Butterworth Laboratories’ latest article, published on the Pharmaceutical Technology website, explains why the latest guideline is significant in analytical procedure development for pharmaceuticals.

To read the article, click here

Come and join us at the JPAG Meeting being held at the Royal Society of Chemistry, Burlington House, London at the JPAG Meeting on 21st March 2024.

Raw materials, APIs and excipients play an important role in the manufacturing of pharmaceutical products therefore it is important to assess and monitor quality of these materials throughout the product lifecycle. This symposium will present an overview of testing and risk assessment of these pharmaceutical product components throughout the life cycle with presentations and a panel discussion covering topics related to our key themes below:
– pharmacopoeial monographs for assessing raw materials
– regulatory perspectives (ICH Q7, ICH Q11) covering aspects for small molecules, biologics and ATMPs
– risk assessment of raw materials
– Good Manufacturing Practice
– physical testing including incoming receipt of API & excipients
– method optimisation and development
– stability of APIs
– supply chain impact & resilience
– sustainability

Speakers:
Dr Ralph Adams – Manchester University & RSC NMR group
Dr Hisham Al-Obaidi – University of Reading School of Pharmacy
Rodrigo Arias – DFE Pharma & IPEC Federation
Iain Moore – EXCiPACT asbl
Richard Smalley – Consultant and QP Assessor
Trevor Watson – MHRA
Michael Whaley – Medicines and Healthcare products Regulatory Agency (MHRA)
Antonia Wierzbicki – Waters

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HFAs as a propellant in pMDIs for the treatment of asthma successfully addressed the problem of ozone depletion in the 1990s, but its contribution to global warming means it now must be phased out.

As the headlines about the climate emergency get ever more chilling, the propellants used in pressurised metered-dose inhalers (pMDI) for the treatment of asthma are once again under intense scrutiny. Frank Judge, consultant chemist at Butterworth Laboratories Limited, believes the industry is behind the curve in rolling out next-generation pMDIs that reflect the latest scientific understanding about the atmosphere and global warming.

Judge says: “Inhaler propellants have been in the spotlight since the late 1970s when the United States National Aeronautics and Space Administration (NASA), launched the Total Ozone Mapping Spectrometer (TOMS) mission aboard its Nimbus-7 satellite to study the concentration and distribution of global atmospheric ozone. The mission collected data from 1979 until 2004.^(13,14) Environmental concerns have been the driving force of their evolution over the past decades.

“We are now at another turning point for pMDIs and the excipients they use for API delivery and it’s very likely that regulators step in and shorten the timeline for the phasing out of HFAs. Is the industry ready for this – and what will be the propellant of the future?”

The European Pharmacopoeia (Ph.Eur.) defines pressurised metered-dose preparations for inhalation as “solutions, suspensions or emulsions supplied in containers equipped with a metering valve and which are held under pressure with (a) suitable propellant(s), which can act also as a solvent.”

As a contract testing laboratory, Butterworth has extensive experience in the analysis of propellants with medical applications. Its scientists have been at the coal face of the regulatory changes impacting the industry that have come about as a result of greater awareness of the damage manmade pollution is causing to the climate and planet.

The most significant regulatory milestones to date pertaining to the evolution of propellants are set out in the timeline below:

• 1981 – scientific consensus grows about the impact on the ozone layer of ionisation of chlorofluorocarbons (CFCs) in the upper stratosphere. In response, the United Nations Environment Program (UNEP) began negotiations to develop a multilateral agreement for ozone protection.
• 1985 – the Vienna Convention for the Protection of the Ozone Layer was introduced and this evolved into the Montreal Protocol.
• 1987 – In September of 1987, 24 nations signed the Protocol and it was introduced two years later. The Montreal Protocol is arguably the single most significant global accord ever tabled by the UN and which has achieved such a level of universal ratification.⁽²⁾ The Protocol scheduled the phase-down of production of CFCs, with an initial target of a 50% reduction by 1998. MDIs were considered a critical use product and this application involving the use of CFCs was exempted from the protocol schedule. Shortly after the Protocol was negotiated, new scientific evidence conclusively linked CFCs to the depletion of the ozone layer, and revealed that significant damage had already occurred⁽¹⁾ as was witnessed by the expanding ‘ozone hole’ being observed by NASA over the Antarctic. Extensive investigations were now underway to identify suitable CFC replacements for use in pMDIs.
• 1989 – The International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT I) was formed to evaluate HFA 134a as a CFC replacement, followed by IPACT II for HFA 227ea in 1990. These consortia comprised the world’s major pMDI manufacturers, who collectively sponsored toxicological testing of HFA 134a and HFA 227ea to demonstrate their compatibility and safety as pMDI propellants.⁽³⁾
• 1990 – In June, the parties to the Protocol meet in London and agree to amendments requiring more urgent controls on CFCs.
• 1991 – By April 1991, 68 nations had ratified the Protocol. These countries account for more than 90% of the world’s production of CFCs.⁽¹⁾ The London Amendment was published and included a revised 100% phase-down on the production and use of CFCs from January 2000.
• 2016 – October. The Parties to the Montreal Protocol reached an agreement in October 2016 in Kigali, Rwanda to phase down production and use HFAs. Countries agreed to add HFAs to the list of controlled substances and approved a protocol schedule for their reduction by 80% to 85% by the 2040s.

Judge says: “Before the late 1990s, pMDIs were almost exclusively manufactured using the CFCs CFC 11, CFC 12, and CFC 114,⁽⁸⁾ and monographs for these were included in the major pharmacopoeias including the Ph.Eur.

“The benefits of these propellants were their physical and chemical characteristics including stability, low boiling point, low toxicity, and inert pharmacology. When first introduced for use, the CFCs underwent virtually no toxicological testing⁽⁹⁾. They also readily dispersed or solubilised many active pharmaceutical ingredients (APIs).”

The Protocol led to increased use of hydrocarbons such as butane and iso-butane as propellants, in a variety of industries, however, these were not suitable for sensitive respiratory API delivery. The largest single application of pMDIs then, and continues to be, for the administration of the APIs, beclometasone, corticosteroid, salbutamol, salmeterol, budesonide, and formoterol, for the treatment of asthma. Drug formulations can include more than one of these actives, and are often accompanied by percent levels of ethanol to aid the solubility of the APIs.⁽⁹⁾ The last CFC-driven pMDI sold in the UK contained a beclometasone-based formulation, manufactured by Teva and Neolab. This production finally ceased in 2010.⁽⁸⁾

HFAs – a new chapter 

The next step in the evolution of propellants used in pMDIs was the use of HFAs, an important development, Judge argues, as this class of propellants had many of the beneficial physical and chemical characteristics of CFCs but had no ozone-depleting potential. Studies of HFA 134a and HFA 227ea were carried out by the International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT), which was comprised of the world’s major pMDI manufacturers.⁽³⁾  These studies were carried out between 1990 and 1994.

“The only negative characteristics identified by the IPACT I & II studies were that, not surprisingly, both HFAs should be expected to lower the normal 100% oxygen levels in the lungs to a range of between 81% and 93% depending on the number of actuations administered, and also the physical characteristics of pMDI used (this had also been true of CFCs).⁽³⁾ It was however found that both were pharmacologically active and could act as smooth muscle relaxants. These and all other fluorinated hydrocarbons when inhaled, have smooth muscle relaxant properties in the gut, vasculature, uterus, and lungs (bronchial smooth muscle) via calcium channel blocking, which is the end physiological response to HFAs resulting from their action on magnesium sulfate and beta2-agonists.⁽⁹⁾

“Dossiers resultant from the IPACT I and II studies were submitted to all of the major world health authorities including the European Health Authority Committee for Proprietary Medicinal Products (CPMP).”

In 1994 the CPMP ruled that HFA 134a could be a suitable alternative to the CFCs when demonstrated to comply with the approved quality specifications A year later, a similar conclusion from the CPMP followed regarding HFA 227ea.⁽³⁾ Still, it would be many years before these HFAs would see use commercially in pMDIs for human use because of the requirement for toxicological testing to establish the compatibility and safety of each proposed API formulation in conjunction with its propellant, and the subsequent review and approval of each specific Drug Master File (DMF) by the CPMD. 

In the case of HFA 227ea, the specification of Solvay (formerly Hoechst AG, now Daikin) was adopted and published by the CPMP since it had been the manufacturer and sole supplier of HFA 227ea used in IPACT II toxicological studies.⁽³⁾ No monograph for HFA 227ea was published in the Ph.Eur. Solvay had submitted its DMF including its specification for HFA 227ea as part of the IPACT II dossier.⁽³⁾ The generic names Apaflurane for HFA 227ea (1,1,1,2,3,3,3-Heptafluoropropane) and Norflurane for HFA 134a (1,1,1,2-Tetrafluoroethane) were adopted and used extensively from the late 1990s.

In 2016, Norflurane was the most extensively used propellant in the manufacture of pMDIs,⁽⁹⁾ and its regulatory specification is defined in the current Ph.Eur. monograph no. 2257 for Norflurane (04/2013:2257 corrected 10.0). The 1990 IPACT I protocol for the toxicological testing of Norflurane had been incomplete and the anaesthetic activity of Norflurane was missed.⁽⁹⁾ The Norflurane study in humans included inhalation in short doses at a maximum of only 0.8% in air.⁽⁹⁾ For perspective, the highly active isoflurane is the most potent of the currently used inhalation anaesthetics, and a sustained level of 1.15% is required to render 50% of human subjects unconscious of pain.⁽¹¹⁾ Recreational abuse of pMDIs containing Norflurane became common, and it was reported that endurance Olympic athletes using Norflurane pMDIs had a performance advantage.⁽¹²⁾ Toxicological testing in the UK now complies with the more stringent protocols of the Organisation for Economic Co-operation and Development (OECD), the International Conference on Harmonisation (ICH), and the European Chemicals Agency (ECHA) among others and it is unlikely that such anaesthetic activity would go unnoticed.

Looking to the future

Judge says HFAs have defined our success in addressing the problem of ozone depletion but believes our current understanding of atmospheric science now poses an even more critical challenge, that of global warming. We must limit the expected rise in temperature caused by the emission of greenhouse gases to a maximum of 2°C, to avoid catastrophic world disasters. “This will require the ending of production and use of HFAs,” says Judge.

“While HFAs have zero ozone-depleting effect, they have a global warming potential (GWP) immensely greater than that of CO₂. HFA 134a and HFA 227ea for example, have respectively 1,430 and 3,220 times the GWP of CO₂ per metric ton of emission.^(5)” 

In 2016, the parties to the Montreal Protocol reached an agreement in Kigali, Rwanda to phase-down production and use HFAs. Countries agreed to add HFAs to the list of controlled substances and approved a protocol schedule for their reduction by 80% to 85% by the 2040s. The first reductions by developed countries has already begun. Some developing countries will freeze HFC consumption levels in 2024 and 2028. Under the Kigali Amendment, actions to limit the use of HFAs under the Montreal Protocol are expected to prevent the emissions of up to 105 billion tonnes of carbon dioxide equivalent of greenhouse gases, helping to avoid up to 0.5°C of global temperature rise by 2100, the single largest contribution the world has made towards keeping the global temperature rise below 2°C.⁽²⁾

The schedule of the Kigali Amendment may well be brought forward as new research reveals that human fossil fuel emissions are threatening to create the level of global warming years earlier than expected – and could see the world breach the critical 1.5°C number by 2029 rather than the mid-2030s as previously thought. So, what will come next?

Scientists at Butterworth propose hydrofluoroolefin HFO 1234ze(E) (1,3,3,3-Tetrafluoroprop-1-ene) could become the pMDI propellant of tomorrow.

“HFO is not ozone-depleting, has a global warming potential less than that of CO_2, and has fewer physiological side effects than Norflurane,” says Judge, who worked at Huntingdon Life Sciences before joining Butterworth more than thirty years ago. Toxicological studies allowing the use of HFO 1234ze(E) in pMDIs have already been completed and approved by regulators in the UK, Europe and the USA and Judge urges the industry to start exploring next-generation pMDIs like Honeywell, Kindeva Drug Delivery, and AstraZeneca.

In November 2021, Kindeva Drug Delivery announced that it was installing a new pMDI line capable of filling HFO 1234ze(E) and that it expected to launch two products containing HFO 1234ze(E) by 2025.

Last February, Honeywell and AstraZeneca announced a joint venture reporting that Honeywell’s proprietary HFO 1234ze(E) ‘Solstice Air’, will be used in AstraZeneca’s next-generation pMDIs for the treatment of the respiratory conditions asthma and chronic obstructive pulmonary disease. Chiesi and  Recipharm have also both reported that they expect to release pMDI products containing HFO 1234ze(E) before 2025. 

Frank Judge worked as a scientist for Huntingdon Life Sciences in Suffolk, UK, before 30 years of service with Butterworth Laboratories Limited in Teddington, Middlesex, UK. He is a consultant chemist.  This article has been written to provide a summary of the history of propellants used in pMDIs from the 1980s onwards, bringing together information from a variety of sources, gained from Butterworth’s experience of analysing the materials involved.

• Montreal Protocol 1991 Assessment; United Nations Environment Program, Report of the Halons Technical Options Committee, December 1991.
• https://www.unep.org/ozonaction/who-we-are/about-montreal-protocol
• https://www.daikinchem.de/sites/default/files/pdf/Propellants/Daikin%20Propellants%20-%20Solkane%20227,%20134a%20pharma.pdf
• https://www.Honeywell-Solstice%C2%AE-ze-Brochure_EN.pdf
• https://www.epa.gov/climate-hfcs-reduction
• https://www.discover.ukri.org/a-brief-history-of-climate-change-discoveries/index.html
• https://www.un.org/en/actnow/ten-actions
• https://www.centreformedicinesoptimisation.co.uk/phase-out-of-chlorofluorocarbon-cfc-containing-pharmaceutical-metered-dose-inhalers/#:~:text=Pharmaceutical%20metered%20dose%20inhalers%20(pMDIs,CFCs%20is%20being%20phased%20out
• https://aacijournal.biomedcentral.com/articles/10.1186/s13223-017-0202-0
• Ph.Eur. Norflurane monograph 2257 (04/2013:2257 corrected 10.0)
• Pharmacology and Therapeutics for Dentistry (Seventh Edition), Steven I. Ganzberg, Daniel A. Haas, 2017.
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492461/
• https://earthobservatory.nasa.gov/world-of-change/Ozone
• https://eospso.nasa.gov/missions/total-ozone-mapping-spectrometer-earth-probe
• https://www.bbc.co.uk/news/science-environment-67242386

Why hydrogen is a serious contender as a gas chromatography carrier.

Helium is the second-most abundant element after hydrogen, created in stars by the process of nuclear fusion of hydrogen. In contrast, terrestrial helium is rare and is formed through the underground radioactive decay of uranium (²³⁸U). Over time, this helium migrates through permeable rock formations and is released into the atmosphere, where it is quickly lost into space.

Where the rock is impermeable, helium is trapped alongside methane natural gas deposits. Cryogenic high-pressure fractional distillation is used to extract the helium and nitrogen from the less volatile methane. This crude helium contains 50% to 70% helium and 1% to 3% residual methane, with the remainder mainly of nitrogen with a small amount of hydrogen. It is cooled to about -200°C and the resultant liquid methane and nitrogen are drained off. A small amount of air is added and the oxygen combines with the remaining hydrogen impurity by catalytic conversion to produce water vapour. The resultant gas is again cooled and the water is drained off.

Final trace impurities are then removed by pressure swing adsorption – a technique used to separate some gas species from a mixture of gases, typically air, under pressure – which renders ultra-high-purity analytical-grade helium.

Unfortunately, the decay of uranium has a half-life of 4.5 billion years, and therefore the geological formation of helium is negligible compared with the volume of human extraction. Helium is therefore considered to be non-renewable.

Helium crisis?

Are we on the cusp of a helium crisis? There are many examples of scientists predicting that global helium reserves will be depleted in 20 to 35 years but we don’t believe this is credible. The Mineral Commodities Summaries 2023, produced by the US Geological Survey, part of the US Department of the Interior, reports that global reserves of helium total 39,850,700 million cubic metres. The Geological Survey has very detailed accounts of reserves and production, but it does not give consumption figures. If we assume consumption is equivalent to the production of 160,000 million cubic metres, then reserves for 249 years are calculated (4). Based on 2019 data (1), supplies are adequate for an estimated 335 years,

The largest terrestrial helium reserves are in the US. In 2022, the US was responsible for 46.9% of global production (4). About 75% of this helium is extracted from natural gas of the Panhandle-Hugoton field, which straddles Texas, Oklahoma and Kansas. This natural gas is helium-rich, with an average concentration of 0.586% (2). Helium has been found in concentrations as high as 8% in some global sources of natural gas. In the US, the lowest practical helium concentration that can economically justify extraction is about 0.3% (3). Qatar is the second-largest producer, with 37.5% of global production in 2022. The US and Qatar together accounted for 84.4% of world production in 2022, followed by Algeria (5.6%), Russia (3.1%) and Australia (2.5%) (4). 

According to many sources, we are still being affected by a helium shortage that began in 2019 as a result of the prolonged closure of the world’s largest purification facility in the US and critical maintenance at another two of the world’s eighth-largest purification plants. This became more pronounced in 2021 and 2022. The price of helium saw an increase of 300% between 2000 and 2020.

Changes to hardware required

Much helpful literature is available from instrument manufacturers about the changes to hardware and chromatographic conditions required when substituting helium with hydrogen as carrier gas. The manufacturer’s example chromatograms using hydrogen show complex sample components being beautifully resolved in less time than it takes to change a GC injection septa. This is great. In terms of the time taken for any particular GC analysis, hydrogen always produces the best results, but there are other considerations too.

The only unavoidable problem with the use of hydrogen is that it may react with some sample components during chromatography. This would be a significant worry if the aim of the analysis was the identification of unknown sample components. The concern with the flammability of hydrogen has largely been addressed by instrument manufacturers offering oven-leak sensors and gas-flow controllers that will shut off the gas flow if unexpected increases in flow due to back-pressure drops are noted.

Butterworth, like other laboratories, has decided to commission hydrogen generators, which will remove the safety risks associated with handling large gas cylinders, along with the cost and environmental impact of transporting them over long distances.

With Gas Chromatography – Mass Spectrometry (GCMS), there may be a requirement to use a modified ion source for best operation with hydrogen, and these are becoming available. When changing from helium to hydrogen, it is a relatively quick operation to change ion sources on modern instruments, and many do not require venting of the system vacuum to do so. The MS spectra obtained using hydrogen rather than helium may exhibit different ion fragment intensities from those of our current spectral libraries, which were produced using helium.

It is hoped that spectral libraries obtained using hydrogen will soon be available.. Specific detectors such as Electron Capture may not operate as effectively while using the required flow rate of hydrogen required for packed-column or mega-bore capillary analysis.

Regulatory compliance

When budding chromatographers ask me when the move to hydrogen will happen, my usual reply is “when the pharmacopeia says so”. The type of carrier gas is not an allowable adjustment in any of the pharmacopeia, and I believe the prescription of hydrogen in new and revised monographs will have more of an impact on the use of hydrogen than the price and supply of helium in the short term.

At present, and for the foreseeable future, helium, nitrogen and hydrogen will all be required as carrier gases, based on compliance requirements. There has been movement in the pharmacopeia; for example, in the revised USP Monograph for Castor Oil (2019), the determination of fatty acids has been changed from a titration to a GC assay using hydrogen as a carrier.

Indeed, there are now a number of methods in both the PhEur and USP requiring hydrogen, and so it looks like we are seeing the predicted shift starting to come into play. I think that for methods using nitrogen, there may be little sense in costly revalidation using hydrogen. A measure of the speed of historical updates to compendial methods can be seen in the number of monographs still requiring the use of packed columns and nitrogen carrier gas.  

One point often misunderstood is that while hydrogen is a major step forward in terms of productivity, in terms of chromatographic efficiency (theoretical plates), nitrogen is surprisingly the best. For any given column, the carrier gas with the highest molecular weight will generate more theoretical plates because diffusion is minimised. Nitrogen gives about 15% more plates than hydrogen, the trade-off being that in order to achieve this, the run time would have to be 3.5 times that of hydrogen. The optimum nitrogen flow rate being 12cm/s, compared with 40cm/s for hydrogen, according to van Deemter curves.

Looking to the future

As protocols for the development and validation of chromatographic procedures for non-compendial APIs and raw materials are being agreed by the projects department, Butterworth is advising clients of the benefits of hydrogen, after taking into account concerns such as hydrogenation of sample components. In closing, and perhaps not least, the financial savings realised from a move from helium cylinders to hydrogen produced by in-situ generators is very significant and will have a real impact on analytical costs.  

Link to Associated Whitepaper

References

1. LCGC blog, 11/4/22. https://www.chromatographyonline.com/view/not-another-helium-crisis-
2. Brown, A (2019). Origin of Helium and Nitrogen in the Panhandle-Hugoton Field of Texas, Oklahoma and Kansas, US. AAPG Bull. 103 (2), 369–403. doi:10.1306/07111817343
3. National Academies of Sciences, Engineering and Medicine (2000). The Impact of Selling the Federal Helium Reserve. Washington, DC: The National Academies Press. https://doi.org/10.17226/9860
4. Mineral Commodities Summaries 2023, US Geological Survey, US Department of the Interior.           https://pubs.usgs.gov/periodicals/mcs2023/mcs2023.pdf

A string of fatalities linked to contaminated cough syrup in 2022 puts the spotlight on quality assurance in pharmaceutical manufacturing.

At the start of this year, the World Health Organisation (WHO) said that more than 300 children had died in The Gambia, Indonesia and Uzbekistan in 2022 in deaths linked to contaminated medicine. The medicines – over-the-counter cough syrup – were contaminated with ethylene glycol (EG) and diethylene glycol (DEG). These can cause acute kidney injuries and be fatal even when ingested in small amounts. Most of the children were under the age of 5.

To read the article published on Pharmaceutical Technology website in full, click here

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In January 2022, the United Kingdom adopted ISO 10993-7:2008 / Amd 1:2019 as BS EN ISO 10993-7:2008 / A1:2022 without modification. The amendments include new allowable limits for neonates and infants. In the article written by Frank Judge, our Consultant Chemist Chromatography, he reviews to amendments to the previous version which is applicable to medical devices but not fabrics, drapes, contact lenses or some other particular devices such as dialysis blood flow components.

To read the article in full, click here

Butterworth have just completed the validation of an ICP-MS Method to show equivalence to Graphite Furnace Monograph tests for Lead, Cadmium and Nickel.  ICP-MS analysis is routinely used to meet ICH Q3D requirements for Elemental Impurities in accordance with the Ph Eur and USP. It was a logical move to show the equivalence of this test to the established Graphite Furnace Atomic Absorption Spectroscopy (GFAAS) outlined in the monographs for Magnesium Stearate.

The reason for this methodology shift is prompted by a reduction in requests for analysis using GFAAS and AAS, especially following the introduction of ICP-MS in the Elemental Impurities general chapters.  As such it is becoming harder for contact laboratories to justify the replacement of Atomic Absorption Spectrophotometers (AAS) as they come to the end of their life cycle.

There are already signs that the pharmacopoeias are replacing older metallic methodologies with elemental impurities analysis and this trend is likely to continue. Validation and verification will be something that outsourcers will need to consider as this change gathers pace. Butterworth are perfectly placed with the right experience and knowledge to help you get one step ahead and to provide more robust methodology.

For more information on this analysis: More information

Frank Judge has just published an article on the Pharmaceutical Technology website, which has been used to produce are latest Whitepaper. To download the whitepaper, see Whitepapers