In this episode of the Drug Solutions Podcast, Jennifer Markarian, manufacturing reporter, talks about the continuous manufacturing of oral solid-dosage drugs with Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company.
Meg: Pharmaceutical Technology presents the “Drug Solutions” podcast where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions from the technologies, to the strategies, to regulations related to the development and manufacture of drug products. This is the “Drug Solutions” podcast. Hello, everyone, and welcome to this episode of the “Drug Solutions” podcast. I’m Meg Rivers, senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International. Without further ado, I’m going to turn it over to the editors who will share more about what you can expect in this episode.
Jennifer: Hello, everyone. Welcome to this episode of the “Drug Solutions” podcast. On this episode, we’re going to talk about continuous manufacturing for oral solid dosage drugs. Continuous manufacturing is an advanced manufacturing technology that promises a lot of benefits like more flexibility and efficiency. We heard on a previous episode that this type of technology can possibly be used in reshoring or onshoring efforts in pharma manufacturing. Continuous manufacturing has been adopted by several pharma companies, the first in 2015, but it’s been slow to be taken up by the broader pharmaceutical manufacturing community. And today we’re going to look at some of the challenges in that area.
I’m Jennifer Markarian, a manufacturing reporter for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International. I’ll be speaking with Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company. Lawrence worked at Janssen for many years, including eight years on their continuous manufacturing effort and has been involved in many industry organizations and working groups dedicated to advancing continuous manufacturing for the pharmaceutical industry. Lawrence, what are some of the challenges or roadblocks to additional use of continuous manufacturing in the pharmaceutical industry?
Lawrence: Well, the benefits for continuous manufacturing are clearer. So, they are very broad. There are many benefits in development, tech transfer, and in commercial manufacturing. But the drivers for additional use, so on top of what people already know, what is stopping the pharmaceutical industry to use more continuous manufacturing than they do today? I assume that is the question. I think that’s a few things, one is equivalent cost is too high at this moment still. Very often in business cases, the continuous manufacturing equipment needs to compete with existing batch equipment that very often is written off already. That’s one. Second, it’s not flexible enough. If you would be able to buy a continuous manufacturing line knowing that you buy it for one product, but in a few years there might be something else and you can just easily switch it over from one to the other, it would lower that impact of that investment cost, but the equipment is not so flexible either, so at this moment continuous manufacturing equipment is not very modular by nature.
Unit operations are not interchangeable. And that would be very helpful, I think, for additional use in the industry today. If unit operations would be interchangeable between different types of lines for if something changes in the future, if the better machines come up or if machines that you already have you want to bring them in into a continuous manufacturing line that you run. And to be able to get to there, the designs need to become modular, interfaces needs to be standardized in the future so that interchangeability of unit operations becomes easier. So, that’s, I think, one thing. So, more flexible and lower cost equipment. Second thing is easier access to knowledge, experience, and capability. There is not so much experience in the industry today. There’s only a few CMOs out there that have continuous manufacturing lines. There’s only one or two that have actually filed the product on their lines. There’s not too many consultants out there with real experience that can support companies that want to take this step. There are a number of guidelines that are mainly written by the FDA and other health authorities. There’s a number of standards and documents, but not enough. There’s not enough guidance documents that help you from A to Z to assist you in doing everything that you want. And there’s not enough lab support for models that you want to develop for PAT tests that you need to do to help you with experiments in the early phases. So, a general package of support in consultancy, in lab work, in guidance documents, and potentially CMOs even would be very helpful as well.
Jennifer: Are there any other challenges that you see or benefits that have yet to be realized and ways that you see the industry needing to get there beyond the ones that you’ve mentioned already?
Lawrence: Yeah, there’s many things that can be done and improved and there’s many hurdles. So, to be able to have a full-fledged broad acceptance and implementation of continuous manufacturing, I think quite a few things will need to happen. First of all, time because it’s a very slow process. A lot of companies and people need to gain experience, which takes a long time. That’s one thing. Second thing is the business cases need to be in place. Companies need to realize that it makes sense to invest in continuous manufacturing equipment, need to put the money aside and then the year after when the budget is released, they have to invest and then it takes two years or so before the equipment is really qualified and can be used. And only then it starts to start developing the first products creating the knowledge and a few years later the first product might be filed and it takes still years before you have an approved product before it really comes to the market.
So, it’s a very slow process. So, time will be an important factor. And there’s many companies already that have equipment, especially in their R&D departments, but more and more also in their commercial network. So, over time, we will see more and more coming of continuous manufacturing, especially in drug products and bit by bit more also for drug substance, but maybe not end to end, but for portions of the chemical processes. We will see this more and more.
And then another thing that would be needed, I think, is a more global harmonization of the requirements of the health authorities. The health authorities…many health authorities are very supportive today already, but many do not have experience or hardly any experience and it’s not clear what the requirements are for many of those other health authorities. And that’s, I think, a big hurdle for companies that want to launch globally products that do not… Well, that fear that they can do an implementation in many of the countries but then there’s a few that say, “No, you cannot do it like this or this, or you need a lot more data,” or even say, “You cannot do it in continuous manufacturing.” So, the global harmonization of the requirements on health authorities is something that would be helpful as well. I see HQ13 is a good step in the direction but that’s only a limited amount of countries. And also, it’s not an overall harmonization yet. It’s just an agreement on a number of aspects of it yet still.
Jennifer: I know back in the beginning of talking about continuous manufacturing, it was said that, you know, getting to real-time release was sort of the goal, but that a lot of things had to happen in PAT and feedback control and so on in order to get to that. Do you have any thoughts on where the industry is now? It’s still kind of in-process towards that? Have they made progress or still some of the same limitations just being worked on?
Lawrence: Yeah. Maybe first clarification that real-time release is… It’s a term that covers quite a few things. So, you can… For every quality aspect that needs to be covered of your final product, you can have a real-time release or for a number of those, you can have a real-time release portion in there. So, you can do that for aspects like assay or for the dissolution. But the dissolution is a very difficult one because there is no inline test possible that directly measures the solution. And normally you’d bring that to the lab, you do a number of tests that take quite a bit of time. And there’s nothing fast that can inline immediately measure the solution of your tablets.
So, to achieve that, what some companies do that have achieved real-time release for the solution is by replacing that by a surrogate method, so inline measurements of things of which have been proven that they are one-on-one related to the dissolution of the product afterwards, so not directly but indirectly measured. And that one-on-one link is just not there for every product. That’s one. Second, it takes a lot of data, experiments, and a lot of knowledge of your product before you can really prove that link. So that means it can cost a lot of money and a lot of time and a lot of material before you have collected enough data to show that the solution or to build that model that will help you for the real-time release for the solution.
That means that many companies most likely will not do real-time release for the solution because it’s not possible or because there is no business case for it because the real-time release for the solution, it will not help your quality really, it will just help you reduce your time that you need to release your product and it will reduce the effort in the lab so that it reduces the costs. That’s the two main reasons why you would do real-time release for the solution phases. But if the business case is not there, it doesn’t make sense to do it. Right? So, if it’s too costly, that will be dropped. But still, there’s other portions of real-time release that you can do for ID, for assay. These are things that need to be measured as well and you can do them directly…you can measure them most of the time directly in line. So, that type of real-time release very often is and will be done in the future for your product as well. So, bottom line, I think that companies are already doing real-time release in continuous manufacturing typically for a number of the critical to quality attributes, they call it that, that are linked to a product, but unlikely that they will do it for all. And I think that will remain like that in the future as well.
Jennifer: Can you speak to how the data from PAT, Process Analytical Technology, are being used for process control and what areas might need further improvement?
Lawrence: So, the evolution of the PAT implementations is something that we see in continuous manufacturing. Initially, it was thought that it was the smartest to put PAT tools everywhere to measure as much as possible and to try to be redundant. For instance, if one PAT tool would fail, you have another one somewhere else that can measure something similar like this, you still have the data. But over time, we see that a number of the pharma companies are evolving to only install the PAT tools for commercial manufacturing which are really needed for the product. So, they do risk assessments, risk analysis to see where is it really needed for your control strategy and where is it not really needed, and only install it for commercial manufacturing where it is really needed because additional PAT tools mean additional models. They need to be created. There’s a lot of API to create them. But also you need to maintain them. And the maintenance of PAT models is also cumbersome and it asks a lot of work and resources and it’s scarce resources because that’s the type of experience and knowledge that is not spread around thick in the industry.
So, therefore, we see that evolution is ebbing away a little bit from a full-blown PAT everywhere to only where it’s strictly necessary. Of course, within development, PAT is very valuable there, the more the better, because it helps you collect data that you need to understand your process. That’s something else. But in the commercial manufacturing, we see that it first went up to do a lot more and now it’s less again. The overall evolution that we see is that the whole industry is very enthusiastic, but there’s still a number of hurdles that is stopping the full industry to embrace continuous manufacturing at full. And the biggest reasons are what I explained there. So, it’s the cost of equipment that needs to go down. To help that, luckily, there’s a number of vendors, there’s more and more vendors that are bringing equipment to the market, the realization that this equipment needs to be modular in kind and that interfaces need to be standardized and harmonized to make unit operations interchangeable between different brands and lines. That becomes more and more clear to vendors and to the industry itself. So, that’s a good evolution.
We also see that the equipment at this moment is not fully mature yet. There’s quite a bit of things that need to be worked out further. We see that PAT tools today, they are not always capable of handling very low concentrations of API, which is sometimes needed in a formulation. So, accurate PAT measurements for low concentrations is something that needs to be worked on further. PAT solutions in the drug substance for different types of measurements in chemical processes is something that needs to be further worked on. Feeders are one of the key components in a continuous manufacturing line. The working out of feeders that are accurate in dosing very low concentrations or in small amounts dosing is something that there is still a gap in the industry. Working on it, but, for instance, the dosing of magnesium steroids, which is typically something that is dosed right before you go tableting. It’s a lubricant that is added to assure a smooth tableting of your powder. The consistency of those feeders is still not ideal yet. And because of that they… Well, it’s something that stops lines regularly because they go out of specification of the amount that they are feeding. Stops the line, you need to restart, etc.
So, consistency and high accuracy of dosing low amounts of powder. And then, yeah, in general, the software is something that needs to be improved overall. And so the control software of continuous manufacturing lines would need to be modular of kind as well as modular as possible. So, that means that if in a continuous manufacturing line you want to add a feeder, you can just add a module in your software and you can get it up and running and that’s it. That sounds logical that you would be able to do that, but if you didn’t program that in from the beginning, today, typically that doesn’t work. So, it’s not… The software typically is not very flexible. And that’s something that would be helpful in the future for all the lines that would come out there so that if things changed that it’s relatively easy to adapt it to the changes that are coming.
Meg: Thank you to our editors and experts for sharing their insight. Stay tuned for future episodes of the “Drug Solutions” podcast with the Pharmaceutical Technology editors. If you want to stay in touch with the Pharmaceutical Technology team, subscribe to this podcast as well as to our newsletters. When you sign up for our e-newsletters, you will be updated about future episodes of “Drug Solutions,” receive our magazines, learn about upcoming webinars, and hear about episodes of Drug Digests, which is a video series. Thank you to everyone for joining us for this episode of the “Drug Solutions” podcast. We will see you next time.
This paper is a comparative analysis between the application of the FDA Process Validation Guidance (2011) to new products and legacy products.