  strategies
might  be  appropriate  to  different  circumstances.  When  it
comes  to  selecting  the  most  appropriate  strategy  for  the
EC,  it  is  useful  to  consider  the  criteria  which  it  must
meet  to  be  successful.  These  include:

-(cid:217)phasing  out  CFCs  as  soon  as  reasonably  possible

-(cid:217)ensuring  that  patients  continue  to  have  access  to

necessary  medicines

CFCs  is  triggered  by  the  real  availability  of  alternatives,
rather  than  being  based  on  predictions  of  when  these
alternatives  might  be  available.

is  available 

launched.  Under 

reformulations  are 

7.7.(cid:218)(cid:217)It  is  also  difficult  to  defend  a  strategy  under
which  CFCs  have  to  remain  available  until  every  single
product  now  using  them  has  been  individually  refor(cid:220)
mulated.  This  would  prolong  the  phaseout  indefinitely,
as  certain  products  currently  using  CFCs  may  never  be
reformulated  and  others  may  take  many  years  before
successful 
the
Protocol’s  essential  uses  exemption,  CFCs  must  be
withdrawn  once  there 
"a  technically  and
economically  feasible  alternative  or  substitute  which  is
acceptable  from  the  standpoint  of  environment  and
health.’  This  does  not  imply  that  the  alternative  must  be
identical  either  in  brand  or  active  substance  to  the  CFC
product  it  replaces.  For  example,  some  patients  currently
using  one  brand  of  beta  agonist  might  find  they  could
switch 
to  an  alternative  manufactured  by  another
company.  Others  currently  using  an  inhaled  steroid  such
as  beclomethasone  might  find  they  could  easily  change
to  another  active  substance  with  similar  properties,
whether  or  not  manufactured  by  the  same  company.
Some  patients  currently  using  a  CFC  MDI  could  change
to  an  existing  or  new  multi(cid:220)dose  dry  powder  inhaler.

-(cid:217)being  clear,  equitable,  consistent  and  transparent

Phaseout  of  existing  CFC  MDIs  in  the  EC

-(cid:217)being  understood  and  supported  by  doctors  and

patients

-(cid:217)setting  a  clear  direction  to  allow  future  planning  with

confidence

-(cid:217)being  able  to  reflect  the  different  circumstances  of

each  Member  State

7.6.(cid:218)(cid:217)If  patients  are  to  continue  to  have  access  to  the
including  where  necessary  a
medicines  they  require, 
choice  of  suitable  therapies,  it  will  be  important  to  ensure
that  CFCs  are  not  withdrawn  prematurely  before
adequate  alternatives  are  available.  In  this  context,  "avail(cid:220)
and
ability’  will  mean 
distribution  capacity,  together  with  evidence  of  the  effec(cid:220)
tiveness  of  the  alternative  and  the  absence  of  any  serious
side(cid:220)effects.  A  simple  targets  and  timetable  approach
could  not  meet  these  criteria.  A  general  cut  in  CFCs,  for
example  50(cid:216)%  in  1999,  would  be  somewhat  arbitrary,
and  could  not  protect  the  patients  using  CFC  products
for  which  no  alternative  had  yet  been  developed.  It  is
therefore  safer  to  adopt  a  strategy  where  the  phaseout  of

sufficient  manufacturing 

7.8.(cid:218)(cid:217)A  strategy  based  simply  on  a  brand  by  brand  or
active  substance  by  active  substance  substitution  would,
without  any  particular  justification,  freeze  the  current
production  and  use  patterns  of  branded  medicines.  It
the  flexibility  between
would  also  restrict  some  of 
different  brands  and  between  different  types  of  products
which  will  be  a  necessary  part  of  a  successful  transition
away  from  CFC 
inhalers.  Not  all  the  current  CFC
products  will  be  reformulated  and  some  switching
between  brands  and  between  products  will  be  necessary.
Therefore  this  strategy  is  based  on  phasing  out  CFC’s  as
far  as  possible  category  by  category  while  taking  account
of  known  limitations  to  substitution  within  categories  of
active  substance,  the  need  to  ensure  that  all  patients
continue  to  have  access  to  the  medicines  they  require
and  the  different  circumstances  operating  in  different
Member  States.

7.9.(cid:218)(cid:217)As  has  already  been  noted,  products  for  the
treatment  of  asthma  and  COPD  are  classified  into  the
following  6  categories:

A Short(cid:220)acting  beta  agonist  bronchodilators 

e.g.

salbutamol  terbutaline,  fenoterol

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B

Inhaled  steroids  e.g.  beclomethasone,  budesonide,
fluticasone,

C Non(cid:220)steroidal 

anti(cid:220)inflammatories 

e.g. 

cromo(cid:220)

glycate,  nedocromil

D Anticholinergic  bronchodilators  e.g. 

ipratropium

bromide,  oxytropium  bromide

E

F

Long(cid:220)acting  beta  agonists  bronchodilators  e.g.
salmeterol,  formoterol

Combination  drugs

in 

these 

Categories  A  and  B  together  account  for  approximately
[80(cid:216)%(cid:129)  of  CFC  MDIs  used  in  the  EC.  There  are  many
different  brands  currently  available 
two
categories  while  in  the  other  categories  there  are  only
one  or  two  brands  on  the  market.  The  active  substances
in  each  category  are  pharmacologically  closely  related,
are  indicated  for  the  treatment  of  the  same  conditions
and,  with  adequate  consideration  of  dosages  and  action,
most  patients  would  be  able  to  use  another  product
within  the  category  as  an  alternative.  In  addition  to
MDIs,  there  is  also  a  complete  range  of  DPIs  for  each  of
the  Categories  A  to  E.  While  they  may  not  currently  be
the  alternative  of  choice  for  many  doctors  and  patients,
dry  powder  inhalers  could  provide  an  effective  and  envi(cid:220)
ronmentally  benign  alternative  for  a  significant  number
of  patients,  if  appropriate  actions  are  taken  at  national
level  to  encourage  their  use.  For  these  reasons  and  under
this  strategy,  CFCs  can  be  phased  out  for  the  manu(cid:220)
facture  of  MDIs  within  the  EC  without  waiting  for  each
individual  MDI  currently  using  CFCs  to  be  refor(cid:220)
mulated.

7.10.(cid:218)(cid:217)Pharmaceutical  companies  who  have  developed
CFC  free  MDI  alternatives  will  need  actively  to  manage
the  transition  through  doctor  and  patient  education
programmes.  A  company  which  has  introduced  an  alter(cid:220)
native  and  has  adequate  production  and  distribution
the  new  product  and  successful  post(cid:220)
capacity  for 
marketing 
the  CFC
should  withdraw 
product  over  a  maximum  of  12  months  following  the
introduction  of  the  new  product  onto  the  market.

surveillance 

Technically  and  Economically  Feasible  Alternatives

the  Montreal  Protocol,  essential  use
7.11.(cid:218)(cid:217)Under 
"no
exemptions  are  granted  only  where 
available 
technically  and  economically  feasible  alter(cid:220)
natives  or  substitutes  acceptable  from  the  standpoint  of
environment  and  health.’  This  section  of  the  strategy
explains  how  it  can  be  determined  when  technically  and
economically  feasible  alternatives  are  available,  and  the
essential  use  exemption  withdrawn.

there  are 

can 

7.12.(cid:218)(cid:217)Among  existing  CFC  products, 
there  are  a
number  of  active  substances  identified  as  necessary  for
to  be  available  as
patient  health  which  will  have 
CFC(cid:220)free  products  before  CFCs 
finally  be
withdrawn.  Other  CFC  products  are  not  considered
necessary  for  patient  health  and  some  may  never  be
reformulated.  Salbutamol  accounts  for  over  90(cid:216)%  of  the
European  MDI  short(cid:220)acting  beta  agonist  market  and
some  50(cid:216)%  of  the  total  MDI  market.  Beclomethasone
accounts  for  over  90(cid:216)%  of  the  European  MDI  steroid
market  and  some  25(cid:216)%  of  the  total  MDI  market,  while
the  most
in 
important 
like
these,  it  is  necessary  to  ensure  that  sufficient  alternatives
are  available  to  meet  the  requirements  of  patients  before
CFCs  are  withdrawn.

inhaled  steroid.  For  active  substances 

some  Member  States,  budesonide 

is 

the  products 

"Epinephrine’  and
7.13.(cid:218)(cid:217)Conversely, 
"Phenyl  Ephrine’  are  no 
longer  considered  essential.
Therefore,  the  Commission  will  not  approve  any  CFCs
for  their  manufacture  after  1  January  1999.

Criteria  for  determining  when  sufficient  alternatives  are
available

7.14.(cid:218)(cid:217)The  criteria  fall 
into  two  groups:  those  for
determining  when  the  use  of  CFCs  would  no  longer  be
considered  essential  for  individual  products,  and  those
for  determining  when  the  use  of  CFCs  would  no  longer
be  considered  essential  for  a  whole  category.  These  two
systems  will  operate  in  parallel.

Individual  products

7.15.(cid:218)(cid:217)CFCs  for  inhalers  containing  salbutamol  will  no
longer  be  considered  essential  when  two  alternative
CFC(cid:220)free  MDIs  containing  salbutamol  are  available  in
an  adequate 
two  different
producers.

range  of  doses 

from 

longer  be  essential  when 

inhalers  containing  beclomethasone
7.16.(cid:218)(cid:217)CFCs  for 
two  alternative
will  no 
CFC(cid:220)free  MDIs  containing  beclomethasone  are  available
in  an  adequate  range  of  doses  from  two  different
producers.

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7.17.(cid:218)(cid:217)CFCs  for  inhalers  containing  any  other  active
substance  will  no  longer  be  considered  essential  when
one  alternative  CFC(cid:220)free  MDI  containing  the  same
active  substance  is  available.

Categories  of  products

Category  A  -  Short(cid:220)acting  beta  agonist  bronchodilators

7.18.(cid:218)(cid:217)CFCs  for  inhalers  in  this  category  will  no  longer
be  considered  essential  once  two  CFC(cid:220)free  products
containing  salbutamol  and  one  other  CFC(cid:220)free  product
containing  an  active  substance  defined  as  necessary
under  this  strategy  are  available  in  an  adequate  range  of
doses.

Category  B  -  Inhaled  steroids

7.19.(cid:218)(cid:217)CFCs  for  inhalers  in  this  category  will  no  longer
be  considered  essential  once  two  CFC(cid:220)free  products
two  other  CFC(cid:220)free
containing  beclomethasone  and 
products  containing  different  active  substances  defined  as

necessary  under  this  strategy  are  available  in  an  adequate
range  of  doses.

Categories  C,  D  and  E

7.20.(cid:218)(cid:217)CFCs  for  inhalers  in  each  of  these  categories
will  no  longer  be  considered  essential  once  one  CFC(cid:220)free
product  containing  an  active  substance(s)  defined  as
necessary  under  this  strategy  for  the  category  is  available
in  an  adequate  range  of  doses.

Category  F  -  Combination  products

7.21.(cid:218)(cid:217)CFCs  for  inhalers  in  this  category  will  no  longer
be  considered  essential  once  there  are  CFC(cid:220)free  MDI
alternatives  for  each  of  its  component  active  substances
or  when  the  essential  use  status  has  been  withdrawn
from  the  relevant  category  or  product.  A  CFC  free
combination  MDI  would  not  be  considered  an  alter(cid:220)
native  for  either  of 
its  components  when  deciding
whether  there  are  sufficient  technically  and  economically
feasible  alternatives  available.

TABEL  A

Category  A
Short(cid:220)acting  beta  agonist  bronchodilators

Products

Alternatives

Producers

Salbutamol(cid:216)(*)

Terbutaline(cid:216)(*)
Fenoterol(cid:216)(*)
Orciprenaline
Reproterol
Carbuterol
Hexoprenaline
Pirbuterol
Clenbuterol
Bitolterol
Procaterol

Products

Beclomethasone(cid:216)(*)

Dexamethasone
Flunisolide
Fluticasone(cid:216)(*)
Budesonide(cid:216)(*)
Triamcinolone

2  non(cid:220)CFC  Salbutamol
products

2  different  producers

CFCs  for  all  category  A  products  will  no  longer  be  considered
essential  once  there  are  available  2  alternative  Salbutamol  products
produced  by  2  different  producers  plus  1  other  product  defined  as
necessary  under  this  strategy.  Therefore,  these  products  will  be
replaced  by  a  minimum  of  3  CFC(cid:220)free  inhalers  (two  salbutamol  +
one  other)

Category  B
Inhaled  steroids.

Alternatives

Producers

2  non(cid:220)CFC  Beclomethasone
products

2  different  producers

CFCs  for  all  category  B  products  will  no  longer  be  considered
essential  once 
there  are  available  2  alternative  Beclomethasone
products  produced  by  2  different  producers  plus  2  other  products
containing  different  active  substances  defined  as  necessary  under  this
strategy.  Therefore  these  products  will  be  replaced  by  a  minimum  of
4  CFC(cid:220)free  products  (2  Beclomethasone(cid:216)+(cid:216)2  others).

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Cromoglicic  Acid(cid:216)(*)
Nedocromil(cid:216)(*)
Note: Both 
considered  necessary 
Member  States.

these  products  are
some

in 

Category  C
Non(cid:220)steroidal  anti(cid:220)inflammatories

CFCs  for  both  category  C  products  will  no  longer  be  considered
essential  once  there  is  one  alternative  CFC(cid:220)free  product  available  to
replace  either  of  the  two  current  CFC  products.  Therefore,  the  2
CFC  products  will  be  replaced  by  a  minium  of  one  CFC(cid:220)free
product,  except  where  both  products  are  considered  necessary.

Category  D
Anticholinergic  bronchodilators

Ipratropium  Bromide
Oxitropium  Bromide

CFCs  for  both  category  D  products  will  no  longer  be  considered
essential  once  there  is  one  alternative  CFC(cid:220)free  product  available  to
replace  either  of  the  two  current  CFC  products.

Salmetero(cid:216)(*)
Formoterol(cid:216)(*)
Note: Both 
considered  necessary 
Member  States.

these  products  are
some

in 

Category  E
Long(cid:220)acting  beta  agonist  bronchodilators

CFCs  for  both  category  E  products  will  no  longer  be  considered
essential  once  there  is  one  alternative  CFC(cid:220)free  product  available  to
replace  either  of  the  current  CFC  products.  Therefore,  the  2  category
E  CFC  products  will  be  replaced  by  a  minimum  of  one  CFC(cid:220)free
product,  except  where  both  products  are  considered  necessary.

Category  F
Combination  products

Combination  products  will  be  treated  on  a  case(cid:220)by(cid:220)case  basis.  CFCs
for  combination  products  will  no  longer  be  considered  essential  once
CFC(cid:220)free  products  are  available  for  each  of  the  separate  components
in  the  combination.

(*)(cid:217)This  denotes  products  deemed  necessary  under  this  strategy  in  one  or  more  Member  States.

7.22.(cid:218)(cid:217)The  European  Commission  will  apply 
the
criteria  set  out  in  paragraphs  7.15  to  7.21  and  in  Table  A
to  determine  whether  CFCs  remain  essential  for  a  given
MDI  product.  However,  to  reflect  the  different  circum(cid:220)
to  be
stances  of  Member  States,  CFCs  may  have 
approved  for  a  particular  product  in  a  particular  Member
State  even  after  the  criteria  for  transition  have  been  met.
This  would  be 
the
competent  authority  of  that  Member  State  confirms  to
the  Commission  that  the  product  remains  necessary
despite  the  availability  of  alternatives.  Note,  however,
that  any  derogation  along  these  lines  would  have  to  be
temporary  and  would  not  delay  the  transition  elsewhere
in  the  Community.  It  is  important  to  note  that  the
continued  use  of  CFCs 
the
is  only  possible  with 
agreement  of  the  Parties  to  the  Montreal  Protocol.

for  example,  where 

the  case, 

7.23.(cid:218)(cid:217)The  following  conditions  will  also  need  to  be
is  considered  that  there  are  sufficient
met  before 

it 

technical  and  feasible  alternatives  available  for  CFCs  to
be  withdrawn:

-(cid:217)adequate  production  and  distribution  capacity  of  the
CFC(cid:220)free  MDIs  to  meet  the  need  of  all  patients
covered  by  the  product  or  category  concerned.

-(cid:217)an  adequate  range  of  doses  and  strengths  to  cover
distinct  patient  subgroups  such  as  the  elderly  or
young  children.

-(cid:217)efficacy  of  the  alternative  products  and  treatments
generally  comparable  to  the  CFC  product  they  are
replacing.  Some  patients  may  have  a  personal  pref(cid:220)
erence  for  CFC  MDIs,  but  this 
likely  to  be
overcome  by  education  and  would  not  be  the  basis  of
a  continued  exemption  under  the  Montreal  Protocol.

is 

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-(cid:217)sufficient  post(cid:220)marketing  surveillance  of  the  refor(cid:220)
mulated  products  and  no  safety  problems  identified.

The  Commission  will  seek  advice  from  the  competent
authorities  of  the  Member  States  and  other  experts  to
determine  when  all  these  conditions  have  been  met  and
the  CFCs  withdrawn  from  a  particular  product  or
category.

categories  in  Table  A.  Using  forecasts  from  the  MDI
manufacturers  about  the  likely  submission,  approval  and
registration  of  alternatives,  it  is  possible  to  predict  some
years  into  the  future  the  likely  demand  for  CFCs.  These
forecasts  can  be  used  as  a  basis  for  the  Community’s
nomination  to  the  Parties  to  the  Montreal  Protocol  two
years  in  advance  of  need.  This  is  the  "targets  and  time(cid:220)
tables’  approach  to  transition  advocated  by  the  MDI
manufacturers.

How  CFCs  will  be  phased  out  once  alternatives  are
available

inhalers 

7.24.(cid:218)(cid:217)Manufacturers  of  metered  dose 
for
asthma  and  COPD  currently  obtain  their  CFCs  after
agreement  to  their  essential  use  requests  in  two  stages.  In
stage  1,  the  European  Commission  applies  to  the  Parties
to  the  Montreal  Protocol  for  authorisation  of  a  total
quantity  of  CFCs  to  be  used  to  manufacture  MDIs  in  the
European  Community  in  a  future  year.  The  Parties  to
the  application  and
the  Montreal  Protocol  review 
approve  a  certain  quantity,  usually  two  years  in  advance.
At  their  8th  Meeting  in  Costa  Rica  in  1996,  the  Parties
agreed  on  a  total  of  5(cid:216)610  tonnes  to  be  used  by  manu(cid:220)
facturers  in  the  Community  during  1998.  At  their  9th
meeting  in  Montreal  in  1997,  the  Parties  agreed  to  a
total  of  5(cid:216)000  tonnes  for  use  by  manufacturers  in  the
Community  during  1999.  These  CFCs  are  intended  for
the  manufacture  of  MDIs  both  for  the  European  market
and  also  for  export.

7.25.(cid:218)(cid:217)In  stage  2,  each  manufacturer  applies  to  the
European  Commission  for  authorisation  to  acquire  and
use  a  quantity  of  CFCs  to  produce  MDIs.  Their  requests
to  the  Commission  are  received  in  the  autumn  of  each
year  in  respect  of  the  following  year.  The  Commission
reviews  the  requests  and,  after  seeking  the  opinion  of  a
Management  Committee  composed  of  representatives  of
all  Member  States,  takes  a  decision  on  the  precise
quantities  allocated  to  each  producer  for  the  following
year.  This  decision  is  notified  directly  to  the  companies
concerned,  and  is  published  in  the  Official  Journal  of  the
European  Communities.  The  total  quantity  authorised  by
the  Commission  in  stage  2  for  use  by  the  manufacturers
cannot  exceed  the  total  quantity  approved  by  the  Parties
to  the  Protocol  under  stage  1  for  the  year  in  question.

two 

stage  process  means 

the
7.26.(cid:218)(cid:217)This 
Community  has  a  rather  flexible  means  to  ensure  that
CFCs  can  be  phased  down  carefully  in  line  with  the
availability  of  CFC(cid:220)free  alternatives  for  each  of  the

that 

in 

cooperation  with 

7.27.(cid:218)(cid:217)Within  these  overall  totals,  the  Commission,
the  Management
working 
Committee  of  Member  States  and 
the  companies
concerned,  can  use 
the  annual  decision  on  CFC
quantities  to  "fine  tune’  the  actual  quantities  approved
for  each  company.  For  example,  should  alternatives  be
approved  earlier  than  forecast  or  producers  have  large
stockpiles  of  CFCs,  the  quantities  approved  by  the
Commission  would  be  reduced  accordingly.  Conversely,
should  alternatives  not  be  available  as  quickly  as
predicted,  there  would  be  some  flexibility  to  distribute
the  available  CFCs  among  producers  and  among
particular  products 
that  vital
medicines  remained  available.  Should  the  Community’s
transition  be  delayed  for  some  reason,  the  Commission
could  even  submit  a  revised  bid  to  the  Parties  one  year
ahead  requesting  additional  CFCs.  However,  such  a
request  would  only  be  submitted  under  exceptional
circumstances.

to  ensure 

in  order 

7.28.(cid:218)(cid:217)As  regards  the  likely  timetable  for  phasing  out
CFCs  in  line  with  the  availability  of  alternatives,  much
depends  on  how  "availability’  is  defined.  A  new  alter(cid:220)
native  could  not  be  considered  "available’  on  the  day  of
launch.  Some  considerable  time  is  necessary  for  doctors
and  patients  to  become  aware  of  the  new  product,  to  try
it  out  and  to  gather  information  on  its  performance  and
acceptability.  This  information  would  form  part  of  the
post(cid:220)marketing  surveillance  information  which  would  be
a  vital  part  of  the  transition.  Only  when  adequate  post(cid:220)
marketing  surveillance  data  is  available  to  show  that  the
new  alternative 
is  effective,  acceptable,  and  without
serious  side(cid:220)effects  would  it  be  justified  to  remove  the
CFC  product  from  the  market.

7.29.(cid:218)(cid:217)Gathering  adequate  post(cid:220)marketing  surveillance
data  would  take  12  months.  Therefore,  once  an  alter(cid:220)
native  is  launched,  the  Community  could  reflect  that
launch  in  a  reduced  quantity  of  CFCs  requested  from  the
Parties  to  the  Procotol.  The  next  year,  when  the
Commission  comes 
its  decision  on  CFC
take 
quantities,  the  post(cid:220)marketing  surveillance  data  would  be
available  and  if  the  alternative  has  proved  successful,  no

to 

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more  CFCs  need  be  authorised  for  the  manufacture  of
that  product.  Within  a  maximum  of  12  months  from  the
launch  of  an  alternative,  the  CFC  version  it  replaces
would  no  longer  be  manufactured  for  use  in  the  EC.

Stockpiles  of  CFCs  and  CFC  containing  MDIs

7.30.(cid:218)(cid:217)Using  the  essential  use  decision  to  phase  out
CFCs  for  particular  products  or  categories  would  not  in
itself  ensure  that  all  the  CFC  products  concerned  were
taken  off  the  market  in  due  time.  Companies  might
continue  manufacture  using  CFCs  intended  for  MDIs  in
other  categories,  and  manufacturers  outside  the  EC
might  try  to  import  CFC  MDIs  to  fill  the  gap  in  the
market.  These  problems  will  be  addressed  by  careful
monitoring  of  production  and  stockpiles,  import  controls
and  making  CFCs  available  only  for  those  products  still
meeting  the  essential  uses  criteria.

7.31.(cid:218)(cid:217)Once  sufficient 
technically  and  economically
feasible  alternatives  exist  to  enable  the  essential  use
exemption  to  be  withdrawn  for  a  particular  CFC  product
or  category  of  prodcuts,  no  more  CFCs  will  be  available
for  the  manufacture  of  those  CFC  products.  Companies
may  still  be  able  to  sell  stockpiled  MDIs  which  have
already  been  manufactured,  as  there  is  no  obligation  to
withdraw  marketing  authorisation.  However,  companies
should  quickly  reduce  their  sales  of  CFC  products  as  this
would  be  an  important  means  to  ensure  the  successful
take  up  of  their  CFC(cid:220)free  alternative.  It  is  possible  to
envisage  a  period  of  12  months  during  which  the  CFC
product  and  its  CFC(cid:220)free  alternative  are  both  available,
particularly  to  assist  post(cid:220)marketing  surveillance.  After
that  time,  however,  the  continued  presence  of  CFC
products  on  the  market  will  be  unnecessary,  and  might
confuse  doctors  and  patients  involved  in  the  transition.
Companies  should  prepare  plans  to  withdraw  their  CFC
in
suggested 
products  within 
accordance  with  their  doctor  and  patient  education
programmes.

frame  and 

time 

the 

New  MDIs

if  new  MDIs
7.32.(cid:218)(cid:217)This  strategy  will  not  succeed 
containing  CFCs  are  being 
the
European  market  during  the  transition.  To  do  so  would
confuse  patients  and  health  professionals  and  needlessly
prolong  our  reliance  on  CFCs.  Therefore,  as  part  of  this
strategy  from  1  January  1998,

introduced  onto 

-(cid:217)competent  authorities  should  not  give  marketing
authorisation  to  any  new  CFC(cid:220)containing  inhalers;

-(cid:217)the  European  Commission  will  not  approve  the  allo(cid:220)
cation  of  CFCs  for  the  manufacture  of  any  new  MDI
product;

-(cid:217)companies  should  cease  developing  and  promoting

CFC(cid:220)containing  MDIs.

CHAPTER  8

AWARENESS  RAISING

8.1.(cid:218)(cid:217)The  transition  away  from  CFC  MDIs  has  already
started  in  Europe  and  should  largely  be  completed  by  the
year  2003.  The  level  of  awareness  of  dry  powder  inhalers
(DPIs)  and  CFC(cid:220)free  MDIs  among  health  professionals
and  patients  is  still  limited,  however,  and  this  has  to
is
change.  As  more  alternatives  become  available, 
essential  that  an  active  strategy  to  inform  and  involve
patients 
is  developed.  This  will  require  a  concerted
effort,  led  and  coordinated  by  national  governments  with
the  support  and  input  of  health  professionals,  health
services,  patient  associations  and  the  manufacturers  of
asthma  medicines.  Adequate  funds  need  to  be  identified
for  raising  awareness  among  health  professionals  and
patients  if  successful  transition  is  to  occur.

it 

Changeover  and  education

recognised.  There 

8.2.(cid:218)(cid:217)Changeover  to  CFC  free  products  is  unlikely  to
occur  smoothly  without  a  national  or  regional  strategy
being  in  place.  Although  the  strategies  may  differ  in
detail  between  Member  States,  some  common  features
should  be  co(cid:220)operation
can  be 
between  the  professionals  involved  on  a  local  or  regional
basis  to  discuss  how  the  transition  is  to  be  implemented.
Contacts  with  patient  representatives  should  be  estab(cid:220)
lished  at  an  early  stage  to  ensure  that  patients  receive
adequate  information,  both  orally  and  in  writing.  This  is
essential  to  build  the  confidence  of  patients  in  the  new
products.  Further,  the  changeover  of  patients  in  one
region  or  area  should  be  done  at  roughly  the  same  time
the  problems  of  providing  primary  and
to  reduce 
secondary  care  and  the  difficulties  which  would  arise
from  a  long  period  during  which  both  the  old  and  the
new  products  would  be  available.

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8.3.(cid:218)(cid:217)Choice  of  medication  is  invariably  made  by  the
physician  and  not  by  the  patient.  Patients  consider  this
within  the  competence  of  the  physician  and  a  reason  for
consultation.  The  patient  expects  an  explanation  for  the
choice  of  a  specific  medicine,  especially  where  a  change
from  a  familiar  product  is  involved.  Surveys  have  shown
that  when  a  change  from  CFC  inhalers  to  alternatives  is
recommended  by  the  physician  and  adequate  information
is  given,  most  patients  are  happy  to  change  and  do  so
successfully.

including 

8.4.(cid:218)(cid:217)Education  is  a  continuous  process,  a  partnership
between  professionals  and  patients  involving  an  exchange
of  information  and  adequate  opportunity  for  patients  to
express  their  fears  and  concerns.  Although  physicians  are
the  patients’  first  source  of  information  on  medication,
in  asthma
patients  do  consult  other  professionals 
patient
treatment, 
associations,  when 
the
treatment  of  their  disease.  It  is  therefore  of  the  utmost
importance 
same
information  and  give  consistent  advice  to  patients.  With
adequate  preparation  and  reinforcement  of  the  key
to  enjoy  a
messages,  most  patients  are  expected 
trouble(cid:220)free 
to  a
inhaler 
their  CFC 
CFC(cid:220)free  device.

they  have  questions  about 

these  parties  have 

pharmacists 

that  all 

transfer 

from 

and 

the 

Asthma  Patient  Associations

8.5.(cid:218)(cid:217)Most  European  countries  have  asthma  patient
associations,  although  in  the  majority  of  cases  they  are
rather  small.  The  large  associations  in  the  Netherlands,
United  Kingdom,  Italy  and  the  Scandinavian  Countries
have  already  established  their  reputation  as  an  important
smaller
source  of 
information 
associations  can  also  provide  vital 
for
patients.  Some  associations  have  already  produced
written  information  for  patients  on  the  transition.  The
European  Federation  of  Asthma  and  Allergy  Associations
(EFA) 
information  by
the  provision  of 
distributing  fact  sheets  and  other  written  information  to
members  and  associated  organisations.

for  patients.  The 

information 

supports 

Raising  Awareness

8.6.(cid:218)(cid:217)To  raise  awareness,  the  following  actions  should
be  taken:

(i)(cid:217)at  government  level:

Health  departments  should  ensure  that  information  is
including  unbiased
provided 

to  health  professionals, 

information  leaflets  for  patients.  Appropriate  sources  of
finance  should  be  identified  to  support  the  awareness
raising  campaign.  National  health  systems  and/or  health
insurance  schemes  should  prepare  a  plan  to  manage  the
period  during  which  new  products  become  available
while  cheaper  CFC  products  remain  on  the  market.

(ii)(cid:217)at  professional  and  patient  association  level:

8.7.(cid:218)(cid:217)Doctors,  nurses  and  pharmacists  need  to  be  aware
that  the  transition  is  not  optional,  and  that,  over  the  next
few  years,  all  patients  currently  using  CFC  products  will
have  to  change  to  CFC(cid:220)free  devices.  They  should  be
prepared  to  help  patients  understand  the  reasons  for  the
change  and  assist  them  during  the  transition.  Patients
will  require  reassurance  that:

-(cid:217)the  new  inhaler  is  as  safe  and  as  effective  as  the

previous  CFC  inhaler;

-(cid:217)the  new  inhaler  devices  operate  in  very  similar  ways

to  the  CFC  inhalers;

-(cid:217)CFCs  are  damaging  to  the  global  environment  and
not  damaging  to  the  health  of  the  individual  when
inhaled  from  an  MDI;

-(cid:217)although 

they  will 

in
appearance,  dosage,  taste  and  sensation  when  using
the  new  products,  these  differences  do  not  imply  any
reduction  in  effectiveness  of  the  medicines.

experience  differences 

8.8.(cid:218)(cid:217)In  cooperation  with  patient  associations,  an
awareness  campaign  for  patients  should  be  started.  To
prepare  patients  for  the  change  to  alternatives,  various
together  with
methods  are  needed.  Spoken  advice, 
written  and  audio(cid:220)visual  reinforcement  is  likely  to  be
necessary,  involving  some  or  all  of  the  following:

helplines, 

- Patient  associations  -  Patient  associations  have
opportunities  for  direct  contact  with  patients  through
telephone 
regional
branches  and  regular  meetings.  These  associations
can  help  to  produce  written  material  in  a  form  which
in  medical
patients  understand.  Similarly,  articles 
journals 
the  need  and
timetable  for  transition.

inform  professionals  of 

support 

groups, 

- Treatment 

guidelines  -  National  Asthma
Guidelines  should  include  reference  to  the  phaseout
the  new  reformulated
of  CFCs 

in  MDIs  and 

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products.  The  US  National  Heart,  Lung  and  Blood
Institute  (NHLBI)  and  WHO  have 
introduced  a
Global  Initiative  on  Asthma  (GINA).  This  will
increase  international  awareness  of  this  subject  at
symposia  throughout  Europe,  and  on  the  Internet.

brochure  for  professionals  entitled 
"Moving  Towards
CFC(cid:220)free  Metered  Dose  Inhalers’,  produced  by  the
International 
Pharmaceutical  Aerosol  Consortium
(IPAC).

symposia  are  planned. 
the  World  Asthma  Meeting 

- Medical  Symposia  -  Physicians,  researchers  and
pharmaceutical  development  experts  will  present,
discuss  and  evaluate  the  advances  and  latest  devel(cid:220)
opment  of  alternative  treatment.  During  the  next  few
In
years,  many  more 
December  1998, 
in
Barcelona  will  have  CFC  transition  as  a  plenary
session.  The  different  associations  of  general  practi(cid:220)
tioners  and  lung  physicians  can  provide  a  forum  for
discussion  and  evaluation  of  the  latest  developments
in  alternative  treatments,  and  the  promotion  of  a
wider 
and
of 
understanding 
management  of  the  transition.

timetable 

the 

- Promotional  Material  -  Advertising 

and
promotional  material  placed  in  medical  journals  and
circulated  to  physicians  by  pharmaceutical  companies.
It  will  be  critical  that  patients  understand  that  the
need  for  the  change 
is  based  on  environmental
considerations  and  not  for  reasons  of  product  safety
or  cost.

- Support  Groups  -  which  provide  information,
seminars  and  programmes  aimed  at  both  the  general
community  and  targeted  through  schools,  sporting
groups  etc.  For  example,  the  UK  National  Asthma
Campaign  has  produced  a  fact  sheet  to  help  prepare
patients  for  changeover  of  their  inhalers.

important  role 

- Media  Coverage  -  both  national  and  local  media
in  raising  awareness
can  play  an 
among  patients  and,  in  particular,  encouraging  them
to  discuss  their  transition  with  health  professionals.
As  with  all  media  contacts,  care  is  required  to  ensure
that  the  right  messages  are  communicated 
in  a
positive  way.

(iii)(cid:217)at  industry  level:

by 

profession 

advertising 

8.9.(cid:218)(cid:217)Manufacturers  of  MDIs  can  help  in  educating  the
medical 
placing
educational  material  in  medical  journals,  by  supporting
medical  symposia  and  by  making  available  reprints  of
pertinent  articles  and  reports.  They  can  also  produce
information  sheets  for  patients  and  invent  strategies  to
help  inform  both  professionals  and  the  public  of  devel(cid:220)
the
opments  and  alternatives.  A  good  example 

and 

is 

activity 

educational 

8.10.(cid:218)(cid:217)This 
involve
increasing  awareness  of  DPIs  as  well  as  the  reformulated
MDI  products.  As  more  alternatives  become  available  it
is  essential 
is
developed  to  prevent  confusion.

that  a  more  active  patient  strategy 

should 

How  and  When  to  proceed

to  be  ready  by 

the  phaseout  of  CFCs  and 

8.11.(cid:218)(cid:217)The  awareness  raising  campaign  should  start  as
soon  as  possible,  as  many  new  products  are  expected  to
become  available  during  1998.  Strategies  to  manage  the
transition  of  most  patients  to  non(cid:220)CFC  alternatives  will
need 
the  end  of  1998.  General
their
information  on 
replacement  by  alternative  forms  of  treatment  have  to  be
available  when  the  campaign  starts  or  soon  afterwards.
Specific  information  and  relevant  facts  on  reformulated
MDIs  should  be  provided  by  the  pharmaceutical  industry
in  advance  of  the  launch  of  new  products,  and  during
the  period  of  transition  from  CFC  MDIs  to  the  new
alternatives.  Sources  of 
these
activities  have  to  be  identified  as  some  partners  in  the
awareness  raising  campaign  might  not  have  sufficient
means  to  cover  the  costs  of  their  contributions.

financial 

support 

for 

8.12.(cid:218)(cid:217)References

EFA:  The  Patient,  Your  Partner.  Symp.  EFA  in  ERS
Congress,  Nice,  4  Oct.  1994,  Abstracts.

EFA:  Information  and  Decision:  Patients’  Rights.  Symp.
EFA 
in  EAACI  Congress,  Budapest,  4  June  1996.
Abstracts.

M.(cid:216)R.  Partridge:  The 
in  practice:  health
professionals  and  patients.  BJCP  suppl.  89,  1997:32(cid:220)36.

transition 

M.(cid:216)R.  Partridge:  CFC(cid:220)free 
Asthma  Journal,  June  1997,  vol.  2:  No  2:  48.

inhalers:  are  we  ready?,

M.(cid:216)R.  Partride:  Managing 
for
healthcare  professionals,  physicians  and  patients.  Eur.
Resp.  Rev.  1997:7:41.  40(cid:220)41.

the  change: 

issues 

National  Asthma  Campaign  (UK):  NAC  CFC  Free
Inhalers  Survey  1997,  press  release,  7  May  1997.

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J.(cid:216)Molema,  E.M.A.L.  Rameckers,  T  Rolle:  Empower(cid:220)
ment  of  Patients:  a  Threat  or  a  Help?  Monaldi  Arch.
Chest  Dis.,  1995;  50:5,  337(cid:220)339.

E.M.A.L.  Rameckers,  What  do  Patients  Want?  ECACI
1995  Proceedings,  Monduzzi  Editore  1995.

CHAPTER  9

EXPORTS  OF  MDIs  FROM  THE  EC

9.1.(cid:218)(cid:217)Half  of  the  world’s  production  of  MDIs  takes
place  in  the  EC,  and  25(cid:216)%  of  the  Community’s  MDI
production  is  exported.  Approximately  10  million  units
go  to  developing  countries  each  year.  In  addition,  MDI
manufacturing  facilities  located  in  developing  countries
and  operated  by  multinational  companies  often  import
supplies  of  pharmaceutical  quality  CFCs  from  the  EC.  It
is  important  that  the  transition  to  CFC(cid:220)free  MDIs  in  the
EC  does  not  in  disrupt  the  supply  of  important  asthma
and  COPD  medicines  to  developing  countries.  Decision
VIII/10  of  the  Parties  to  the  Montreal  Protocol  requests
companies  to  report  on  steps  being  taken  to  provide  a
continuity  of  supply  of  asthma  and  COPD  treatments
(including  CFC  MDIs)  to  developing  countries.  Decision
IX/19  says  that 
"in  preparing  a  transition  strategy,
Parties  should  take  into  consideration  the  availability  and
price  of  treatments  for  asthma  and  COPD  in  countries
currently  importing  CFC  MDIs’.

Special  situation  of  developing  countries  under 
Protocol

the

9.2.(cid:218)(cid:217)The  Montreal  Protocol  distinguishes  between
developed  and  developing  countries  in  the  phaseout  of
ozone(cid:220)depleting  substances.  Whereas  CFCs  have  been
phased  out  since  1  January  1996  in  developed  countries
(1  January  1995  in  the  EC),  except  for  essential  uses,
developing  countries  have  a  "grace  period’  under  which
CFCs  may  continue  to  be  produced  and  consumed  until
2010  to  meet  "basic  domestic  needs’.

in  developing  countries 

9.4.(cid:218)(cid:217)Demand  for  MDIs 
is
likely  to  increase  with  increased  incidence  of  asthma  and
COPD,  better  access  to  health  care,  improved  diagnosis
and  effective  treatment  becoming  affordable  for  more
people.  Access  to  medicines  in  developing  countries  is
constrained  by  costs,  particularly  for  chronic  conditions
like  asthma  and  COPD.  Maintaining  access  to  affordable
is  a  priority  for
treatment  for  asthma  and  COPD 
involve  the
developing  countries,  and  will 
MDI  producers  in  the  EC.

inevitably 

Strategies  and  targets  for  moving  export  markets  to
alternatives

9.5.(cid:218)(cid:217)While  the  EC  is  managing  its  own  transition  to
CFC(cid:220)free  MDIs,  we  should  also  consider  what  to  do
about  MDI  exports  to  developing  countries.  Steps  should
be  taken  to  ensure  that  the  benefits  of  the  development
and  educational  efforts  carried  out  in  the  EC  to  enable
the  transition  to  CFC(cid:220)free  MDIs  are  transferred  to
developing  countries.  As  part  of  the  nomination  process
to  obtain  essential  use  CFCs  for  exports  of  MDIs,
companies  will  be  asked  to  report  on  what  measures  they
are 
their
the 
customers  in  developing  countries.

transition  among 

facilitate 

taking 

to 

9.6.(cid:218)(cid:217)For  example,  each  MDI  manufacturer  should
strive  to  obtain  regulatory  approval  for  their  CFC(cid:220)free
MDIs  in  developing  countries,  and  make  them  available
there  as  soon  as  possible.  It  makes  little  sense  to  start
new  patients  in  other  countries  on  CFC  inhalers  when
the  CFC(cid:220)free  version  is  already  available.  Companies
increase  awareness  and
should  also  make  efforts  to 
acceptance  of  alternative  inhalation  treatment  methods,
like  DPIs  and  nebulizers.  In  accordance  with  Protocol
Decision  VIII/10,  companies  should  consider  upgrading
their  MDI  manufacturing 
in  developing
countries  to  enable  them  to  produce  CFC(cid:220)free  MDIs.

facilities 

9.3.(cid:218)(cid:217)Developing  countries  currently  obtain  their  MDIs
from  one  or  more  of  three  possible  sources:

Forecast  of  CFC  requirements  to  manufacture  MDIs  for
export  until  2010

-(cid:217)imports  from  developed  countries,  particularly  the

EC;

-(cid:217)production  within  developing  countries  by  multi(cid:220)

national  companies;

-(cid:217)production  within  developing  countries  of  low(cid:220)cost
generic  products  by  independent  local  companies.

9.7.(cid:218)(cid:217)Currently,  companies  request  quantities  of  CFCs
for  MDI  manufacture  for  both  their  home  and  export
markets  together.  Decision  VIII/9  sets  out  an  accounting
framework  for  essential  use  requests  which  will  sepa(cid:220)
rately  identify  the  volumes  of  CFCs  used  in  MDIs  sold
in  the  Community  and  those  used  in  MDIs  for  export.
Even  with  this  change,  it  will  remain  difficult  to  make

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long(cid:220)term  forecasts  of  CFC  requirements,  particularly
for  developing  countries,  where  economic  growth  rates
will  drive  future  demand  for  asthma  treatments.  This  will
be  further  complicated  by  difficulties  in  predicting  the
timing  of  the  transition  away  from  CFC  MDIs  in  these
countries.  Despite  these  difficulties,  predicitions  of  future
CFC  requirements  in  MDIs  for  export  will  have  to  be
made  to  ensure  that  sufficient  pharmaceutical  grade  CFC
is  available  to  meet  demand.

9.8.(cid:218)(cid:217)Production  of  CFC(cid:220)containing  MDIs  for  export
will  have  to  continue  in  the  European  Community  for
some  time  after  our  own  transition  has  been  accom(cid:220)
plished.  Companies  applying  for  essential  use  CFCs  to
manufacture  MDIs  for  export  need  will  need  to  demon(cid:220)
strate  that  they  are  taking  active  steps,  in  co(cid:220)operation
with  the  competent  authorities  of  the  countries  to  which
they  export,  to  promote  the  transition  to  CFC(cid:220)free
inhalers  as  quickly  as  possible,  while  maintaining  the
supplies  of  necessary  medicines  to  patients.

Obtaining  CFCs  to  manufacture  MDIs  for  export  after
phaseout  in  the  Community

9.9.(cid:218)(cid:217)In  order  to  meet  the  commitment  entered  into  in
Decision  VIII/10  of  ensuring  adequate  and  continuing
supplies  of  MDIs 
to  developing  countries,  MDI
producers  will  need  access  to  reliable  sources  of  pharma(cid:220)
ceutical  grade  CFCs  in  sufficient  quantities  to  meet  the
requirements  for  CFC  MDIs  until  these  are  phased  out
in  developing  countries.  Three  possibilities  exist:

-(cid:217)continued  CFC  production  in  the  EC  as  normal;

-(cid:217)periodic  "campaign’  production  in  the  EC;

-(cid:217)import  of  CFCs 

from  producers 

in  developing

countries.

These  possibilities  are  discussed  further  in  Chapter  10,
"CFC  Production  Issues’.

CHAPTER  10

CFC  PRODUCTION  ISSUES

Introduction

10.1.(cid:218)(cid:217)CFCs  for  use  in  the  production  of  MDIs  are
manufactured  in  the  EC  by  4  producers.  These  are:

AlliedSignal  (The  Netherlands)
Ausimont  (Italy)
Elf(cid:220)Atochem  (Spain)
Rhone  Poulenc  (UK)

These  producers  also  produce  CFCs  for  the  manufacture
of  MDIs  in  a  number  of  developed  and  developing
countries.

10.2.(cid:218)(cid:217)These  manufacturing  facilities  produce  CFCs  to
a  defined  purity  specification  as  laid  down  by  the  indi(cid:220)
vidual  MDI  manufacturer.  CFCs  of  specified  purity  are
necessary  to  meet  the  requirements  of  product  regis(cid:220)
tration  in  the  countries  where  the  CFC  MDIs  are  sold.  If
an  MDI  manufacturer  had  to  change  to  a  different  CFC
producer  (even  amongst  those  within  the  EC)  with  a
different  product  purity  profile,  this  could  mean  that  the
MDI  manufacturer  would  have  to  re(cid:220)submit  its  MDIs
for  registration.  As  a  result,  MDI  manufacturers  tend  to
purchase  their  CFC  supplies  from  one  or  two  CFC
producers  only.

Future  Supply  of  CFCs  for  MDI  Manufacture  within  the
EC

10.3.(cid:218)(cid:217)CFC  producers  within  the  EC  produce  mainly
CFC  11  and  CFC  12  for  use  in  MDI  manufacture  within
the  EC  and  world(cid:220)wide.  They  also  produce  CFCs  to
meet  the  basic  domestic  needs  of  countries  operating
under  paragraph  1  of  Article  5  of  the  Montreal  Protocol.
In  1996,  EC  CFC  producers  produced  3(cid:216)062  tonnes  of
CFC  11  and  4(cid:216)757  tonnes  of  CFC  12  for  MDI  manu(cid:220)
facture  world(cid:220)wide  and  9(cid:216)430  tonnes  of  CFC  11  and
14(cid:216)280  tonnes  of  CFC  12  to  meet  the  basic  domestic
needs  of  developing  countries.

10.4.(cid:218)(cid:217)There  has  been  extensive 
industrial  rational(cid:220)
isation  of  CFC  production  within  the  EC  during  the  last
few  years,  and  the  number  of  producers  has  reduced  by
half.  CFC  production  has  been  concentrated  upon  small
manufacturing  facilities  which  are  more  economically
viable.  These  facilities  are  only  cost(cid:220)effective  while  their
production 
level.  This
remains  above  a  minimum 
minimum  level  is  determined  by  a  number  of  parameters
and  will  be  different  for  each  producer.  The  remaining
plants  stay  above  the  minimum 
level  of  production
through  a  combination  of  production  for  MDIs  and  for
the  basic  domestic  needs  of  developing  countries.  The
reduction  in  the  quantity  of  CFCs  required  by  MDI
manufacture  during  the  transition  period  will  cause  CFC
producers  in  the  EC  to  review  the  operation  of  their
facilities  and  may  lead  to  further  closures.  However,

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although  further  rationalisation  of  production  capacities
cannot  be  excluded,  over  the  next  five  years  it  is  likely
that  demand  for  CFCs  for  the  basic  domestic  needs  of
developing  countries  will  enable  the  continued  operation
of  at  least  some  CFC  production  facilities  within  the  EC.

10.5.(cid:218)(cid:217)It  has  been  indicated  in  the  April  1997  TEAP
Report  that  once  demand  for  CFCs  reduces  to  below  the
minimum  cost(cid:220)effective 
level  for  the  producers,  CFC
production  could  be  maintained  by  running  "production
campaigns’  and  storing  the  CFCs  until  needed.  For  the
reason  set  out  above,  it  is  unlikely  that  this  will  be
necessary  for  the  EC  during  the  transition  period.
However,  the  option  of  a  final  production  campaign
should  be  maintained  for  the  period  towards  the  end  of
the  EC  phaseout  of  CFC  MDIs.  Such  a  "final  campaign’
would  help  maintain  the  economic  viability  of  CFC
producers.  The  implications  for  developing  countries  are
discussed  below.

is 

important  to  remember  that 

integrated
10.6.(cid:218)(cid:217)It 
licensing  of  CFC  plants  requires
pollution  control 
forward  planning  and  does  not  allow  for 
"ad  hoc’
production  or  extensions  of  production  periods.  A
managed  transition  strategy  will  help  to  forecast  future
CFC  requirements,  including  the  possible  need  for  a
"final  production  campaign’.

Production  of  CFCs  for  MDI  Manufacture  for  Export  to
Developing  Countries

to 

the  Parties 

the
10.7.(cid:218)(cid:217)Decision  VIII/10(cid:216)(9)  of 
Montreal  Protocol 
requests  MDI  manufacturing
companies  to  take  steps  to  provide  a  continuity  of  supply
of  asthma  and  chronic  obstructive  pulmonary  disease
(COPD)  treatments  (including  CFC  MDIs)  to  importing
countries.  In  order  that  these  supplies  can  be  maintained,
MDI  producers  need  access  to  reliable  sources  of  phar(cid:220)
maceutical(cid:220)grade  CFCs  in  sufficient  quantities  to  meet
the  needs  of  importing  countries  where  the  transition  to
non(cid:220)CFC  products  will  proceed  more  slowly.

10.9.(cid:218)(cid:217)Given  that  there  is  no  immediate  prospect  of
CFC  shortages  for  MDIs,  it  is  premature  to  make  firm
decisions  on  CFC  production  for  the  future  manufacture
of  MDIs  for  export  to  developing  countries.  A  number
of  possibilities  exist,  and  it  is  not  yet  clear  which  would
represent  the  best  way  forward.  One  option  would  be
"production  campaigns’  whereby  CFC  manufacturing
facilities  would  be  operated  from  time  to  time  to  produce
a  sufficient  stockpile  of  CFCs  to  supply  MDI  manu(cid:220)
facture  for  export.  Considering  this  approach,  the  April
1997  Technical  and  Economic  Assessment  Panel  (TEAP)
Report  indicated  that  a  period  of  2  years  might  be
required  to  establish  an  adequate  stockpile  of  CFCs
through  "campaign  production’,  should  this  be  required.

10.10.(cid:218)(cid:217)While  this  idea  is  prima  facie  appealing  in  terms
of  possible  production  cost  savings,  its  main  disadvantage
is  the  difficulty  of  accurately  assessing  future  demand  for
CFCs.  Further,  there  are  no  assurances  that  CFCs  which
are  stockpiled  for  perhaps  5  years  will  not  degrade,  nor
that  the  MDIs  ultimately  produced  with  these  stockpiled
CFCs  will  not  deteriorate  faster  than  MDIs  produced
with  freshly(cid:220)produced  CFCs.  Current  experience  is  that
CFCs  are  stable  over  2  years  storage.  Another  potential
risk  from  the  point  of  view  of  patient  health  is  that  CFC
producers  will  produce  large  batches  of  CFCs  and  will
then  close  down  their  production  facility.  This  could
mean  that  CFCs  would  no  longer  be  available  to  manu(cid:220)
facture  MDIs  for  export  to  countries  where  they  remain
essential  to  patient  health.

10.11.(cid:218)(cid:217)A  second  possible  source  of  CFCs  for  MDI
producers  would  be  from  production  facilities  located  in
developing  countries.  This  is  not  currently  thought  to  be
a  realistic  option.  Production  facilities 
in  developing
countries  would  need  to  be  registered  and  the  CFCs
obtained  approved  by  the  competent  Regulatory  Auth(cid:220)
orities,  including  those  in  the  country  of  MDI  manu(cid:220)
facture.  The  CFC  production  would  have  to  comply  with
stringent  good  manufacturing  practice 
(GMP)  and
demonstrate  reliable  and  consistent  production  to  a
defined  purity 
specification.  This  could  present  a
challenge  for  CFC  producers  in  developing  countries.

10.8.(cid:218)(cid:217)While  this 
is  unlikely  to  present  a  problem
during  the  EC  transition  period  for  the  reasons  already
discussed,  there  is  a  concern  that  once  CFC  MDIs  have
been  phased  out  in  the  EC,  pharmaceutical(cid:220)grade  CFCs
could  become  in  short  supply  for  the  continued  manu(cid:220)
facture  of  MDIs  within  the  EC  for  export.

10.12.(cid:218)(cid:217)Given 
the  continued  production  of  CFCs
within  the  EC  to  supply  the  basic  domestic  needs  of
developing  countries,  it  is  most  unlikely  that,  over  the
period  of  the  EC  transition,  there  will  be  a  shortage  of
pharmaceutical(cid:220)grade  CFCs 
the  manufacture  of
MDIs  in  the  EC,  whether  for  use  in  the  Community  or
for  export.

for 

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CHAPTER  11

11.5.(cid:218)(cid:217)Assessment

THE  ESSENTIAL  USE  PROCESS:  OVERVIEW  AND
TIMETABLE

11.1.(cid:218)(cid:217)This  Chapter  describes  the  process  by  which  an
essential  use  exemption  for  the  Metered  Dose  Inhaler
(MDI)  is  obtained  in  the  European  Community  and
outlines  the  timetable  for  the  completion  of  that  process.

-(cid:217)The  Technical  Options  Committee  (ATOC)  and  the
Technology  and  Economic  Assessment  Panel  (TEAP)
of  the  Parties  to  the  Montreal  Protocol  review  nomi(cid:220)
nations  and  determine  if  they  meet  the  criteria  for  an
essential  use  established  by  Decision  IV/25  and
whether  the  quantities  requested  are  justified.  TEAP
its  findings  and  recommendations  to  the
reports 
Open(cid:220)Ended  Working  Group 
the
Montreal  Protocol;

(OEWG) 

to 

The  Essential  Use  Process:  Overview

11.2.(cid:218)(cid:217)The  Parties  to  the  Montreal  Protocol  established
the  framework  for  the  essential  use  process  at  their
Fourth  Meeting  in  1992  in  Copenhagen.  The  essential
use  process  in  the  Community  is  implemented  through
the  provisions  of  Regulation  (EC)  3093/94.

-(cid:217)The  OEWG  reviews  TEAP’s  recommendations  and
forwards  a  draft  decision  on  essential  uses  for
consideration  by  the  Meeting  of  the  Parties;

-(cid:217)The  Meeting  of  the  Parties  decides  whether  the
nominations  meet  the  essential  use  criteria  and,  if  so,
what  quantities  of  controlled  substances  are  to  be
authorised.

11.3.(cid:218)(cid:217)The  essential  use  process 
Community  involves  three  distinct  elements:

in 

the  European

Time  Required:  approximately  6(cid:220)9  months.

1.(cid:217)the  nomination  of  essential  uses  for  future  years,
including  a  request  for  specific  quantities  of  CFCs  for
essential  uses  in  a  given  year;

11.6.(cid:218)(cid:217)Licensing

2.(cid:217)the  assessment  of  those  nominations  and  a  decision  by

the  Parties  to  the  Montreal  Protocol;

3.(cid:217)the  review  and  licensing  of  essential  use  quantities  by
the

the  European  Commission 
assisted 
Management  Committee  of  Member  States.

by 

The  steps  that  must  be  taken  under  each  of  these
elements  are  as  follows:

11.4.(cid:218)(cid:217)Nomination

-(cid:217)The  Commission  issues  a  Notice  to  Users,  calling  on
MDI  manufacturers 
for
to 
essential  use  authorisation  indicating  the  quantities  of
CFCs  they  require  for  the  following  year.

submit  applications 

-(cid:217)MDI  manufacturers  submit  applications  for  essential

use  authorisation  to  the  Commission.

-(cid:217)The  Commission,  in  consultation  with  the  Article  16
Management  Committee, 
applications
submitted  by  MDI  manufacturers,  allocates  quantities
of  CFCs  for  essential  uses,  and  issues  essential  use
licenses.

reviews 

-(cid:217)IPAC  prepares  and  submits  nomination  requests  in
each  Member  State  where  MDIs  are  manufactured;

Time  Required:  approximately  3(cid:220)6  months.

-(cid:217)Member  States  review  the  IPAC  submissions,  add
any  approved  quantities  requested  by  non(cid:220)IPAC
companies  and  forward  nomination  requests  to  the
European  Commission;

-(cid:217)the  European  Commission  reviews  the  nominations
received  from  Member  States,  combines  them  and
forwards  a  nomination  on  behalf  of  the  European
Community 
the  United  Nations  Environment
Programme  (UNEP).

to 

11.7.(cid:218)(cid:217)In  any  given  year,  each  element  of  the  essential
is  being  undertaken  concurrently.  For
use  process 
example,  the  essential  use  process 
in  the  European
Community  in  1997  involved  the  approval  and  licensing
by  the  Commission  for  1998,  assessment  by  TEAP  and
the  Parties  of  the  nomination  for  1999,  and  preparation
by  IPAC  and  other  companies  of  the  nomination  for
2000.

Time  Required:  approximately  6  months.

The  diagram  below  shows  the  Essential  Use  Process  in
the  European  Community  in  1997.

20.11.98

EN

Official  Journal  of  the  European  Communities

C  355/29

The  Essential  Use  Process  in  the  European  Community:  1997

UNEP

2000
Nomination

Article 16
Management
Committee

1999
Assessment
and 
Allocation

Consultation

European
Commission
(DG XI)

1998 
Essentiality
Review

Issuance of 1998 
Essential Use
Licenses

IPAC

2000
Nomination

2000
Nomination
Request

Member States

C  355/30

EN

Official  Journal  of  the  European  Communities

20.11.98

PLANNING  FOR  THE  ESSENTIAL  USE  PROCESS:  TIMETABLE

The  diagram  below  describes  the  timetable  for  the  essential  use  process  in  1997:

1st Quarter

Essential  Use  Timetable:  1997
3rd Quarter

2nd Quarter

4th Quarter

1998
LICENSES

1999
ASSESSMENT

2000
NOMINATIONS

May
DG XI 
reviews
essentiality

September
DG XI 
publishes
Notice to
Users

October
MDI
manufacturers
submit license
applications

November-
December
DG XI 
issues
licenses

March-April
Meetings of
Aerosols
TOC and 
TEAP

June 3-6
15th Meeting of
Open-Ended 
Working Group
(OEWG) in
Nairobi, Kenya

September 8-17
9th Meeting of the
Parties in Montreal,
Canada

November
DG XI,
Article 16
Management
Committee
act on 
nomination
requests

January 31
European
Union
submits
nomination
to UNEP

September-
October
IPAC submits
nomination
requests

May-August
IPAC prepares
nomination request