The Pharma Formulation Fixer: Interview with Chris Moreton

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Chris Moreton has spent decades working as a formulation scientist and is a past president of IPEC-Americas. Here, we learn more about his career and why formulation is such a fascinating field to pursue.

My father, who was an organic chemist. He worked for ICI, a company that no longer exists. He worked there all his professional life apart from his military service during the Second World War. I’ve always been interested in science, but my father’s only regret was that I never really learned organic chemistry! I originally went to undergraduate school to study biochemistry but that changed for various reasons and I ended up studying pharmacy.

On leaving pharmacy school, I first worked in the hospital department as a trainee pharmacist. I was, quite frankly, not impressed! I counted the meds and that was it – and I felt like it would drive me crazy! I decided to reconvert myself in the industry. I got a job with a small CMO, which fortunately no longer exists, because it was a dump! (This was before GMPs were mandatory in the UK; the first GMP inspections in Britain did not take place until the summer of 1972.) I stayed with the company after completing my registration as a pharmacist. After my boss changed jobs, I was promoted to chief pharmacist. We received a letter from the Medicines Control Agency (now the MHRA) informing us of our upcoming GMP inspection and referring to a previous letter requiring the company to do certain things. I took the letter to the CEO and asked to see the letter from the previous year. None of the action points in that letter had been addressed, but he thought we had gotten away with it so far, so why change? I returned the letter to him, returned to my office and started looking for another job. It wasn’t the kind of company I wanted to work for.

After that, I worked in various companies, including Pfizer, where I stayed for just over seven years. After a total of almost 15 years working in different companies, I returned to university for a master’s degree in pharmaceutical analysis and a doctorate. Later, I found a job in the excipient industry. I have worked in many different places and there are many stories to tell! At one time, I was in charge of quality in an excipient and drug delivery company. I think it was probably a mistake on their part. I knew what was acceptable and what was not – and when a line is drawn, I will not cross it. If you step over a line once, you will be asked to step over and over again. My boss wasn’t very happy with me at least once when I failed a batch!

I’ve always loved wordsmithing. In fact, I’m fascinated by it too! I also had a knack for finding solutions, but not necessarily with the tools people wanted me to use. For example, some companies have implemented management and research tools. On more than one occasion I have found a solution to the problem that using the tool did not solve!

In some cases, the tools worked well for synthetic chemistry, but not so well for pharmaceuticals. At the beginning of my career, there were also a lot of things that we didn’t know about the formulation. There are still a lot of things we don’t know. For example, two of the most commonly used excipients are magnesium stearate and microcrystalline cellulose and we still don’t know enough about how and why they work – despite the fact that they’ve been used for decades.

For pharmacokinetic/or physiological pharmacokinetic models, we have made progress, but have we had enough? No – we cannot bind a drug structure, subject it to PK/PD modeling and be assured of a result. There are gaps that we need to fill. This is partly a flaw in the formulation, but we also need to better understand how certain drugs are absorbed. Some drugs are absorbed very quickly through the wall of the gastrointestinal tract, some are slow, and some are only absorbed halfway through before being expelled (efflux). As molecular weight increases, drugs are more difficult to formulate. Some drugs must cross tight junctions and require the co-administration of something that can temporarily open the junction. We are only beginning to fully understand tight junctions. In short, there are many factors that models cannot always help with.

In the early 1990s I was working with an excipient company in Britain. After the creation of IPEC Europe, my boss at the time thought it was important to work with them, and he delegated me as a company representative in an IPEC Europe committee (they only had two committees at the time!). I attended the meetings and we evaluated the proposals of the Pharmacopoeias for the harmonization of the monographs. When I was transferred to the United States, my boss was not really interested in IPEC – he wanted to go on the road and promote the company’s products – so the task was delegated to me.

Many key people at IPEC are on the regulatory or quality side, but I bring a different perspective due to my background in formulation. I was president of IPEC-Americas from 2003 to 2004. I have a great interest in excipient performance and have worked with USP on expert committees related to excipients since 2000.

The biggest problem is the low water solubility. Many compounds are simply very insoluble and sometimes formulators also have to deal with a high partition coefficient.

There’s a reason solubility is still an issue after all these years. Back in the 1970s when I was at Pfizer, we didn’t have a lot of poorly water-soluble compounds in the pipeline because the pharmacological screens that we use to evaluate new molecules couldn’t handle them, so they were not active in the screens. But today, changes in chemistry, a better understanding of drug-receptor interactions, and high-throughput screening for pharmacological activity have taught us that useful molecules are often hydrophobic. When we bolt new groups onto the molecule to interact with a specific receptor site, we add more molecular weight, and often more hydrophobicity, which further lowers solubility. It is estimated that approximately 70-80% of new drugs under development are poorly soluble in water.

Determining which formulation option is best for a molecule is a major area of ​​interest for me. Many approaches are available today, such as amorphous dispersions, nanoparticles, solid lipid nanoparticles, liposomes, self-emulsifying systems, self-nano-emulsifying systems, etc. Some work with medication, but others don’t. But we don’t necessarily have a good idea why one works better than the other. If we knew more about how these approaches work – and how excipients work – we might be able to perform molecular functional group analysis and molecular modeling to correlate certain structural parameters of the molecule with potential drug strategies. formulation optimization.

The delivery of proteins and peptides is an area that interests me. I don’t work in this area, but the progress has been interesting to watch. There are a handful of protein and peptide drugs that are taken orally. An interesting example is cyclosporin, which is a cyclic peptide. It has a log P of around four, which is higher than most peptides, and makes it more suitable for oral absorption, although formulation is still key. It’s fascinating. There are always challenges in the formulation area to keep you interested.

I also keep an eye out for advanced manufacturing technologies, like 3D printing. Only one drug using 3D printing has been approved so far (Spritam, which uses an innovative formulation approach to dissolve quickly). However, some people in the industry are very passionate about the potential of the technique. Some drugs have a very narrow therapeutic index and the dose must be closely tailored to the patient. 3D printing could be a good solution here, but I think the technology still has a long way to go – and new excipients may also be needed.

In fact, I will say two things. First, I would love to see the FDA’s pilot program for new excipients succeed and become permanent. IPEC-Americas is very passionate about this program and its importance to the industry. New excipients will lead to improved formulations. And second, I would like to see more pharmaceutical production brought home. Some overseas organizations are doing good work in the manufacturing sector. Others try to do a good job, but don’t always succeed. Some deliberately try to cut as many corners as they can. For example, there have been a lot of quality issues in some countries – which was highlighted in presentations at the recent World Excipients Conference in Kissimmee, Florida. In some cases, people are too obsessed with price, which can lead to quality issues. For patient safety, we need to focus more on quality and ensure that good manufacturing practice standards are not compromised.

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