‘Don’t change horses in midstream’ is an adage the pharmaceutical industry might well employ to defend its sloth-like movement away from traditional batch-processing methods. While continuous processing has long been adopted by other manufacturing industries, its development within pharma has been conspicuously slow; due not least to the expense of the all-new machinery that continuous production requires in plants saddled with existing equipment known to do the job.

Though worth much more per kilo, the small production volumes pharma companies manufacture compared with other industries make any change of method more high-risk, and investment harder to justify. Consequently, processes for existing drug lines are seldom adapted.

Markus Krumme, head of continuous manufacturing at Novartis, sums this up as the "sunk capital trap", a predicament hindering the faster uptake of new technologies.

"Traditionally, the pharmaceutical industry has produced much larger volumes, because the indications we were going after were much larger – cholesterol-lowering agents, high-blood pressure treatments – where you had millions of patients," Krumme says. "The volumes of material that needed to be produced were relatively high and the capacity that we have built over the last decades was accommodating that.

"In recent years, we have shifted towards smaller indications where more life-threatening diseases are treated, but with fewer patients, meaning that the material volumes are getting lower and lower but we still have these large manufacturing capacities from our older products. If we are investing in new technology, we need to justify what we do with the existing facilities."

As orphan drugs and more personalised medicines become the norm, such volumes are only becoming smaller. While this may leave the question unanswered as to what should become of the large-scale capacity of existing equipment, it also makes the case for continuous processing stronger because there is an argument that the very model of drug distribution will change to match these smaller indications.

"For us, the focal point is to revolutionise the entire manufacturing chain, not just smaller sequences out of it; that means integrating continuous processing into the chemistry as well." 

Currently, production takes place over many weeks and often at several sites too, with API synthesis and the various stages of batch production taking place at different facilities before drugs are packaged and shipped off to local markets around the world. As companies seek to cut costs, improve sustainability and speed up time to market, a move towards small-scale local plants producing drugs in pre-approved end-to-end continuous processes looks increasingly likely.

Slow development

The pace of development may be slow, but for Krumme – whose employer Novartis is arguably ahead of the curve on continuous production – it is also where it needs to be for a sustainable transition. The machinery needed for a continuous process is completely different from that used in discrete (batch) processes; it is not a case of retrofitting existing reactors but rather of investing in completely new equipment and development. Consequently, progress can only inch forward as product lines are added.

"If you look at the percentage of products across the industry produced in a continuous fashion right now, it is extremely low," Krumme says. "There is no project that can claim an entire continuous chain yet as far as I know, but there are a few containing individual continuous steps. The industry is generally moving new products towards the new manufacturing paradigm, and it will come with the replenishment of new products as they replace the older ones. This is really the natural pace that is to be expected, unless we redevelop existing product lines for new manufacturing technology, and that’s something that you would do as the exception rather than the rule."

In 2007, Novartis announced a ten-year partnership with the Massachusetts Institute of Technology (MIT), looking to develop new continuous processing technologies. Developments to-date by the Novartis-MIT Center for Continuous Manufacturing (CCM) as it is known, include the creation of an API-to-coated tablet continuous manufacturing prototype in late 2011, and the integration of a control system to automate the process, in 2012. Novartis meanwhile, has been steadily applying the research to its manufacturing processes, piloting industrial-scale projects on its own pharmaceutical products.

In development of these projects, what has been important at Novartis is that the outlook on continuous methods is as broad as possible. While solid-dose processing has seemed to dominate the popular imagination across the industry, Novartis hopes to employ the methodology across the widest range of applications.

Broader scope

"The majority of pharmaceutical companies is focused on the manufacture of oral solids, and clearly we are looking at them too, but we are also looking at a much broader scope.

For us, the focal point of our activities is to revolutionise the entire manufacturing chain, not just smaller sequences out of it; that means integrating continuous processing into the chemistry as well. And what we expect from that is superior quality management of the product; a much smaller footprint, because our plant size will likely be reduced, and much faster throughput times."

While quality beckons as a potential advantage, it is also the benchmark that continuous production must meet as it seeks the regulatory approval required for any new process. To facilitate this, quality markers must be reported in real time throughout the reaction and production process, so that the drug reaches the required state at all stages. Process analytical technology (PAT), a technique introduced by FDA around a decade ago, provides a framework for doing so. Currently applied within batch processing, PAT is seen as the key to perfecting continuous production.

Measured factors

Factors measured along the continuous production line include process parameters such as blend uniformity, particle-size distribution, moisture and temperature, but PAT goes beyond this network of interspersed spectrometers. It also reports the state of the material at a particular point in the process as it passes through. These two measurements combined allow PAT to act as a framework for measuring the quality and accuracy of the process as a whole.

Krumme illustrates how the technique helps steer production within tight parameters.

"In the batch process you have a holding point after each completed batch sequence where you can take a look, draw samples, characterise the quality and make a decision." 

"Consider a flight trajectory in an aeroplane; the pilot needs to navigate while he continues to fly, that means he needs to know in real time the precise position of his plane; he cannot stop and take time to make a decision, he has to maintain a minimum air speed," Krumme says. "A continuous process is the same. In the batch process you have a holding point after each completed batch sequence where you can take a look, draw samples, characterise the quality and make a decision. You proceed when the quality is good. In the continuous process you don’t have that time because the apparatus is continuously pushing material, so PAT, with its real-time capability, tells you the state of the material."

Used within a closed-loop system, PAT allows processing to continue without the need for production to be stopped, or any product discarded. This is because the process and state of the product is continually monitored, so that any minute deviation from the target parameters can be addressed and adjustments made before the product is affected, closing the loop.

While PAT and the continuous production methods within which it is being applied are still very new, lessons can be carried over from current instances of PAT being used within batch processing. And the major driving force for progress within PAT, Krumme believes, will be harmonisation.

"As we continue to integrate PAT into the continuous manufacturing world, the challenge – like in every new technology – is the absence of standards at this point in time. There is a variety of communication protocols between process control systems and PAT instruments; there is a variety of flavours of how data are managed electronically, how they are stored and how they are interpreted. I would expect there to be a development and consolidation of new industry-wide standards that will help further advancement and drive the further adoption of PAT."

Alongside such coalescence within PAT approaches, progress in relation to the way continuous production is controlled and managed is likely to accelerate as the industry adopts the new methods more widely. Krumme is more than optimistic about the next decade.

"I do expect major steps forward in the field of process control, in the field of consistency of quality production and quality management, of our processes on the basis of an electronic method," he says.

"If I’m looking back considering, ‘what did we have ten years ago and where are we now?’, that is already day and night. To extrapolate ten years further into the future, I would expect us to continue to see development at that pace."