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Reformulation
of MDIs
Reformulation of MDIs
has proven far more difficult than initially anticipated. At first,
it was widely assumed that CFCs could be replaced with new propellants
without significant change to the medicinal formulation or the mechanical
device itself.
However, CFC MDIs constitute
a highly successful balance of complex forces. A change in one element
of the design–the propellant–has required changes to varying
degrees of other components resulting, ultimately, in an entirely
new delivery system.
The major steps in the
CFC-free MDI development process are summarised below:
- Formulation development
using HFC propellants
- Toxicology studies
on HFC propellants
- Component and package
development (valve, elastomers, etc.)
- Toxicology studies
on new HFC-based formulation
- Stability testing
on finished MDI product
- Clinical studies
on new formulation (tests in humans)
- Regulatory review
and approval, including post-market surveillance
- Market introduction
- Payor, physician
and patient acceptance
Challenges
Figure 1 shows the elements
of the MDI delivery system. Figure
2 indicates the extent to which individual elements may have to
be replaced in the development of CFC-free MDIs.
Elements
of an MDI
Figure
1
Figure
2
CFC-Free Development Physical
Components
An MDI is made up of
numerous physical components, including a canister, elastomers,
a valve, and an actuator. Some of these components are themselves
extremely complex. A single valve, for example, may consist of over
25 separate parts. Many of these components were found to interact
with the new propellants in ways never previously imagined.
Formulations
In addition to creating
a new device, MDI companies have had to develop new formulations.
The surfactants and co-solvents that worked so well with CFCs have,
in many instances, proven incompatible with the new HFC propellants.
Almost every element in this mix is being redeveloped. Only the
active ingredients remain unchanged.
Regulatory
Review
Today’s requirements
for demonstrating safety and efficacy, dosing consistency, stability,
and purity are more stringent than ever before. As a result, the
process of pharmaceutical development and approval is far more time-consuming
than it was just a few years ago.
Industry
Efforts
In 1990, the pharmaceutical
industry undertook an unprecedented joint testing program to demonstrate
the safety of HFCs -134a and -227 as propellants for medical inhalers.
Currently, more than 1,400 scientists, at 90 laboratories, in 10
countries, are at work on the development of replacement products
with these new propellants. The industry has already spent over
$1 billion on this project and anticipates continued considerable
investment to complete it.
These efforts are now
bearing fruit, with CFC-free MDIs introduced into at least 40 countries.
Others are in the regulatory pipeline, and their approval is expected
within the next several years.
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