History of the Pharmaceutical Propellants
HFA 227 and HFA 134a –
IPACT I, IPACT II, and the Role of Solvay

When it was confirmed in the 1980s that fully halogenated CFCs harm the ozone layer in the upper stratosphere, extensive investigations were carried out to identify suitable CFC replacement components for various applications including MDIs.

In 1989, a consortium by the name of IPACT I formed to investigate HFA 134a as a potential CFC replacement candidate for use in medical sprays. This was followed by IPACT II for HFA 227 in 1990. Both, IPACT I and IPACT II (International Pharmaceutical Aerosol Consortium for Toxicity Testing) comprise major pharmaceutical aerosol manufacturers sponsoring the extensive toxicological tests for HFA 227 and HFA 134a to confirm their use for medical products including
MDIs.

The main studies – carried out from 1990 to 1993/4 and laid down in IPACT I/ II dossiers submitted to all major countries for support of medical product applications containing HFA 227 and HFA 134a – were reviewed by the European Health Authorities (CPMP – Committee for Proprietary Medicinal Products) and received positive opinions as cited below:

Solkane® pharma –
History of the Pharmaceutical Propellants HFA 227 and HFA 134a –
IPACT I, IPACT II and the Role of Solvay

IPACT I International Pharmaceutical Aerosol Consortium for Toxicity Testing of HFA 134a
IPACT II International Pharmaceutical Aerosol Consortium for Toxicity Testing of HFA 227
CPMP Committee for Proprietary Medicinal Products

“The Committee considers that HFA-134a of the specified quality (in annex) could be a suitable alternative to the CFCs currently used in the formulation of medicinal products, incl. metered dose inhalers for the treatment of asthma.” [1]. In this report, the specifications for HFA 134a were disclosed in the annex.

The positive opinion for HFA 227 was similar, but did not publish the specifications. Instead, it referred to “the specification as applied for” as follows: “The Committee considers that HFA 227 at the specification applied for is a suitable alternative to the CFCs currently used in the formulation of medicinal products, incl. metered dose inhalers for the treatment of asthma.” [2].

Thus, both HFA 277 and HFA 134a can be used in medical products when they comply with the quality assessed by Health Authorities because there are still no monographs established for either HFA 227 or HFA 134a. In the case of HFA 227 it must comply with Solvay’s quality standards because all the IPACT II toxicological studies were carried out with Solvay’s (formerly Hoechst AG) support as the sole supplier of HFA 227. Solvay (formerly Hoechst AG) submitted its Drug Master File for the manufacture and quality control of HFA 227 as part of the IPACT II
dossier.

In the case of HFA 134a, the quality must comply with the quality standards as disclosed in Europe by the CPMP as referred to above, or for the US market as proposed by the FDA CDER October 1998 Draft Guidance for Industry on MDIs and DPIs [5].

Since then, Solvay has optimised its manufacturing processes and quality with many DMF updates, and finally initiated an independently coordinated CPMP review of all amendments. These were finally “approved” in December 1998 and June 2001 with the following conclusion:

”Conclusion
The toxicological properties of HFA 227 were previously assessed to an adequate extent (CPMP/391/97).

Comparing the purity of Solkane® 227 pharma with that of the Hoechst test batches used to perform the toxicity tests reported by IPACT II, it can be concluded that Solkane® 227 pharma complies with the pharmaceutical grade specifications for this compound and that it contains less concentrations of the comparable impurities than the Hoechst tox test batches. [...]

Overall Conclusion
HFA 227 produced by Solvay, Solkane® 227 pharma, is a suitable alternative to the CFCs currently used in the formulation of medicinal products, including metered dose inhalers for the treatment of asthma.” [3]

The approved DMFs were subsequently submitted to all countries for customer support.

As such a review is unique in the case of HFA 227, Solvay is setting the standard for HFA 227 in the medical world.

In the case of Solkane® 134a pharma, Solvay submitted its Drug Master Files in Canada in 2001, in the USA in 2002, and to the rest of the world, including all European countries in 2003. Hereby Solvay fully complies with all specifications published by the CPMP [1, 4, 6] as mentioned above and the FDA [5].

MDI Technology for Inhalation and Nasal/Buccal Drug Delivery

Metered Dose Inhalers (MDIs), first introduced in the 1950s as a novel therapy for treating respiratory diseases like asthma and chronic obstructive pulmonary disorder (COPD), are important medicines.

Asthma often occurs in the form of life threatening, acute attacks which need immediate treatment. Therefore, patients always have to carry with them the necessary active substance in the small pocket-sized dispensers, the metered dose inhalers. The dispenser contains a mixture consisting of the propellant and the pharmaceutical active substance dissolved or suspended in the liquefied propellant and sometimes with further excipients such as cosolvents and /or surfactants added in very small amounts. When the patient actuates the MDI, the propellant immediately evaporates at ambient conditions and produces a fine spray, the aerosol.

The incidence of asthma in developed countries is around 5 to 8% of the population and increasing at an average rate of around 5% per year. Asthma and COPD are particulary prevalent amongst children, as the incidence in this group now approaches 15% in Western Europe.

Worldwide, at least 300 million people suffer from asthma, and a comparable number from COPD. A minimum of 50 to 60 million patients therefore rely on metered dose inhalers. There is international consensus that the primary treatment of these diseases should be via inhalation – with the MDI remaining the dominant inhaled delivery system in most countries and for all categories of drugs.

Major advantages of MDIs over oral therapy and stationary nebulisers are the ease of use, its reliability, its self-contained power source, the low costs per unit, and most important, the high patient compliance, including use by young children.

Fig. 10: Metered Dose Inhaler (MDI)

The MDI is a pocket-sized, hand-held, pressurised multiple-dose inhalation delivery system. It delivers small, precisely measured therapeutic doses, greatly minimising the risk of adverse side effects. Unlike most nebulisers, it is portable and convenient to use.

The function of an MDI is the consistent delivery of the same amount of medication in the form of an aerosol. This allows deposition in the passageways of the lungs.[36]

MDIs are used for the inhalation of all commonly prescribed respiratory medication and account for 70% of all inhalation therapy in the world’s fifteen largest patient populations.[36]

A broad range of medications worldwide has been developed for the treatment of asthma, chronic obstructive pulmonary disorder (COPD) and respiratory infection.

Already available as HFA-MDI medications are e.g. disodium cromoglycate, nedocromil, reproterol, isoproterol in combination with atropinmethylbromide and dexamethasone, procaterol, salmeterol, salbutamol, beclomethasone, fenoterol, ipratopium bromide, fluticasone, and combinations thereof.[35]

HFA MDIs are more efficient than CFC MDIs because virtually every aspect of MDIs has improved in recent years.

Moreover, MDIs are capable of systemic delivery, including proteins and peptides, and are also developed for nasal and buccal drug delivery.

Diseases currently targeted for pulmonary or buccal drug delivery include, among others, diabetes, Alzheimer’s, influenza, multiple sclerosis, pain disease, cystic fibrosis and osteoporosis.

Fig. 11: HFA 227 propelled MDI Product “Stomerin” launched by Fujisawa in September 2001 in Japan

Fig. 12: Development of world asthma market