Pharmaceutical Manufacturing Handbook: Production and

FIGURE 1
Schematic of MDI.
METERED DOSE INHALERS 691
ing CFC propellants were granted essential - use exemptions until viable alternatives
became available. Therefore, with this impending withdrawal, a consortium of pharmaceutical
companies (IPACT - I and IPACT - II) worked to identify and toxicologically
test alternative propellants for MDIs. HFA 134a and HFA 227 were identifi ed
as viable alternatives and the task of reformulation began. At fi rst look, it appeared
that the most expeditious route to replacing a CFC product would be to produce a
suspension HFA MDI with exactly the same in vitro characteristics as the CFC
MDI. This would prove to be a time - consuming route [123, 124] . While some manufacturers
focused on producing HFA products with identical characteristics to the
current CFC versions to accelerate the pathway through clinical testing to market.
Others undertook extensive research and development in the area of HFA formulation
options, and this has led to the possibility of utilizing the MDI for both local
and systemic administration. During this reformulation effort, the industry has
taken the opportunity to address some of the other shortcomings of the MDI [125] .
Among these issues were poor peripheral lung delivery, variable dose delivery, and
limitations as to the dose capable of being delivered to the lung (typically about
1 mg) [126] .
The replacement of CFC MDIs with inhalers formulated with the HFA propellants
is now well underway in Europe. Although progress in the United States has
been slower, with the introduction of suitable alternatives for albuterol inhalers, the
FDA has ordered that CFC albuterol MDIs be withdrawn from the market by the
end of 2008 [127] . Examples of reformulated products available in the United States
include Ventolin HFA, which is a suspension albuterol sulfate formulation using
HFA 134a alone. ProAir is an alternative albuterol sulfate product manufactured
by Ivax which contains ethanol and HFA 134a. Xopenex HFA has recently been
approved for marketing in the United States [128] . This product contains levalbuterol
tartrate (R - albuterol enantiomer) together with HFA 134a, dehydrated
alcohol, and oleic acid as a suspension formulation. Table 1 summarizes the HFA