How Big Pharma implements analytics in continuous manufacturing

While advanced analytics remain a point of study in continuous manufacturing, their level of adoption in the pharmaceutical industry is an open question. 

Continuous manufacturing has increasingly attracted interest over the past decade, becoming more relevant as the industry faced supply challenges due to the Covid-19 pandemic. Such manufacturing approaches are being explored particularly in light of the increasing drive to make the pharmaceutical industry more environmentally sustainable. But while this more agile method is being tested by both Big Pharma and smaller players, its eventual large-scale adoption will likely be more selective due to financial considerations. 

Alongside this comes the question of incorporating process analytical technology (PAT) in manufacturing protocols. The US Food and Drug Administration (FDA) describes PAT as a system used for designing, analysing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials, per a September 2004 document. This includes the use of tools such as spectrometers and process analysers. Although PAT is widely used by manufacturers, advanced forms of PAT may not be used once continuous processes are fully implemented by some players. Pharmaceutical players are often content with adopting simpler processes as they turn to continuous manufacturing in their production strategies. 

In an interview with Pharmaceutical Technology, Allan Myerson, PhD, professor in the Department of Engineering at Massachusetts Institute of Technology in Cambridge, talks about the adoption of continuous manufacturing by the pharmaceutical industry, the use of sophisticated analytics and the challenges that may come with implementing this method. He heads the Myerson Research Group at MIT and serves as the principal investigator at the Novartis-MIT Centre for Continuous Manufacturing, a research collaboration between the company and the university. 

This interview has been edited for clarity and length.

Allan Myerson: Let's [first] define what we're talking about. There is continuous manufacturing of the active pharmaceutical ingredient (API), continuous manufacturing of a drug product and there is continuous integrated manufacturing of both together. 

Interest in continuous manufacturing was relatively low 12 or 13 years ago. At the Novartis-MIT Centre for Continuous Manufacturing, which started in 2007, we built the first integrated continuous manufacturing line, which [went] from raw materials through chemical synthesis, purification, and formulation of the final drug product, in a shipping container side plant. And that got a lot of publicity… and a lot more companies started working on continuous manufacturing in a more serious way. 

Different companies took different paths. Some focused on API and intermediate continuous manufacturing to get the advantages of continuous flow chemistry. And focused on continuous drug product manufacturing. Today we have several, at least, approved products on the market that are continuously manufactured. There are probably a few continuous manufacturing lines for different parts of the chemical process. And virtually all of Big Pharma is investigating continuous processes for both API and drug product to determine where and when this would make economic sense.

Allan Myerson: It takes time and effort to develop such a process. And a lot of this is economic. Companies often have dedicated facilities that are already built to do batch processes, and whether they want to invest in a new continuous [manufacturing] facility is an economic decision. 

Secondly, Big Pharma is interested in getting the drug to market as fast as possible. And if the continuous process development takes longer, [then] that might be an issue. On the other hand, if they have a high-volume product, they might realise the economic advantage to developing continuous processes from the beginning. 

So, there are challenges that are technological, economic, and regulatory. While the regulatory bodies are favourably disposed towards the idea of continuous manufacturing, it is still challenging [to get] inspectors in and getting the continuous process approved.

Allan Myerson: During the development of a continuous process for making API, you'll make use of advanced PAT, things like inline Fourier transform infrared (FTIR) [spectroscopy]-, inline particle size analysis, as well as traditional things like temperature, pH, flow rates. But ideally, what you often end up doing is develop a digital twin of the process and develop an inline control system. And, once you know all of this, you might just use very simple PAT like flow rate, pH, and temperature to operate the plant. That’s typically what we see, but [this is] not to say that you cannot use more advanced PAT in the manufacturing process as well.

Allan Myerson: They all use advanced PAT in development [but] whether they need those in controlling the process after its running is a different question. For example, PAT may be used for simple things [like] pH, flow rate, temperature. There might be some concentration measurements, like FTIR or other spectroscopy as well. Whether they'll use advanced PAT in the actual manufacturing line is hard to say.

Allan Myerson: While implementing any PAT, you must validate the method and make sure it actually measures [what’s intended]. You need to get the probes [sensors] in your system and make sure they do not foul (have deposit accumulate on the surface). The need to be compatible with the solvents, temperatures and the pH. Some of the PAT requires a kind of a continuous small sampling loop, which also can be challenging. 

But these are all things that a typical engineering scientist is used to developing as they work on a process. And it just depends on what you're trying to measure. And, of course, there's a tremendous advantage to measuring things in line or online, as opposed to sampling and going offline to measure things.

Allan Myerson: At this point, more companies are working on limited sets of integrated steps for continuous manufacturing of an intermediate, and some are working on integrated continuous manufacturing of the final API.  There is significant movement on the drug product side for the continuous manufacturing of certain products since a lot of the equipment can be commercially bought, which helps a lot. 

Allan Myerson: There's continuous movement of the industry to reduce waste and use more benign materials. And I think that's going to continue. But it can be very difficult to manufacture an important pharmaceutical and the need to manufacture it might outweigh the need to delay developing a process using greener methods. But all things said, everybody is looking to improve the environmental impact of their processes.

Allan Myerson: I do not think we're going to see huge adoption in the near term, but I think slowly, there'll be more and more of this as the years go.