When most of us think about medicines, it is the finished products that come to mind: the shiny tablets or capsules that come in jars and packets. We may think about the research that went into the discovery of a drug sometimes but we rarely take time to consider what happens during the manufacturing of the product.
It is a subject to which we should be paying much closer attention given that there are 25,000 people involved in pharmaceutical manufacturing in this country and the sector accounts for more than 50 per cent of total exports. Its importance was not lost on a group of academics in the University of Limerick (UL), however.
Greater support
This group, led by Prof Kieran Hodnett and including researchers at Athlone IT, Waterford IT, Trinity College Dublin, University College Cork, University College Dublin and NUI Galway, came together about six years ago to establish the Synthesis and Solid State Pharmaceutical Centre (SSPC) in the University of Limerick as a means of offering greater support to the pharmaceutical manufacturing industry in Ireland.
“About six years ago a group of us academics got together with the leading technical people in the pharmaceutical industry to set up SSPC,” Prof Hodnett says. “We felt that the universities were not offering enough support to the industry in the sold state area.”
The solid state area is where the drug is taken from being a molecule and turned into a powder form. “There are two components to a drug, the active ingredient and the excipient,” says Hodnett. “The active ingredient can be very small. For example, patients on Lipitor might have a daily dose of 10mg. You can’t actually see 10mg of a substance so it has to be mixed with an excipient.”
The area the SSPC has concentrated on is crystallisation. “This is an area which causes a lot of angst in the pharmaceutical industry worldwide,” he says. “When we approached the industry and said we could help them with this problem they jumped at the opportunity and this lead to what I call SSPC 1.”
Crystallisation as a process is very simple, says Hodnett, and he cites the example of sugar in tea to illustrate it. “If you have a cup of hot tea and put a few spoonfuls of sugar into it, the sugar will dissolve. But when the tea cools, it will separate out and crystallise on the bottom of the cup. That’s essentially what the pharmaceutical industry does, it puts the active ingredient in a solution and allows it to crystallise.”
But what appears a straightforward process can be fraught with difficulty. For example, the powder has to be filtered out of the solution following the crystallisation stage but, if the particles are the wrong size, the filter can clog causing a process which should take hours to take days instead with obvious cost implications.
Another issue is the actual content of the solution. "The pharmaceutical industry wants to use less solvents in the process. These solvents have to be either incinerated or recycled after use. A move to aqueous solutions would be far more environmentally friendly and less costly. The industry is also seeking to use more biocatalysts to accelerate reactions and speed up the process gain making it more efficient. They can use these enzymes, recover them and reuse them meaning that they don't have such a problem with waste."
Diamonds and pencils
The SSPC has been assisting with these issues and another known as polymorphism. Polymorphs are different shapes of materials, with sometimes completely different characteristics, which are made of the same material. Examples of commonly known polymorphs are the graphite that makes up the lead in a pencil and diamonds – both of which are made of carbon.
“The reason this happens is that different sets of conditions exist during the crystallisation step,” Hodnett says. “And with medicines, only one particular polymorphic form is usually allowed to be used. This is because the rate at which different polymorphs can release into the body can vary – too quick and you can get an overdose and too slow and the medicine could be ineffective.”
Hodnett is quick to share the credit for SSPC’s work. “It is a collaborative effort. In Ireland we have some of the world’s best innovators in terms of pharmaceutical engineering and these are principally people who are working in the industry. They have a fantastic record of manufacturing excellence and compliance going back as far as 1960. What we are doing in the universities is to support those people in developing solutions to challenges which are coming down the line.”
The collaboration, which includes world leading industry partners such as Pfizer, Glaxo Smith Kline, Eli Lilly, Merck, Janssen Pharmaceuticals, Roche and Bristol-Myers Squibb, is almost unheard of outside Ireland, according to Hodnett.
“The pharmaceutical industry is known for being ultra-secret but we work on problems of what might be called generic interest, such as making the right polymorph each time, ensuring that particles are the right size for the filtration process, or assisting in the development of new just-in-time manufacturing processes. They are problems of common interest to the industry.”
For the future SSPC has moved onto a new phase following an investment of €30 million from Science Foundation Ireland and a further €10 million from its industry partners earlier this year.
“We saw the opportunity to move beyond the crystallisation steps and we are going a step further back and taking in the whole process from what could be called the molecule to the membrane,” he says.
“We are now looking at new and more efficient ways of making the molecules and in future will look at the tablet manufacturing itself.”
