CFC replacements: safety testing, approval for use in metered dose inhalers

Area of Science:

• Pharmacology and Toxicology
• Respiratory Medicine

Background:

• Hydrofluoro-alkanes (HFAs), specifically HFA-134a and HFA-227, are being evaluated as replacements for chlorofluorocarbons (CFCs) in metered dose inhalers (MDIs).
• Extensive nonclinical safety testing is sponsored by industry consortia (IPACT-I, IPACT-II) to assess the safety of these propellants.

Purpose of the Study:

• To predict the safety of HFA-134a and HFA-227 as propellants in metered dose inhalers (MDIs).
• To determine if repeated exposure to multiples of patient doses causes adverse reactions in animal models and in vitro systems.

Main Methods:

• Nonclinical safety testing involving intact animals and in vitro systems.
• Exposure to HFA-134a and HFA-227 at multiples of patient doses under conditions simulating human administration.
• Evaluation of systemic exposure levels, frequency, and intervals of use.

Main Results:

• The primary concern for toxicity with HFAs appears to be indirect effects from oxygen deprivation at very high concentrations, rather than intrinsic toxicity.
• The U.S. FDA's requirement for proof of toxic effects, even at excessive doses, is questioned for these essentially inert gases.

Conclusions:

• HFA-134a and HFA-227 are likely to be approved as MDI propellants if intrinsic toxicity is not detected.
• Given the lengthy testing timelines (estimated 5 years), CFCs will likely remain available for MDI use in the interim.