Medical Propellants – a journey from CFC to HFA 152a

We interviewed Dr. Tim Noakes, Koura’s Technical Associate, who has had a fundamental role in the creation of the HFA medical propellant business for ICI up to today with Koura.

Having worked in this area for over 30 years he talks through the background, challenges, and outcomes during the journey from CFC to HFA 152a medical propellants.

The catalyst for change came in the early 1980s, when evidence was found that chlorofluorocarbons (CFCs) might be involved in the destruction of stratospheric ozone.

At the time, CFCs were found in a number of applications, from hairspray to refrigerators, and they were also in pressurized meter dose inhalers (pMDIs), commonly used to treat asthma and other lung illnesses.

By 1987, a global consensus was reached that a ban on future use of CFCs was needed, and the Montreal Protocol was enacted.

At the time, it was a revolutionary approach at tackling the growing concern of ozone depletion on a global scale. However, it had major ramifications for pMDI filling, as all changes in the manufacture or use of medicines must be demonstrated to be properly safe by law – and this was going to take time that was in scarce supply!

The Montreal Protocol phased out general use of CFCs between 1992-1996 in the developed world, and somewhat later in the developing world. However, it was recognised that substantial difficulties would slow down the qualification and adoption of alternative non-ozone depleting propellants in the pMDI application.

This was due to the safety and regulatory processes that proposed changes to pMDIs must go through before receiving approval.  This was expected to be around a 10-year period, so a system of annually reviewed CFC Essential Use Allowances was put in place to manage the process.

The race was on!

The introduction of the Montreal Protocol not only made the search to find a new environmentally sustainable medical propellant a priority, but it also opened the door for sweeping manufacturing and quality improvements through pressure from regulators and customers.

Prior to the Montreal Protocol, the lines were somewhat blurred between industrial and medical use of CFC propellants, and you could find CFC manufacturers supplying their industrial grade propellant for the medical market with no significant alteration to the product for medical use, just some extra testing.

So not only did we have to find a new, safe, non-ozone depleting propellant that worked in pMDIs, we also had to manufacture or otherwise finish it in such a way that it was fully in compliance with medical industry quality requirements, in particular current Good Manufacturing Practice (cGMP).

This ‘double-barrier’ of requirements drastically thinned the number of propellant manufacturers prepared to invest in producing a specialist ‘niche’ grade of their new HFC gases, such as 134a! Whilst there had been at least ten CFC manufacturers who supplied the ‘old’ pMDI industry, this number reduced to three in the change to HFC propellants; ICI was the leading player in this group.

Quality defined

In the days of CFC pMDI propellants, medical propellant supply sat alongside its counterpart on the industrial aerosol side, with no great attention or differentiation between the two from regulators or customers – for example, there was no need for a DMF (Drug Master File) – but that changed with the advent of new ‘modern’ medical propellants driven by compliance with the Montreal Protocol.

Suppliers and users found that though candidate HFCs such as 134a had been proven safe for industrial use, the toxicological trials carried out were not rigorous enough for inhalation use.  Toxicological work had to be repeated and extended to prove the safety, to the satisfaction of both European and US regulatory authorities.

Furthermore, it was appreciated that ‘modern’ medical propellant manufacturers would have to produce DMFs which would need to be lodged with the relevant regulatory authorities.

These were documents they would have to fully comply with in future; describing all key aspects of the development, manufacturing, quality control, release and transport of the propellants, where any deviation could spell trouble at audit time.  Processes described in the DMF could then not be changed without formal updating and change control – a real shock to refrigerant manufacturers unfamiliar with these standard requirements of the medical industry!

These changes in aggregate led to the birth of a new business – the production of top quality inhalation excipients under the Zephex^© brand.

Over the years, we have become much more familiar with these requirements. Nowadays, the Zephex^© team prides itself in advancing and defining current best practice for producing these gases – putting body to the ‘c’ in cGMP.

Today, Koura is the world’s favourite supplier of these propellants – indeed, in a number of markets (such as the US), we are the only accredited or active supplier due to the hurdles involved in demonstrating the right levels of regulatory compliance.

Being at the forefront of change

Back when we were searching for suitable CFC replacements, we followed a carefully staged approach that led us to identifying HFC 134a as the lead candidate replacement for CFC-12 in pMDIs. A large number of candidate molecules were first listed.

To get on the list, the candidate molecule had to have physical properties which would seem to make a possible pMDI propellant. The list was then sent through a number of sieves (in rough order of priority, going down to ‘nice to have’):

• Is there good evidence suggesting that this molecule, if subjected to a full inhalation tox study, would pass?
• Has it zero ozone depletion potential?
• Can it be produced at a cost similar to medical CFCs? Is it already at scale, or will be made at scale soon?
• Are there any perceived major issues in formulating drugs in this material?
• Is it non-flammable?

A daunting list – not many molecules made it through! In the end, two HFC molecules, 134a and 227ea, were selected by propellant manufacturers as candidate medical propellants, with ICI leading with 134a.

Medical standard toxicological studies and a long and complex development programme followed, all of which were happily crowned with success, leading to the range of pMDI formulations that we employ to this day.

At the forefront of our work, as we’ve always done and continue to do, we have care and awareness regarding the environmental impact of our products at the heart of our development programmes.

FA 152a. Back in the 1980s, the focus was on finding a product which had no impact on stratospheric ozone. Now science has moved forward, and environmental stewardship is focused on Global Warming Potential (GWP) of products – and we’re at the forefront of change again.

Having been through the experience (at times painful), of going from CFC to HFA, we were a good place to use essentially the same methodology to find a molecule which has a GWP so low that any environmental interaction would be truly de minimis – whilst at the same time being at least as effective and safe as the incumbent propellants.

We operated the sieves and we were successful, although HFA 152a was the only molecule to pass our stringent criteria. This has ensured that patients will have access to the pMDI dosage form for decades to come.

The knowledge and experience we have built up since the 1990s; from cGMP as applied to these propellants, to quality assurance and to package management, all acted as a solid foundation to build a world-class team, which has been further added to at Koura.

When I look at the world leading highly skilled team and business we have today, it’s a long, long, way from a (long retired) senior manager telling me to have a quick look at some CFC specs and ‘make them look medical’.