Sitting surrounded by terracotta Tuscan roofs in the hills overlooking the historic centre of Siena might not immediately appear the typical location for a business meeting. It's not John McGrath's usual habitat either. He's more generally to be found in Belgium, where pharma company GlaxoSmithKline has one of its largest vaccine manufacturing plants.
McGrath is the man responsible for making sure sufficient supplies of vaccine are available when the Health Service Executive starts immunising infants against meningitis B from December. And our meeting in Siena is apposite, as GSK's Bexsero – the first meningitis B vaccine worldwide – was developed here and all global supplies of the vaccine are produced at its sister site in Rosia just a few kilometres down the road.
While, for most people, Siena is a stop on a travel itinerary, it has a long history in vaccines. Achille Sclavo, who made his name by developing a serum against anthrax in 1895, founded a vaccines institute on part of what is now the GSK site back in 1904. The site has since been at the forefront of development and manufacture of vaccines to protect against many diseases including polio.
Originally from Clonmel in Co Tipperary, McGrath is well travelled and was headhunted by Novartis to run its vaccine manufacturing business. It's no small task – particularly since GSK took over the Novartis vaccine business to become one of the major players in the sector.
GSK is now the largest producer worldwide of vaccines, though it’s not the one with the highest sales – a legacy of its European roots and a continuing focus on emerging markets.
Before taking on this latest job, McGrath had never worked with vaccines though he has a very long track record in biologics manufacturing with some of the biggest names in the business, having spent much of his 30-year career in the United States.
Biotechnology course
It’s all a long way from home for the youngest of seven children. As McGrath tells it, he ended up in biopharmaceuticals almost by accident. Looking around at further study options as he finished school, he cam across a course in biotechnology at what was then called NIHE Dublin, now Dublin City University.
“I didn’t really know what it was about and my careers guidance teachers couldn’t tell me what it was about, but I just thought I’d give it a go,” he says.
After a stint in Cork firm, Biocon when he left college, which he refers to as a “great formative experience”, he got restless and decided to head abroad, initially working for a biotech company called Celtic in Slough, outside London.
And he might have stayed there but for pressure from his brother who was determined to go to the US under the Donnelly visa programme.
“I had no intention of going but he talked me into putting in an application,” says McGrath. “I put one letter in and I got a visa, and then it was use it or lose it time.”
His initial instinct was to move away from biotechnology. But. after a few months travelling around the US, the reality that he’d need to do something for a living set in. The job he took was with Swiss biotech Serono in Boston.
Boston and the east coast generally was to remain home for the next 23 years. After Serono, he spent a decade with fast-growing Genzyme, then Millipore and finally another Swiss company, active ingredient specialist Lonza.
While on a short-term relocation to Lonza’s Swiss headquarters, another Swiss group, Novartis, came calling and he decided to take on the new challenge.
Now he is in charge of a global manufacturing network that ships about two million doses of vaccine every day. The meningitis B vaccine, Bexsero, is his first big rollout.
Meningitis is a life-threatening disease. It can kill within days of the first symptoms showing. There are five main strains, differentiated by letter – A, B, C, W and Y. A vaccine already exists for four of those but, until now, none was available for Men B, which is the most common form. It proves fatal in about 5 per cent of cases in Ireland and, even among those who survive, there can be life-changing complications.
Most at risk are infants and that is why the Health Service Executive, like its UK counterparts, has decided to focus its efforts on this group, with the vaccine being made available free to children born on or after tomorrow.
The rapid take-up of the Bexsero vaccine has presented challenges for McGrath. Most particularly, it takes time to build a modern vaccines plant. Typically, design takes between six and 12 months.
“During that year, you continue to work with commercial colleagues to check what kind of indications are we getting, are we getting approvals in the countries we expect and do we think the pricing is where we believe it will be?” says McGrath.
Construction itself can also take a year and that applies also to much of the customised equipment required. “If you look at a bioreactor, a typical bioreactor might cost you a million dollars, so companies don’t have them sitting on the shelf. It’s not economically viable.”
Wriggle room
It’s important to get it right as plants cost millions and have limited flexibility. It’s not just a matter of switching them from one product to another. And there is always need to build in a little wriggle room – either scope for extra shifts, or room to add more equipment to increase production. In an effort to derisk the process as much as possible, accurate projections are vital, McGrath says.
“Let me give you an example. We are about to launch a vaccine and we know, based on our demand estimates, we are good for supply up to 2021 or 2022. Now that’s about at the edge of where we need to consider ‘Do we build another plant?’ and we won’t have the answer to that until a couple of years into launch. It could go the way we think, or demand could go a lot heavier.
“So what you try to do is you try to be as clever as you can on when you start and on what kind of stage gates we look at for market demand to tell us that things are going okay or we should accelerate or we should slow down.”
GSK acquired the Novartis vaccines business in 2015 as part of a complicated deal that saw the British firm’s cancer drugs business move the other way and the two companies forming a joint consumer healthcare business.
As it started integrating the Novartis vaccines business, the prospects for the new vaccine Bexsero were top of the agenda. The Swiss company had planned ahead for significant demand but building up gradually over time. The decision by the UK to authorise an immunisation programme accelerated the timeline and, as McGrath admits, “We were caught unawares to some extent”, but he’s confident that they can cope.
“If you look at the lead time of two years, we have the capacity but it is a a matter of how quickly we can ramp up,” he says. While the physical structure might be in place, people need to be trained to man it and the whole process needs to be tested.
“So we are ramping it up right now and our intent for Ireland and everywhere else is to get the safety stocks ahead of the demand, so that when you have the inevitable manufacturing issues it is invisible to the end customer.”
Actually making the vaccine is a complicated process in itself. Bexsero was “reverse engineered”, which means scientists started by decoding the genomic sequence of the bacteria and whittling what were in this case 570 proteins that could potentially kill it down to the four that were eventually chosen to formulate the vaccine.
The Men B bacteria was the first on which the technique was employed by Dr Rino Rappuoli, who is GSK's Siena-based chief vaccines scientist.
Once the scientists have finished with it, and it has worked its way through the trials process, it is up to McGrath to work out how to build the plants to produce it commercially and manage supply to meet often erratic demand. The manufacturing process takes a number of weeks but the single greatest element of that is testing. McGrath understands why.
“The big difference to me when I started here three years ago is that, for the first time in my life, I am doing something for healthy people. They start healthy. The rest of my career was for people who did not have options and sometimes the government would be right behind you telling you to move faster. I mean it is risk-reward. If you are dealing with an anti-cancer drug where the patient is going to die and there is no option, governments’ risk profile tends to be different. When you are injecting thousands of healthy babies, your risk profile tends to be conservatives, which is correct.”
Quality is king in this business and despite increasing competition from the east, notably China and India, McGrath believes that, for now, despite budget pressures from buyers, a GSK logo on the side of the product is reassuring for doctors and patients.
“Over the next decade, these lower-cost producers will come at us but we will have repositioned some of our network with newer plants in low cost countries. We will still keep the plants we have because experience counts and then new entrants’ cost base will rise in that period of time. And then it will come down to how efficient we have become in that time.”
Process engineering
Process engineering has been one area where Ireland has become a leader within the pharma sector and there are many people, like McGrath, who learned their trade close to home before moving up the ranks of international business. Looking back over his 30 years in biotech, he is struck both by how much has changed but also how much has stayed the same.
“If I look at when I started in the industry, we were running fermenters to make proteins and, if you got a couple of hundred grams of protein, that was the biggest scale out there,” he says. “Recently, in my previous job, we’d run a 20,000-litre fermenter which would deliver 70kg protein – something that would have been unheard of. So the scale has changed dramatically.
“At the same time, because we are in a very conservative industry we still make product in eggs. It is proven in terms of risk profile, you have 40 years of experience and it works.”
Certainly it could probably be done more quickly but, in a world where doing something in a different way can lead to a major clinical trials process costing hundreds of millions of dollars, it’s easy to see why even the most cutting-edge pharma business think twice about messing with the tried and tested.
“In this business, proven technology stands for a lot. You don’t want to be on the bleeding edge.”
The life cycle of an average pharmaceuticals plant means people in McGrath’s position rarely deliver more than one full cycle in their careers.
“You don’t get to like it but you get used to the fact that with what you do, you won’t see the effect of for six months, 12 months, three years.
“What you have to do is spend a considerable amount of time planning for it, telling yourself that you know how to build it today but that it is going to have to run for 20 years, so what flexibility do we have to build in so the person who gets my job next is not cursing me for the rest of their lives?”
