Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

Steffen Thirstrup, chief medical officer, EMA, emphasizes the importance of transparency in investigating potential safety issues of CAR-T therapies.

Europa Perspectives: EMA Transparency in Investigating CAR-T Secondary Cancers

In a Jan. 25, 2024 interview, Chris Spivey, editorial director, 

®, spoke with Steffen Thirstrup, MD, PhD, chief medical officer, European Medicines Agency (EMA), for the Europa Perspectives series. In this third installment, Thirstrup emphasizes the importance of transparency in investigating potential safety issues, such as secondary cancers linked to certain chimeric antigen receptor T cell (CAR-T) therapies, while highlighting the need to balance regulatory diligence with maintaining trust within the community and among stakeholders. Full the interview transcript, 

This segment of discussion focuses specifically on warning labels for secondary cancers, recently applied to some CAR-T therapies. Thirstrup says, “[It’s] an area for a regulator to consider, or be aware of, or at least to understand. But I think it’s unavoidable if we, as regulators, pick up a signal that might be a potential signal of a safety issue with a product or classes of products that we have approved, we need to investigate that. But we are also obliged to be transparent towards developers, patients, all stakeholders that we are investigating this and ultimately explaining the conclusion of that investigation. So, whether there’s something or not—and as you can see in what’s been published around CAR T cells and secondary cancer—I think that’s what you’re alluding to, that’s a signal we are investigating as well. We also know that patients with cancer get secondary cancers. So, the challenge is again to disentangle the hen and the egg question, more or less. I think it’s important for us to be transparent, and we have no interest in … putting a black thumb on any of those products. But on the other hand, we need to be transparent. We owe this to the community, we owe this to the patients, and we are a public body, so we cannot hide what we’re doing. We don’t have any interest in hiding what we’re doing. That would be more devastating than being transparent.”

Thirstrup is a medical doctor with a PhD in pharmacology and broad clinical experience in general internal medicine. He has a track record of working with the European Union regulatory network. He previously led the Division for Medicines Assessment and Clinical Trials at the Danish Health and Medicines Authority and was the Danish member of EMA’s human medicines committee (CHMP). He was also a member of EMA’s Committee for Advanced Therapies (CAT), the chairperson of the CHMP’s Respiratory Drafting Group and co-chair of the European Commission Working Group on Market Access of Biosimilars.

Articles

Steffen Thirstrup, chief medical officer, EMA, emphasizes the importance of transparency in investigating potential safety issues of CAR-T therapies, while highlighting the need to balance regulatory diligence with maintaining trust within the community and among stakeholders.

Steffen Thirstrup, chief medical officer of the EMA, discusses manufacturing supply, drug shortages, commercial incentives, politics, and patient wellbeing.

Europa Perspectives: Helping to Navigate the Regualtory System

Steffen Thirstrup, MD, PhD, chief medical officer, European Medicines Agency (EMA), was interviewed on Jan. 25, 2024 by Chris Spivey, editorial director of 

® for the Europa Perspectives series. For the full interview transcript, click 

This segment of discussion pivots around manufacturing supply, drug shortages, commercial incentives, politics, and, ultimately, patient wellbeing. A less well-understood role of the EMA is how the agency’s activities intersect with the factors driving pharmaceutical science forward. Thistrup outlines that, “We've done [much] in expanding our help into academia that are early in development, to small- and medium-size enterprises. We have an innovation task force where you can come and bounce off your idea and have a less formal conversation with us, how you could move those ideas into further development. [In addition], we still have our full-blown scientific advice procedure, which, coming back to the prices, we can do in conjunction with the health technology assessment bodies. So, independent of what happens on the patent side and data protection side, I think we are happy to help. That's our opportunity, and, fundamentally, the only role we have in driving innovation forward is to put our knowledge and our insight into drug development and the rules we are governing to the benefit of the developers, and try help them navigate the system.” He continues on to add, “So, engage early with us, and we don't bite. Sometimes regulators are seen as conservative and stubborn, but I think on the other, we are here to safeguard public health, but we are also here to help drive innovation forward, and especially drive innovation of potentially better products forward.”

Planet Earth from Space EU Europe Countries highlighted, elements of this image courtesy of NASA | Image Credit: © Sono Creative - stock.adobe.com

Prof. Steffen Thirstrup is a medical doctor with a PhD in pharmacology and broad clinical experience in general internal medicine. He has a track record of working with the European Union regulatory network. He previously led the Division for Medicines Assessment and Clinical Trials at the Danish Health and Medicines Authority and was the Danish member of the European Medicines Agency’s (EMA’s) human medicines committee (CHMP). He was also a member of EMA’s Committee for Advanced Therapies (CAT), the chairperson of the CHMP’s Respiratory Drafting Group and co-chair of the European Commission Working Group on Market Access of Biosimilars. In this interview with 

®, Thirstrup gives his insight on pharmaceutical regulatory challenges from a Europe-based perspective.

 Can you please outline recent challenges and successes you’ve had as regulators?

I think the biggest success, but also challenge met, was the COVID-19 pandemic. Managing, reviewing [many] different products, and ultimately reviewing the vaccines … but also monitoring those vaccines after they got approval, and picking up some very rare side effects, that put stress on the system to act in a very quick manner, and departing from the usual review process, and being more agile with rolling reviews, and so forth (which is not really part of the legislation in Europe) was a big, big challenge. We learned [much], and we are still picking the fruits of that learning and thinking about how we could implement some of those learnings moving forward. On the other hand, I think apart from being a challenge, it was definitely also a success because we managed to bring those vaccines onto the market. Like FDA [US Food and Drug Administration], we continue to update those vaccines. So, I think that’s the biggest and most recent major success.

Our system may require a little bit of background to understand. The EMA is located in Amsterdam with almost a thousand employees. We are highly reliant on the national competent authorities coming from the 27 EU member states. They provide the expertise, they provide the members of our decision-making bodies, our committees. So, unlike [FDA], which is one body that can issue marketing authorization for all 50 American states, we actually have a layer of national expertise. We are more a network organization, and sustainability of that network is a challenge for us. COVID was a big strain on the system. There’s also an age distribution that means that many people are retiring. People want to do something differently after COVID-19. We had Brexit as a major challenge to the system because the MHRA [Medicines and Healthcare products Regulatory Agency], the UK regulatory authority, was a major contributor to the European system, both in terms of taking on responsibilities but also providing expertise to us. So that loss created a hole in our expertise.

We are still working on maintaining the sustainability of our network, getting the right experts on board and so forth. It’s not that we are in a critical situation and don’t have the experts, but we can see there are areas where we need to pay extra attention to get the right expertise on board. So that is a challenge, and an ongoing challenge.

Another challenge I want to highlight are shortages of medicines. And again, being a network organization, shortages are hitting different European member states in different ways, different products in different countries, due to different demand and supply. We are monitoring shortages and trying to deal with shortages—again in the network situation. So, we collaborate with the national competent authorities in the 27 member states, but we are doing [a significant amount of work], and we can come back to that later on to create pan-European solutions to deal with this.

 Did the COVID challenge strengthen collaboration globally?

 Prior to COVID, we had already a strong collaboration with [FDA]. Last year we celebrated the 20-year anniversary [of] our mutual recognition and confidentiality agreement with FDA. So, we’ve been talking to FDA, but I think COVID-19 added to that collaboration, but also added to collaboration with other regulators around the globe. The International Coalition of Medicines Regulatory Authority (ICMRA) is a network of almost every regulatory authority, for example.

 From EMA’s perspective, could you describe current attitudes to drug pricing and reimbursement, particularly for advanced therapeutic medicinal products (ATMPs), such as cell and gene therapies (CGTs).

: It’s important to make the audience aware that we are not dealing with pricing and reimbursement at [EMA]. That’s a national issue because pricing and reimbursement are highly linked to how individual healthcare systems are organized, how you pay for hospital care and medicines and so forth. We are actually not involved in any way in pricing and reimbursement. It’s simply outside our remit. Having said that, we acknowledge … and of course we can see what happens, especially for CGTs, but also [many] oncology medicines with a biological background, this is a challenge in many member states with the pricing and reimbursement bodies because the discussion sometimes points back to us, and because the endpoint we use for approval may not always be the endpoints that the pricing and reimbursement bodies are looking for.

So, it’s not only the price—the cost per se—but it’s also the endpoints available to judge the added benefit from a societal and economical perspective that is being challenged by national pricing and reimbursement bodies. But we are moving a bit closer because by January 2025—within a year’s time—the new health technology regulation will come into force in Europe, and it will be mandatory for developers within oncology and within advanced therapies. That would be [where] CGTs fall, to have a parallel assessment of the regulatory needs—the assessment for getting a marketing authorization and assessment by a joint committee that is preparing the health technology assessment. So, again, keeping the pricing and reimbursement aside, but having a joint technology assessment on a European level. And that’s new. So, we are getting a little bit closer here. We will be spending [time in] 2024 discussing with this body: how can we develop guidances? How can we exchange information? Hopefully, developers will create files that are more suitable to satisfy our needs for benefit risk assessment, and the health technology assessment bodies need to assess the added value of the products. That’s a major change. So, we are not getting into bed together, but we are at least getting closer to each other.

 That’s a very interesting point. What kinds of people would the assessment board be comprised?

 It’s set up in the same manner as our scientific committees. People from the national authorities with knowledge in health technology assessment of pharmaceuticals and other medical products. Many of them have a health economics background for this role. It’s stepwise because they will be assessing the added benefit from a health technology point of view. That will then be carried over on a national level to add pricing and reimbursement to fit the national healthcare system setup.

 From the European perspective, and especially for essential medicines, how is Europe situated, in particular about supply chain resilience and the proximity to manufacturing infrastructure?

 I think we face the same challenges as FDA. It might be different products that we are facing the shortages with. Shortages are scattered differently around Europe. Some countries may report shortages of antibiotics, others painkillers. We have been mandated to develop a shortage-monitoring platform. We will be the central holders of a platform, and the idea is, of course, that the earlier we get warnings from either hospital systems, pharmacies, or from industry, [then the earlier] [we] can foresee a change in supply or a change in demand that could be addressed. But I think also the learning has been that, fundamentally, no one [will] have the complete overview of the supply chain and supply demand level in Europe. Not even the manufacturers, because when the product leaves their factory, it enters into a quite complicated trade system of retailers and sub-retailers and sellers and so forth.

The other thing that makes things difficult in Europe, maybe as compared to the United States, is that packages are sold in national languages, so, [for example] the outer package and the insert leaflets are translated into national languages. We speak 24 different languages in Europe. That means changing packages from one country to another will always require a repackaging to fit the local requirements. We are also working on how we can deal with emergency situations. Could we make exemptions? Could we have an electronic patient insert leaflet (PIL) Instead of having the paper insert, you might have a QRC code, and then you could select your language. That means that when I’m travelling on summer holiday in Greece, where I don’t read Greek, and I don’t read Cyrillic letters, I could still scan and get an insert leaflet in English or Danish, depending on what I wanted. That idea is still percolating and hasn’t been completely put into law. It is a proposal as part of the new pharma legislation proposal. The discussion around this is: should it be an electronic insert leaflet only? It could at least add some flexibility to the transfer packages across borders.

The other issue you’re asking about—could Europe move more production back home? We realize that most of the medicines are being produced outside Europe, at least the starting materials. COVID-19 showed us that we depend on trade routes for availability of raw materials. Closures in one part of the world could impact medicines in our part of the world. I don’t think we … as medicines regulators, have any firm standpoint, this is a political discussion. Could we home shore more of the medicines manufacturing in Europe, and how are we going to deal with this? I would say for us, it will still be a matter of approving those production sites, and for us it’s fundamentally independent on whether they are located down the street here in Amsterdam, or whether they are located in India. We will impose the same requirements.

 Observers seem to tie the flow of investment dollars to manufacturing, to the availability of research dollars for new drugs. Can you please explain?

 Manufacturing and R&D are two different things. If the product is being developed in Europe (the intellectual work around this, the clinical trials), then the product itself can be manufactured anywhere else, [which means there will be] uncertainties and challenges of getting the product here, especially during a pandemic or something [similar]. Whether products should be manufactured in Europe or not, fundamentally, the producers will have to live up to our standards, and we will be able to inspect them. That will be fundamentally what’s the key.

 Somewhat related, how do you balance the need for patents and intellectual property protection concerns versus the desire for innovation?

 That goes back a little bit to the cost question we talked about earlier. Patent protection is not governed by us. That’s a legal matter, so to speak. Politicians can decide whatever patent protection and property protection they like. We will be looking at the benefit-to-risk equation, and we will of course do that within those frameworks. But whether the company ends up getting one or two more years or less years is not our business. But of course, as you imply, we are not blind [to the fact] that that has an impact on what drives innovation. But again, since we are not dealing with the patent themselves, it’s basically nothing we can interfere with; [however] we acknowledge the need to drive innovation forward. Therefore, independent of how the patent rules are put together, we offer the opportunity for developers to come to talk to us. We’ve done [much to expand] our help into academia that are early in development, to small- and medium-size enterprises. We have an innovation task force where you can come and bounce off us your ideas and have a less formal conversation with us [around] how you could move those ideas into further development. And we still have our full-blown scientific advice procedure, which comes back to pricing, [where we can discuss issues] in conjunction with the health technology assessment bodies. [Thus], independent of what happens on the patent side and data protection side, we are always happy to help. Fundamentally, the only role we have in driving innovation forward is to put our knowledge and our insight into drug development and the rules we are governing to the benefit of the developers and try help them navigate the system.

Regarding patent inhibition or encouragement,
could you talk about warning labels for secondary cancers, recently applied to some CGTs?

[It’s] an area for a regulator to consider, or be aware of, or at least to understand. But I think it’s unavoidable if we, as regulators, pick up a signal that might be a potential signal of a safety issue with a product or classes of products that we have approved, we need to investigate that. But we are also obliged to be transparent towards developers, patients, all stakeholders that we are investigating this and ultimately explaining the conclusion of that investigation. So whether there’s something or not—and as you can see in what’s been published around CAR [chimeric antigen receptor] T cells and secondary cancer—I think that’s what you’re alluding to, that’s a signal we are investigating as well. We also know that patients with cancer get secondary cancers. So, the challenge is again to disentangle the hen and the egg question, more or less. I think it’s important for us to be transparent, and we have no interest in … putting a black thumb on any of those products. But on the other hand, we need to be transparent. We owe this to the community, we owe this to the patients, and we are a public body, so we cannot hide what we’re doing. We don’t have any interest in hiding what we’re doing. That would be more devastating than being transparent.

 Are there areas of the science that you think our audience should be more aware of? And this is a very broad topic, but I think it gives you a chance to talk about an area that you’ve personally been interested in or just a trend that you’re seeing.

 We meet [many] scientists, not necessarily in the biggest companies, but in small-to-medium-sized companies, spin-out companies from academia, and so forth. They have [many] brilliant ideas. Unfortunately, they sometimes arrive extremely late and bounce those ideas [off of] us. We may send them home with a less nice message around their product. The best message I can give here is actually come rather earlier than late to discuss your scientific ideas. Especially those who are [somewhat] outside the normal framework. Come and discuss with us, and we are happy to give our ideas and guidance, not necessarily firm guidance, but just give you an indication around how regulators are thinking about your bright ideas. That can sometimes save you some sleepless nights later in the process where you have invested a lot of time and money … and suddenly being told this is not what we were expecting, and why didn’t you do X, Y, and Z? So, engage early with us—we don’t bite. Sometimes regulators are seen as conservative and stubborn … here to safeguard public health. But we are also here to help drive innovation forward and especially drive innovation of potentially better products forward.

 With your own EMA goals, what is it that you would like to create more awareness for, or just push a little harder, perhaps?

 There are [many] industry folks that don’t believe FDA and EMA are talking together. We are talking together [a great deal], and I think FDA is the stakeholder with whom we have most interactions. We have a lot of clusters around different therapeutic areas, so don’t be afraid [to come] to us [after having] talked to FDA, maybe even ask to have your product discussed in a mutual teleconference between EMA and FDA. I think that’s an important message to convey.

We may not, in the end, end up making the same decision. I think that’s also understandable because we may be looking for different things. Again, these products get approved and wind up in healthcare systems that are slightly different. Therefore, it’s also understandable when FDA and EMA may not reach the same conclusion every time. And as you also know, looking at science is not black and white. Sometimes we will end up making different conclusions based on the same scientific evidence. That’s definitely one important aspect.

It’s also essential to be on top of what is happening in the world around us, in particular in medical sciences, knowing new developments, new potential promising or less promising developments. Where is science moving? Because coming back to other points we touched upon here, engaging earlier with developers, sustaining our network, all of these things are highly reliant on having the right expertise and knowing what is happening. We can go back to the vaccines. If we didn’t have experts who could deal with the mRNA [messenger RNA] technology, we would have had a problem dealing with those vaccine applications. We knew mRNA technology had been investigated, not for vaccines in particular, it was in cancer development, and suddenly COVID-19 shifted the potential into vaccines. So again, having a radar looking at what is happening, and being on top of that, is important for us because otherwise we will not be able to deal with the applications we see, and we will not be able to give developers useful guidance.

 If you had a magic wand, if you just wanted to make something happen, (and it could even be just having something stop happening) what would you do?

 If I could roll things back, I would roll Brexit back. Because I think Brexit was, looking purely from my regulatory EMA chair and hat, an enormous loss of expertise, enormous loss of good colleagues and experts. We had to reshuffle a [significant amount of] rapporteurships to other members. It created a large hole.

We are now located in Amsterdam. I had [many] colleagues who had (if they wanted to continue working for the EMA) to relocate themselves and their families to the Netherlands, from the UK [United Kingdom]. So it had an enormous impact on the expertise [and] the availability of expertise, but it also had a big impact on people working here.

Chris Spivey is the editorial director of 

When referring to this article, please cite it as Spivey, C. European Medicines Agency Viewpoint.

Steffen Thirstrup, chief medical officer at the European Medicines Agency, provides insight on regulatory challenges in Europe.

European Medicines Agency Viewpoint

semaglutide is a hormone that is used as a medication for improve blood sugar | Image credit: © Fernanda - stock.adobe.com

Me-too drugs typically follow a strong novel medicine into a developing market segment. The therapeutic advantages of me-too drugs may include “improved target specificity, reduced risks of off-target adverse reactions and drug-drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics. Me-too drugs can also demonstrate incremental innovation. Their availability may help in coping with drug shortages” (1). So far so good. This clinical pharmacology review article goes on to point out, however, that “they may occasionally cause unexpected adverse reactions that are not class effects” (1).

When it comes to semaglutide, tirzepatide, and thymalin, the picture is a lot more complex than for a standard me-too entrant. For example, “the GLP-1 weight loss drugs are projected to hit $100 billion in prescription sales by early 2030s, making it the largest therapeutic market we’ve ever seen, … and to alleviated bottlenecks, production capacity is expected to double in 2024, and rise again by 50% in 2025” (2). This is in part driven by Hollywood’s least-best kept secret being shouted from the rooftops. However, apropos to drug shortages and the ongoing manufacturing glitches that helped create GLP-1 scarcity, pharmaceuticals arrived at astonishing juncture in 2023; Novo Nordisk stated “to avoid stimulating further demand for this medicine, we’re pausing some key Wegovy promotional efforts. We are pausing all local television advertising and postponing planned national television advertising for Wegovy. We are also assessing our promotional efforts to healthcare professionals and adjusting accordingly” (3).

Alongside weight loss drugs, US Chem labs has started compounding thymalin. Thymalin helps regulate the thymus, especially in creating T-lymphocytes or T-cells, but also modifies cardiovascular endocrine feedback loops. It is used for “immunodeficiency in adults and children (from six months to 14 years) with infectious purulent and septic processes; acute and chronic viral and bacterial infections; regenerative processes disorders; and Immunosuppression and hematopoiesis after chemotherapy or radiation therapy in cancer patients” (4). While thymalin has no clearly reported adverse effects, the same has yet to be verified for the new weight loss drugs. FDA had this to say on that subject, “preliminary FDA evaluation does not suggest a causal link between GLP-1 RA’s (glucagon-like peptide-1 receptor agonists which mimic natural hunger-suppressing hormones that are triggered when the stomach is) and suicidal thoughts” (4).

The reason driving that announcement was the large number of reports received in FDA Adverse Event Reporting System. The announcement went to say, “our reviews of the clinical trials, including large outcome studies and observational studies, did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue” (4). 

In a warning letter to US Chem Labs, FDA called out grave concerns over their compoundingof me-too versions of semaglutide, tirzepatide, and thymalin, saying, “despite statements on your product labeling marketing your products as ‘research chemicals only’ and ‘not for human consumption,’ evidence obtained from your website establishes that your products are intended to be drugs for human use. Your products are drugs as defined by section 201(g)(1) of the FD&C Act [Food, Drug, and Cosmetic Act] 21, U.S.C. 321(g)(1) because they are intended to prevent, treat, or cure disease conditions and/or affect the structure or function of the body” (5).

Despite there being no evidence of adverse effects associated with thymalin, the warning letter went on to say, “in addition, FDA is particularly concerned that you market your ‘Thymalin’ product for use in children. Your product has not been evaluated by FDA for safety, effectiveness, and quality. The use of untested drugs can have unpredictable and unintended consequences, especially in vulnerable populations such as children and infants who may be at greater risk for adverse reactions associated with certain drug products due to differences in the ability of children to absorb, metabolize, distribute, or excrete such drug products or their metabolites” (5).

A similar warning letter was also sent to Synthetix at the same time, for similar reasons. Compounding companies US Chem Labs and Synthetix are in trouble for introducing unapproved and misbranded semaglutide, tirzepatide ,and thymalin products into interstate commerce. Even in the case of thymalin, this caused fears of adverse reactions, particularly in children. The overarching point being, in times of both surplus and also shortage, compounding companies can amplify both good and bad situations, and in their haste to make me-too products, there needs to be a close check on their activities and ambitions.

Aronson, J. and Green, R. Me-too Pharmaceutical Products: History, Definitions, Examples, and Relevance to Drug Shortages and Essential Medicines Lists. 

Chen, E. Novo Nordisk Pauses Ads for Weight Loss Drug Wegovy as It Struggles to Meet Demand. 

FDA. Update on FDA’s Ongoing Evaluation of Reports of Suicidal Thoughts or Actions in Patients Taking a Certain Type of Medicines Approved for Type 2 Diabetes And Obesity, FDA Drug Safety Communication, FDA.gov. Feb. 11, 2024.

FDA. Warning Letter to US Chem Labs dated Feb. 07, 2024. FDA.gov. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/us-chem-labs-669074-02072024

In surplus and shortage, compounding amplifies all.

Are We Compounding Semaglutide, Tirzepatide, and Thymalin Risks?

Blockchain supply chain business smart contract solution network protocol - illustration rendering | Image Credit - © immimagery - © immimagery - stock.adobe.com

With the bio/pharmaceutical industry facing patent expirations in the near-term for key drugs, bio/pharma companies are facing the pressure of staying competitive in a bio/pharmaceutical landscape where the therapies are growing increasingly complex amid a major shift toward personalized medicines. 

® spoke with Informa Markets about the critical role outsourcing plays in today’s competitive environment as well as into the future.

Pharmaceutical Outsourcing Present and Future

Pharmaceutical Technology/Pharmaceutical Technology Europe Outsourcing Innovation

 eBook
Issue 2
February 2024
Pages: 31-32

When referring to this article, please cite it as Spivey, C. Pharmaceutical Outsourcing Present and Future. 

Contract service providers must step up their game to stay competitive in increasingly complex bio/pharma market. 

Not long-ago, automation in pharmaceutical manufacture meant robots picking items from a conveyer belt, placing them for different robotic arms to neatly position them for further processing, and, ultimately, folding them into their packaging. Shortly after robotic pipetting became the norm, the X-Y robot platform began to find a home in research to help build combinatorial libraries in drug discovery, or to deposit samples for experiments, and perhaps off-the-shelf commercial microarray platform products. Revolutionary in their day, these now seem antiquated compared with several generations, spurred in part by FDA’s encouragement of process analytical technology (PAT), of sophisticated spectroscopy and software integration systems.

The pharmaceutical automation market is projected to reach $18.2 billion by 2029 at a compound annual growth rate of 12% from 2022 to 2029 (1). This growth is still partly driven by early FDA encouragement alongside White House and other national programs to modernize industry and each nation’s manufacturing competitiveness. The Advanced Research Projects Agency for Health (ARPA-H) and BioMADE come quickly to mind. BioMADE is a manufacturing Innovation Institute (MII) sponsored by the US Department of defense. In the United Kingdom, the High Value Manufacturing (HVM) Catapult or the Medicines Manufacturing Innovation (MMI) Centre stand out. By pooling funds, adoption of novel, complex, or costly equipment can be quickly trialed, assessed, and encouraged to be broadly adopted. All this is done with a mind’s eye, ultimately, on current good manufacturing practice (CGMP) and regulatory compliance. But if the technology is especially novel or effective in a new way, these adoptions can even help drive evolution in the regulations themselves.

In manufacturing tightly regulated healthcare products, human performance has long been second best. Society has oriented itself more toward the magic of silicon chip processors and digitalization, so manufacturing has embraced what has become admiringly termed “Industry 4.0”, with a view to attain end-to-end task automation. As these manufacturing tasks in pharmaceuticals become not only more complex and diverse but also more expensive, analytical tools and sensors have been raised on high as inseparable from “success” itself. While the complicated and costly new analytics provide a healthy positive return on investment in many applications, they are not always the optimal answer. These analytics necessitate a more highly skilled workforce with cross-team integration that includes built-in flexibility and a willingness to continually learn new skill sets, repeatedly.

Mauricio Futran, owner of Pharmaceutical Engineering Solutions, who spent 40 years in Big Pharma, working for Merck, Bristol Myers Squibb, and Janssen, a Johnson & Johnson company, stated in 2023 that “segregation and lack of uniformity have been a traditional issue in the industry. The beauty of continuous manufacturing is that the issue of segregation goes away … we now have process analytical tool (PAT) sensors that can assure you are on the right quality in real time, the systems are super steady without drift, and also, when talking about tableting, you can actually assay every single table with near Infra-red, and have [individual tablet-level] quality assurance and control of the process” (2).Taking this into consideration, and taking a step back to look at the wider-picture implications of this digitalization, Futran went on to conjecture that “this is going to drive an evolution in regulations ... and in concepts of validation ... on top of which you add multivariate analytics, this gives an assurance that what you are doing is right on track of where it should be, compared with all your preceding batches” (2).

Digital twins and artificial intelligence as employable skills

In the 1960s, NASA pioneered the use of digital twin technology. This in-silico method of comparison and extrapolation kept humans safe while drastically reducing operation and equipment costs for hard to repeat experiments. To better predict risks and reduce trial and error delays, pharmaceutical equipment designers have begun to embrace and deploy digital twin technologies. A recent high-profile example was GSK using digital twin technology “to fine-tune their manufacturing process when scaling up production of their vaccine adjuvant in response to the C[OVID]-19 pandemic” (3). In her study of its use, Alison Doughty goes on to say, “The Empa research center in Switzerland [The Swiss Federal Laboratories for Materials Science and Technology] is working on digital twins to optimize drug dosage for people afflicted by chronic pain, taking into account factors such as age and lifestyle to help customize the digital twin” (3).

In the hopes of early and less costly optimization, the efforts are typically coupled to machine vision and machine learning (ML) models, along with cloud-based historical batch process performance. In this way much can be learned and tried in a quick and cost-effective manner, especially when first approaching a new molecular therapy or chemical modality. When married to artificial intelligence (AI) and ML, this can be perhaps the most effective way to experimentally churn through the largest number of potential solutions in any given pharmaceutical challenge. But turned to more mundane efforts, such as keeping an eye on a bioreactor process or flow chemistry system for, say, critical quality attributes (CQAs), it has revolutionary potential.

In a presentation at the 2022 PDA–FDA Joint Regulatory conference, Martin Van Trieste spoke about drug quality, Industry 4:0, Six Sigma, and the data deluge, saying, “We’re now using machine learning and AI, and that will really help eliminate failures, eliminate deviations, eliminate non conformances, and get past what I call blind compliance” (4).He went on to say that because of AI, “the future looks really bright for patients with improved safety, reliability, and quality, and all at a lower cost, some of which will be passed on to the consumer. Now if the future is bright for this group of people, it must be bleak for somebody else. And it’s going to be bleak for the dinosaurs of the industry, for the large quality organization that have been built around testing and inspecting the product, because if you are doing AI, you don’t need large testing organizations. The computer will not allow a mistake to happen, and it will safety check everything at the end … It’s really good for the patients. It’s not good for the quality unit, so I suggest that you really learn data analytics, you really learn AI‚ become that resource in the company, because that’s how you’re going to keep your job in the future” (4).

Pharmaceutical Automation Market by Component (Plant-level Controls, Enterprise-level Controls, Plant Instrumentation), Mode of Automation (Semi-automatic, Fully-automatic), End User, and Geography—Global Forecast to 2029

. Market Research Report, May 2022.
2. Mirasol, F.; Spivey, C. Drug Digest: Advancements in the Implementation of Continuous Manufacturing. 

, May 5, 2023.
3. Doughty, A. How the Pharma Industry is Using Digital Twin Technology. 

, July 6, 2022.
4. Spivey, C. Six Approaches Making the Most Significant Impact in the Future. 


Volume 48, No. 2
February 2024
Pages 30–31

When referring to this article, please cite it as Spivey, C.Analyzing Exabytes.

Effective analytics will eliminate failures, deviations, and non-conformances.