Drug Digest: Closing the Gap in Modern Process Control and Automation for QC/QA

*Full transcript available below.

Digital transformation and advanced analytics are revolutionizing biopharmaceutical quality control (QC). By synergistically combining formulation and analytical methods, the industry enhances quality, scalability, and innovation. This crucial shift is driving R&D investment, making advanced biotech equipment essential for scalable drug production. This episode of Drug Digest will explore this modernization of QC and examine the role that advanced analytics and digital transformation play in this unfolding revolution.

Interview featuring

Susan J. Schniepp, Fellow, Regulatory Compliance Associates

At Regulatory Compliance Associates (RCA), Schniepp is responsible for training and advising RCA staff and clients on current trends and issues facing the pharmaceutical, biotechnology, and medical device industries. Her background includes current good manufacturing practices, audit readiness, change control, investigations, supplier quality, and batch record review. She has more than 40 years’ experience in quality assurance, serving in leadership roles at Allergy Laboratories, Oso BioPharmaceuticals, Searle, Abbott, and Hospira. She has been on the Parenteral Drug Association (PDA) Board of Directors from 2011–2013 and from 2016–2019 and currently serves as the board’s chair. Schniepp has served on numerous planning committees, including the PDA/FDA Joint Regulatory Conference Planning Committee since 2002.

Siegfried Schmitt, PhD, Vice President, Technical, Parexel International

At Parexel, Dr. Schmitt provides consulting services to the healthcare industry on all aspects of regulatory compliance, particularly the design and implementation of quality management systems. The services cover the entire product lifecycle, from the clinical to the commercial phase, for all aspects of the good practices. His areas of expertise include all aspects of quality and compliance for systems, processes, facilities and operations for drug substances and drug products. Specifically, he consults on compliant quality systems that integrate industry best practices with future-looking compliance approaches. His career spans over 35 years in industry. He is an accomplished editor, author of nearly 200 publications, trainer and presenter.

Sponsors

This episode of Drug Digest is sponsored by:

• LGM Pharma
• Nelson Labs
• Parenteral Drug Association
• Thermo Fisher Scientific
• Veltek Associates

About Drug Digest

Drug Digest is a tech talk video series with the Pharmaceutical Technology® editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

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Transcript

Editor's note: This transcript is a direct, unedited rendering of the original audio/video content. It may contain errors, informal language, or omissions as spoken in the original recording.

Patrick Lavery

MJH, pharmaceutical technology presents drug digest, a tech talk with the pharmaceutical technology editors all about emerging opportunities, obstacles and advances in the pharmaceutical, biopharmaceutical and biotech industries. Join us as we discuss with industry experts the research, development, formulation, analysis, upstream and downstream, processing, manufacturing, supply chain and packaging, as well as business strategies and regulatory issues.

Feliza Mirasol

Hello everyone, and welcome to the joke digest video series. I'm Felice Mirza, science editor for pharmaceutical technology, pharmaceutical technology Europe and BioPharm International. In this episode, industry experts will discuss how digital transformation and advanced analytics are revolutionizing biopharmaceutical quality control and the challenges that the industry faces undergoing this transformation, joining me today will be Susan schneep from regulatory compliance Associates, and Dr Siegfried Schmidt from pyrexel International. But first a few words from our sponsors. This episode of drug digest is sponsored by LGM pharma, Nelson labs, the parenteral Drug Association, Thermo Fisher Scientific and beltek Associates. LGM Pharma is a US based cdmo, providing integrated drug substance sourcing and drug product development and manufacturing from early stage programs through commercial production. Nelson labs, a sotera health company, is an industry leading global provider of laboratory testing and expert advisory services that performs more than 900 rigorous microbiological and analytical laboratory tests across the medical device, pharmaceutical, protective barriers and tissue industries, the parenteral Drug Association is the leading global provider of science, technology and regulatory information, and since its founding in 1946 as a nonprofit organization, has been creating awareness and understanding of important issues facing the pharma community and delivering high quality, relevant education to the industry, as well as scientifically sound, practical technical information and expertise to advance pharma, manufacturing, science and regulation. Thermo Fisher Scientific is the world leader in serving science, enabling its customers to make the world healthier, cleaner and safer. Bell tech Associates is a single source supplier providing solutions for pharmaceutical or biotechnology contamination control requirements. And now, without further ado, let's get to our speakers.

Speaker 1

Hi everyone. My name is Sue Schneep. I'm a Distinguished Fellow with regulatory compliance Associates, a division of Nelson laboratories. I've been in the industry about 40 years, so I guess I'm old and crabby, but I've learned a lot, and we're here with Siegfried Schmidt to impart some of our wisdom and knowledge onto the audience here with that, I'm going to turn it over to Siegfried to introduce himself.

Speaker 2

Thank you. So my name is Siegfried Schmidt, and I'm Vice President technical at PAREXEL, and I've got over 35 years in industry and over 18 years with powerexcel, and so my expertise is really from clinical to commercial, all matters of compliance any regulatory system in the world. So yes, and it's it's always fun and a pleasure to share some of our expertise with the rest. Thank you.

Feliza Mirasol

Now for my first question, I'd like to throw this to Siegfried first, and then Susan, so Siegfried, how are advanced analytical techniques changing the definition of analytical best practices in biopharmaceutical quality control today?

Speaker 2

Well, you see these techniques on the one side, they represent the state of the art, and on the other side, they help expedite analysis. And why do I mention state of the art? Because state of the art is actually a regulatory requirement. This doesn't necessarily mean that all the methods must be cutting edge, but you need to use the methods that are established by industry. So we are no longer talking about thin layer chromatography. We're talking. Talking about really modern analytical methods, HPLC, UHPLC, hyphenated techniques and so on. So from the perspective of the analytical laboratory, you want fast and accurate technologies because they help an increase of throughput of the analysis. It supports the fast creation of certificates of analysis, because these you want to have as early as possible, because you want to release your product or the product for the next step and so on. And being faster also means you reduce cost and you increase revenue, very important, particularly in R and D and so these technologies, they typically run on highly automated equipment, which, again, is an important factor, because Electronic Data Management helps, or is actually essential for data integrity. I am sure sue you have additional information you want to share on this?

Speaker 1

Well, yeah, Siegfried, I think you bring up some excellent points what this new analytical technology is doing, which is, to me, very important, is driving to real time release in a lot of cases, because you've got in line monitoring procedures and processes you've got, you know, the rapid microbiology results that come along with this, and I think driving to real time release. And, you know, like, as you're making it, you're releasing it on the back end, you're manufacturing, you're putting it together on the front end, and you're shipping it out on the back end, all within, you know, 24 hours. I think it's important, because as we get into the biologics and the atmps, I think we're dealing with very sensitive products that may or may not have, you know, a stability, a longevity of stability, you may have to get it out the door relatively quickly in order for it to be viable with the patient, right? I mean, that's kind of where I think we're driving. And I think these are going to get more and more sophisticated, and some of our traditional thinking around compliance to the Compendia is going to need to go away, because the Compendia is not going to be able to keep up, at least under their current operating processes, right with the rapid changes going on with these techniques.

Speaker 2

So you're, you're very right there to go and combine not just the thinking about the analytical method, but about the processes, because you need to look at it holistically, at both what is happening in operations and what is happening in the laboratory. You can't think of things separately. They are integral to each other.

Feliza Mirasol

For this next question, let's start with yusu. What specific impact has the use of innovative tools had on improving quality control?

Speaker 1

I think the impact has been we've been able to get results faster and evaluate the state of the product faster. This becomes important. If you have like a defect or investigation deviation during manufacturing, you can get a result or resolution to that quicker, hopefully, which will allow you to longer you keep that subjective batch running through your process. Hopefully, you know, you don't get to the end, because that's a waste of money. If you have to abort the batch, you want to do it sooner in the process, rather than later. So I think it allows us to kind of close deviations, maybe investigations a little bit quicker. But I think there's a downside to it too, in terms of we know more about the product. In terms of, like, if we did impurity profiling, we probably are picking up with these pieces of equipment, a lot more impurities than we ever picked up with the traditional HPLC. And so now we're chasing, I don't want to say chasing our tails, but chasing our tails, trying to figure out whether the impurities are harmful, you know, and and. At some point we almost know too much about the product that almost negates it from being safe, right? It's kind of that catch 22

Speaker 2

that's very interesting what you say, because the more precise, the more detail an analytical method can detect, the more you can find, but we clearly also have limits defined what is acceptable, what is not acceptable, and just because we can dig deeper doesn't mean do we always have to, but perhaps another point you already brought up is the speed of things. And I think these tools not only help improve the analytical methods to be faster and better, but it's also the processes that they support. They become faster, more reliable, more efficient. And what I recently saw was absolutely astonishing. Some of the tools that big pharma are developing and using, they use, for example, ultrasound, to move samples of meniscus volume in the laboratory so there is no more manual handling. It's ultrasound driven. Sample goes from a to b, phenomenal. And of course, when we talk about tools, we also have to think about, for example, the media that may be needed in the microbiology laboratory, and there are modern methods that help you understand the variability of the various media in the short time. So what we're talking about is something that helps us, not just with the actual analytical method as such, but with all the media that we use around them, the methodologies, the processes, and maybe I'm just repeating what I said before, but we need to look at it holistically. We can't just look at one element only, and I think this is where it's also important for the industry. If you want to improve, say, your processes in the operations part, then you also need to look at your laboratories. Can the laboratory support this? Can they not or the other way around? You may have a super laboratory, but a lousy process operations, and what is the value of a fast laboratory? If your process is still slow,

Speaker 1

I totally agree with you. Sigma freed what and you what you said raised an issue with me on these new pieces of equipment and moving it with ultrasound. And there's also an element of, we're saving resources, right? We're not using as much. So there's an environmental friendly and sustainability quality about many of these new analytical tools that are coming down the line where we're not using, you know, benzene to or acetone, we're using a lot less resources, a lot less waste, which is, you know, more sustainable.

Feliza Mirasol

How would you say companies are leveraging the synergy between formulation development and analytics to enhance product quality, scalability and innovation throughout the entire drug development process. And I'll toss it to whichever one of you wants to start first,

Speaker 2

what I've seen, and I find it quite interesting, is that formulation development rather sticks to standard formulations using standard excipients and formulation processes, I see limited innovation. Perhaps this is mostly with intention to save time and provide an acceptable formulation quickly for clinical trials and commercialization. Now, of course, if you have modern analytical methods and tools, you may get faster, more accurate analytical result. So So overall, I think the key driver is speed is not necessarily innovation,

Feliza Mirasol

and what core R D investments in advanced equipment are most essential for achieving scalable drug production in the next

Speaker 1

decade? I don't know that R and D investment. I think it's going to be in the manufacturing line investments, not necessarily R and D. I think it's the manufacture. Lines that are R and D usually tends to have a lot of creative and clever and cutting edge equipment kind of built into their budgets, and so they're fiddling with, you know, things like the rapid micro. It's what I worry about, is the manufacturing facilities that are a little bit lagging. We tend to not update them on a traditional schedule. You know, we have equipment that's been around for 30 years. It's kind of like one of those cars that you get a little plaque if you get over, you know, 500,000 miles, and you're lucky, it's still running. I think the game to winning this game is going to need to manifest itself into key investments and purchases of new equipment in the manufacturing arena. Now, all is not lost, because there are several companies that are starting to build, you know, Greenfield manufacturing facilities around the world that would accommodate these new biologics that are coming out. But at some point, some of the older biologics are going to be transitioning to contract manufacturing arenas, and they're the ones that are really lagging in terms of updated equipment and facility, at least last time I checked, I'm going to throw it to Siegfried and see if he can correct my misinterpretations on this.

Speaker 2

No, no, no. So yeah, you're right there. You're right. It's not the R and D. R and D can use design of experiments and all sorts, and they have a lot of nice tools, is here really is about commercial manufacture and see what we what you really need to get better and more consistent and more reliable manufactures that we need in line, online, nearline analytics, with feedback loops for continuous, if possible, real time analysis, because otherwise we will be stuck, as you say, with equipment that's 30 years old. Now the vessel itself is not the issue. It is the instrumentation. It's the automation. And when I say automation, I also think it's the integration of automated systems. If you don't have the integration, if you don't have the transmission of the data from one system to another, then you may wait, and it's not unusual days weeks for an analytical result. And what happens in the meantime with production? Nothing, it stops. And just to give you an example, and this was an R and D plant, unfortunately. So this plant that I visited, it takes 15 minutes for a person to manually transport a sample from the line to the laboratory. Yeah. I mean, this is not sustainable.

Speaker 1

I totally agree, Siegfried, and one thing you prompted in my mind is this continuous loop as we're getting information faster and faster, but we're also getting interpretation. We're adding AI to the whole process, and virtual learning and digital twins and all that stuff that you know we're talking about in the AI. The AI world, and so I wonder how fast we, the human can learn, and we've got the machine learning quicker than we can right? Just some thoughts on that from you.

Speaker 2

Well, so AI, everyone mentions AI, and I totally believe that AI will play a role in in the facilities of the future, say the laboratories, and where I think AI really works well is how to manage things, yeah, because these tools are really good at identifying optimal processes. Say, in the laboratory, you have a series of systems available, you have a number of samples waiting, you have a number of analysts and trying to figure out what is the optimal way which sample should go on, which equipment be analyzed by which analyst, etc, etc. We can do it, but slow AI systems are very fast at that, so that's great. And these tools may, may be useful for QA too, not for say, release decisions. But to support the review activities, and again, I have to say it's a connectivity that is absolutely essential to make these systems work. Because again, I see so many companies where analytical results are manually typed into a limbs to create a certificate of analysis. I mean, it's beyond belief. I have to say this is just antiquated, archaic. This is not the way to work.

Feliza Mirasol

Now, in both of your experience, what are the primary challenges contributing to the gap between hype and implementation of digital transformation, particularly concerning process control, automation and process analytical technology?

Speaker 1

That's a very interesting question, and I'm really going to be fascinated to hear siegfried's take on this. But from my perspective, we hold ourselves back in a lot of ways, because we're we're afraid of the regulatory implications or filings or compliance that we need to achieve when we're adding new and innovative technologies, even AI into the even putting in a new line in our manufacturing facility, people tend to shy away because they're afraid of the regulatory implications or doing something, and then having the agencies Say, oh no, no, you didn't do it right? I don't think that should drive our thought processes here. I think what we need to and this is going to sound real old school and old fashioned, but in my way of thinking, what we need to do is revive our skills when it comes to risk based decision making. I think we have lost that talent in quality and regulatory areas of professionals, and we've driven ourselves over the last 20 years to what I would call a checkbox mentality. And we need to go back to those appropriate, risk based decisions and understand that if I can put in a new manufacturing line, it's going to be more beneficial and good for the patient as well as the product, as well as the company. And how do you do that? You need to look at the regulations and figure out which ones apply and how so let's just take an example. I if you're as as I alluded to before, if you're a contract manufacturing organization, you have multiple clients. You're producing multiple products. The traditional pharma thinking has been that in order to put in a new line, you need to build up two years of inventory of all the product that you're making, then you need to decommission the line, then you need to put in the new line, but you got to get permission, a prior approval supplement from in this case, it would be the FDA to put in that new line that may take you a year. So you may be down on a line for two years while you figure out this interesting dilemma of putting in a new line to improve productivity, reduce scrap and improve patient safety. Now, if you read the regulations in the US, you find out that you can do it relatively easy in four months. If you interpret the regulation. So for instance, if I have an old traditional line with what we called shower curtain barriers, and I want to put in a RABs restricted access barrier system, I can do that as an annual reportable, because there is in that particular guideline something that says, you know, any increase between the product and the human, any increase of intervention, which certainly a restricted access barrier, is a lot better than shower curtain, right? That can be an annual reportable so go ahead and make that change as a positive. So I think in some of all of this improvement, the quagmire is one we've made ourselves, and we need to develop a little bit more risk based decision making. Siegfried, I'd like your take on that that was a lot of ways saying we were stuck in the mud.

Speaker 2

We are. We are so and yes, if I hear someone saying, Oh, I don't know, well exactly, why don't you do a risk assessment? Where are the facts? Where the data don't just use good feeling, give us the facts. If it if you say. The regulations don't allow it. Where does it say? Have you spoken to the agency? But I think when we look at these concepts like pa t, they have been around for two decades, and I know facilities where they have been implemented for two decades, and they work, and it's it actually is nothing new. But then we have to ask ourselves, why aren't they everywhere? And something you mentioned is the upgrading and upgrading an older facility to make the facility ready for full digitalization. That isn't trivial. That is really a tricky thing. And again, if you don't have an alignment between analytical and manufacturing technology, this will all be difficult. And so what? What I see, and I'm sure you've seen the same so is a lot of these facilities have absolutely minimal automation and digitalization in there. Yeah, there's very little integration of systems. And there's, there's reliance on laboratories rather than on online, in line analytical systems. And I remember nearly 30 years ago, we put an HPLC right next to the line. We didn't take the sample for 15 minutes to the lab, and perhaps they have some time, some time to give us a result, yeah. And what it seems to me is that the cost benefits of the digital transformation aren't really fully understood by so many companies. Yeah, but when you look at Big Pharma, the picture, to me looks very different, because these companies definitely embrace technology, and they profit greatly from it.

Speaker 1

I really like what you touched on to kind of exemplify a little bit of where we're at. And Siegfried said it really well, some of these lines we're talking about, the manufacturing lines are very old and haven't been updated, and it's so it's like taking a 1968 Mustang and then trying to put in all the computer equipment and sensors of 1925 BMW, right? It's going to take a really long time and a lot of work and a lot of money to bring that kind of technology to an old manufacturing facility or place, right? And that's what we're talking about. So in some ways, you have to ask yourself, Do I scrap the facility and go green field, or do I try to do this very expensive upgrade, and maybe it works, maybe it doesn't right. So I think that was a really key critical point you brought up.

Feliza Mirasol

Siegfried, now Sue going off your previous comment. Have you actually seen any examples where companies like cdmos have made that decision, in other words, to go Greenfield, with a facility, or go with another strategy?

Speaker 1

No, I haven't seen that decision. I think what's kind of happening, although I don't know right, because I haven't been but my guess, or from what I hear in the scuttlebutt, is we're kind of limping along there by adding technology slowly at certain points in the process. You know, so, but the whole transition that really needs to be able to keep up with some of these at Advanced therapeutic, medicinal products that are coming out, it's it's going to be next to impossible, I think, in some ways, to achieve that vision. But Siegfried is much more the expert than I throwing it over to him.

Speaker 2

Well, cdmos find it very difficult to change a facility because it usually affects too many clients. So building a new facility, almost is the only solution. And when we suddenly what I've seen, and sometimes you get the facility of the Year Award for this is new facilities, and they're mainly built by large Big Pharma. They are the ones that are really automated, that leverage all what can. Be leveraged from these tools, and so really, they try not to upgrade the old equipment that's already 30 years old, because it's difficult. It's much easier to build a new one. However, on the other hand, I see many new plants, new facilities where the operators on their mobile phone have more computing power than what's on the equipment, and it doesn't make sense in some way. And what Sue mentioned about atmps, selling gene therapy manufacturing that there has to be a much higher level of automation built in right from the start, because, again, as Sue said, You cannot wait two weeks for an analytical result when you have the cells ready and it's either inject into the patient or put in the waste, either or. And you need results there and then. And so this can only be achieved through rapid methods, through fast, automated systems.

Feliza Mirasol

Well, thank you both, and I'm afraid that's all the time we have today. Thank you to Susan and Siegfried for being on today's episode and sharing their experience and insights. I'd also like to thank our sponsors, LGM pharma, Nelson labs, the parenteral Drug Association, Thermo Fisher, scientific and veltic Associates, for supporting today's episode. You can catch all our drug digest videos at www.pharmtech.com thank you for watching.

Patrick Lavery

Did you enjoy this episode? If you did, please share this video with colleagues who you think would enjoy the content. Thank you to our editors and experts for sharing their insight. Thank you as well to our sponsors for sponsoring this episode. If you want to stay in touch with pharmaceutical technology team, subscribe to this podcast as well as to our E newsletters. When you sign up for our newsletters, you will be updated about future episodes of drug digest. Receive our magazines and more. Thanks to everyone for joining us for this episode of drug digest, we will see you next time you.