Pharmaceutical manufacturing processes are falling behind other industries in terms of technology and efficiency. The advent of personalised medicine requires fundamental changes to be made, and soon. Salvatore Mascia, founder of CONTINUUS Pharmaceuticals, puts forward the case for a move towards integrated continuous manufacturing – an opportunity for pharma to save billions while enhancing patient benefit.
A few years ago, some child cancer patients in the US were unable to access the hard-hitting chemo drug doxorubicin. Johnson & Johnson had been receiving the therapeutic from its contract manufacturer Ben Venue Laboratories, but when the outsourcing company temporarily shut down its manufacturing facility due to quality control issues, supply could not match demand. An unfortunate scenario, but not a rare enough one: availability of medicinal drugs is often limited and patients are dying as a result. Today, the FDA lists more than 300 drugs in short supply.
The pharmaceutical industry’s manufacturing processes have a lot to answer for. You could justifiably say that it has a bad track record for keeping up to date with the latest technology. As FDA commissioner Mark McClellan put it in 2003, the science of drug manufacturing is "behind that of potato chips and soap makers".
Not a lot has changed since then, and it’s now estimated the sector endures annual losses of $50 billion in manufacturing costs from inefficient processes. Is there any hope of it catching up with other industries?
Reasons to be cheerful
There could be cautious cause for optimism if Salvatore Mascia, founder of Massachusetts-based CONTINUUS Pharmaceuticals is to be believed. For years, he researched the best methods for improving manufacturing processes at Cambridge University and MIT before heading up his own organisation. The entrepreneur says his two-year-old company can produce better medicines at significantly reduced costs, with shorter lead times.
"The problem with the pharmaceutical industry is that it hasn’t changed much in the last few decades," he says. "Go into a pharmaceutical manufacturing plant and you will see the same technology you’d have encountered 50 or more years ago."
It’s a highly regulated industry, which has made it reluctant to change, he opines. Most significantly, the sector has been built around blockbuster molecules, where a drug deemed to work for everyone is developed. Pharma has been relying on the high-gross margins made by such therapeutics, and those big profits have masked the inefficiency of the manufacturing processes. There’s never been much financial pressure to change, until now.
Increased competition, key patent expirations and pressure for price controls in the last few years have resulted in declining product revenues. New technologies (from fields like proteomics and biomarkers) appear to reflect a trend that threatens the existence of blockbusters as we know them.
If their replacements are customised small-volume drugs, companies will have to manufacture many more different products while attempting to cut costs.
"We have seen the introduction of the generic drugs, pricing pressure, and increased costs in R&D but the same number of molecules being approved," Mascia explains. "There is a restructure trying to take place in the industry to improve the business model."
Time for change
Conventional manufacturing’s main problem is time; the lag from the start of production to delivery to patient can be as long as a year. This limits a company’s ability to respond quickly to problems, or changes in demand, making drug shortages – particularly with cancer compounds like doxorubicin – likely in such situations.
The current scenario is based upon step-by-step batch processes with fixed methods and extremely expensive, time-consuming recipes. The processing steps are often performed in different facilities around the world and include isolating, testing, storing and transporting the various chemical intermediates. The API itself can be taken elsewhere to be formulated into the final dosage form before it is packaged and shipped to distributors.
A disconnect between API and the resulting product means that feedback from downstream operators on the API’s physico-chemical properties is often limited. Consequently, correction steps, – which might include micronisation and granulation – are common. It’s just no longer a sustainable approach, especially with the industry moving towards more targeted types of therapy, which require many different products, simultaneously.
"This is about the upsurge in personalised medicine, where you need to produce specific types of therapies for certain subsections of the population," reveals Mascia. "For these, you need specific pharmaceutical processes capable of producing these drugs with the correct features, in an efficient way."
As our understanding of the genetic factors responsible for some diseases advances rapidly, personalised therapy has emerged as a big trend for the industry through the use of pharmacogenomics. It’s now thought that drug treatments will soon deviate from the ‘one dose fits all’ approach and eliminate the current trial-and-error method of prescribing, with doctors taking into account their patients’ genes.
Such a concept promises to provide the most effective treatment by targeting the fundamental disease driver with fewer side-effects. This will require manufacturing processes flexible enough to produce several different types of pharmaceuticals efficiently and this is not achievable with current manufacturing technology.
The batch method’s offering is certainly sub-par, and the FDA has made no secret of asking for more modular, flexible and agile manufacturing methods. But where to start? Mascia believes that pharma should study the processes currently employed by the oil, gas and food sectors.
To help bring the pharmaceutical industry up to speed, in 2007, Novartis invested $65 million in a joint research endeavour with MIT. The resulting Novartis-MIT Centre for Continuous Manufacturing would span over ten years and lead to the creation of novel continuous-flow manufacturing technologies for medicines. The project has so far led to the development of a process that synthesises pills without pauses.
It has involved developing `smaller-scale process technologies that can be integrated into seamless end-to-end manufacturing methods. In this vision, chemical reactions can take place as the reactants flow through tubes allowing steps that produce a lot of heat to be run safely. New ingredients can be added to the flow at specific points for medicines requiring multiple steps. Points at which the therapeutic can be purified, then crystallised into a tablet with the necessary excipients integrated into the system.
"The word ‘integration’ is key," says Mascia. "The huge benefit is integrating chemical operation and formulation into one solution, so you end up with a constant, fully automated process in which raw materials are introduced at one end and your products come out of the other."
There are numerous benefits to this approach. The novel processing technologies will enable correction steps (like milling and granulation) to be eliminated because manufacturers would be able to produce an API that has specific physico-chemical characteristics. It will be designed directly with the features it requires for the final dosage form.
"The impact of moving from batch to continuous manufacturing process the way we mean will be huge. It will go from early stage development up to patient care; we’ll be able to bring a drug to market faster," reveals Mascia.
While regulatory hurdles are rife in the industry, he believes this is more of a perceived issue than a genuine cause for caution. He reckons the FDA and EMA see the potential for improving product quality and reducing drug shortages and are enthusiastic about integrated continuous manufacturing.
Plus, it could mean substantial savings for the industry. Manufacturing plants will be rendered more flexible with dial up/dial down capabilities, so the process can easily be changed to match demand. That means far less waste.
"We estimate integrated continuous manufacturing could save the industry $60-100 billion a year," reveals Mascia.
Obviously, some products will be trickier than others if this approach is rolled out: the challenges multiply for compounds requiring long reaction times, or many chemical steps. However, Mascia points out that when you’re taking a process from batch to continuous manufacturing you don’t necessarily use the same number of steps.
"Most of the time we’re changing the chemistry and the formulation, so there is the opportunity to reduce the amount of steps," he says. "That’s been demonstrated at MIT, where we were able to put the entire process for a specific drug into 20m2 footprint. We changed the reaction and formulation process we ran, and it made it faster, with fewer steps."
He does admit, however, that ‘integrated’ continuous manufacturing techniques haven’t been trialled for biologics, where the fermentation and purification processes have mostly been run continuously. The integrated process has been so focused on small-molecule chemical synthesis and – with the bestselling drugs list increasing shifting to reflect larger compounds – this could be an important thing to consider before making the leap to continuous.
Mascia is realistic. He knows it won’t be easy, or quick, to overturn the entrenched ideas of the pharmaceutical industry. Introducing completely new and expensive technology in such a regulated sector will always be challenging, but more than a billion dollars has been invested in different continuous manufacturing initiatives by some of the major companies in the last decade.
Mascia is therefore adamant that the question is not if pharma will move towards the approach, but when it will happen, and who will have the best way of doing things.
"This is a big moment for the pharmaceutical manufacturing industry," he says. "We are going towards a complete reorganisation of drug development and manufacturing functions. The future will see the concept of on-demand manufacturing of pharmaceuticals, which we can all accomplish using a fully integrated system."