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

Chris Spivey

Chris Spivey, editorial director, hosts a wide ranging discussion on the COVID-19 pandemic response, future government communications, and healthcare funding for mRNA with experts Dr. Kate Broderick, Chief Innovation Officer, Maravai LifeSciences and Dr. Tom Madden

President & CEO at Acuitas Therapeutics. 

Highlights include supply chain modalities, ensuring a fully trained manufacturing workforce, combining delivery with gene editing innovations, epigenetic approaches to modulate gene expression moving toward the clinic. We conclude with the huge potential for RNA expression of monoclonal antibodies and protein replacement applications.

, chief innovation officer at Maravai LifeSciences has extensive experience and expertise in leading and liaising with multi-disciplinary groups from discovery and R&D to engineering and clinical teams. She brings strong and broad scientific expertise to TriLink Biotechnologies, which covers multiple areas, including gene delivery, medical devices, gene therapies for the treatment of various infectious diseases, cancer immunotherapies and vaccine development. Additionally, she has extensive experience with non-viral delivery systems for a wide range of vaccine targets and cancer immunotherapies.

, president & CEO of Acuitas Therapeutics, is a world-renowned expert in the area of nanotechnology. Dr. Madden co-founded Acuitas Therapeutics in February 2009 and has guided the company into its position as a global leader through the development and application of lipid nanoparticle (LNP) technology. Acuitas Therapeutics partners with leading pharmaceutical and biotechnology companies and prestigious academic institutions around the world, providing its proprietary LNP delivery technology to enable new drugs based on nucleic acid therapeutics.

 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 strategies, to regulations related to the development and manufacture of drug products.

Podcasts

An mRNA conversation about the recent past, current hot topics, and probable future.

Drug Solutions Podcast: mRNA Past, Present, and Future

In this excerpt from the most recent episode of the 

, Chris Spivey, editorial director, hosts a panel on advances in mRNA. There is promise of personalized cancer vaccines through the inherent nimbleness of mRNA platform. From a manufacturers point of view, how can we best to automate, miniaturize and speed up performance?

For the complete discussion, check out the full podcast episode 

Videos

Experts discuss the promise of personalized cancer vaccines through the inherent nimbleness of mRNA platform.

Miniaturing Personalized Cancer Vaccines Through mRNA

Highlights from a wide ranging discussion on COVID-19 pandemic response, future government communications, and healthcare funding for mRNA with experts Dr. Kate Broderick, Chief Innovation Officer, Maravai LifeSciences, and Dr. Tom Madden, President & CEO, Acuitas Therapeutics.

Topics include supply chain modalities, ensuring a fully trained manufacturing workforce, combining delivery with gene editing innovations, epigenetic approaches to modulate gene expression moving toward the clinic. We conclude with the huge potential for RNA expression of monoclonal antibodies and protein replacement applications.

Catch the full podcast episode featuring Broderick and Madden when it goes live at the 

Dr. Kate Broderick is Chief Innovation Officer at at TriLink Biotechnologies, a Maravai LifeSciences company. Prior to joining TriLink, Kate spent 15 years with Inovio Pharmaceuticals where she assumed positions of increasing responsibility, starting as Scientist, to her most recent position as Senior Vice President, R&D. She received her B.Sc. in Genetics and her Ph.D. in Molecular Genetics from the University of Glasgow.

Dr. Tom Madden is President & CEO at Acuitas Therapeutics. A world-renowned expert in the area of nanotechnology. Dr. Madden co-founded Acuitas Therapeutics in February 2009 and has guided the company into its position as a global leader through the development and application of lipid nanoparticle (LNP) technology. Dr. Madden obtained his BSc. and Ph.D. in Biochemistry from the University of London, U.K.

Articles

Highlights from a wide ranging discussion on COVID-19 pandemic response from Kate Broderick, Chief Innovation Officer at Maravai LifeSciences, and Tom Madden, President & CEO at Acuitas Therapeutics.

Unpacking COVID-19 Pandemic Response

The term microbiome may have first been used in an agriculture paper (1), but widespread traction was sparse until Francis Collins (then head of the National Human Genome Research Institute) talking through upcoming funding limits for simply sequencing yet another organism, with Broad Institute head, Eric Lander, had a true eureka moment, to seize upon sequencing the human microbiome—skin, gut, hair, and so forth, for multiple funding projects going forward. Suddenly all things microbiome became in vogue. However, as recently as February 2020, scientific papers were still proposing vague notions that, “The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown” (2). What had seemed administrative legerdemain at that time of Collins eureka moment is, in 2023, absolutely a therapeutic window to drill down on. The tumor microenvironment as therapeutic approach has come of age, and the tool of the hour is messenger RNA (mRNA).

Acknowledging that bacteria and fungi form complex colonies with solid tumors, an approach to unravel this microbiome community was developed with mRNA molecules encoded to produce a toxin lethal to cohabitating bacteria. In this experiment, pseudomonas exotoxin A domain III was packaged into lipid nanoparticles and injected into the tumor bed. “We hypothesized that encoding the active domain only, without the binding and translocation domains of the original toxin, will allow potent intracellular effect upon mRNA translation, while reducing the risk of side-off effects in case of toxin release from target cells,” related professor Dan Peer, co-lead author of the study (3). Unlike chemotherapy where resistance gathers pace during extended exposure, this approach is easily amenable to simply switching to a different natural toxin. The study goes on to describe that most of the lipid nanoparticles reached cancer cells, destroying 44–60% of them.

While the history of drug discovery science is replete with false dawns, it is encouraging to see mRNA make an alliance with deeper understanding of the mechanics of the tumor microbiome. mRNA may be a modality whose chief advances are yet to come.

2. Xavier, J.; Young, V.; Skufca, J., et al. The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View. 

March 6(3), doi: 10.1016/j.trecan.2020.01.004.

3. Granot-Matok, Y.; Ezra, A.; Peer, D.; et al. Lipid Nanoparticles-loaded with Toxin mRNA Represents a New Strategy for the Treatment of Solid Tumors. 

When referring to this article, please cite it as Spivey, C. New Magic from mRNA. 

mRNA may be a modality whose chief advances are yet to come.

New Magic from mRNA

Data and digitalization have rapidly evolved, along with software and meta-analysis, to become the lifeblood of the pharmaceutical industry. However, decades ago, I opened a biotech conference by stating that biology was becoming one of the computer industry’s fastest growing customers, evaluating huge storehouses of data. This article attempts to demystify the difference between knowledge and information bearing in mind the aphorism of Peter Mere Latham that, “fortunate indeed is the man who takes exactly the right measure of himself, and holds a just balance between what he can acquire, and what he can use” (1). In terms of optimizing a manufacturing process or procedure, fewer data can often mean more. 

A great new challenge in pharmaceutical data governance is how to balance automation with sufficient operator oversight—ensuring that hiccups and missteps are properly captured and reported for compliance purposes. Paige Kane, a member of the Pharmaceutical Regulatory Science Team (PRST) at TU Dublin, suggested it all starts with “understanding of what our processes are, and to understand what data we are really trying to capture, to make sure that we have the right tool for that application, … to do that we need to take a risk-based approach to understand where the risks are and where the operators are intersecting with that. We don’t need to collect all the data [just] because we can, we need to understand what data are really required for the operation” (2).

Garry Wright, European Laboratory Compliance Specialist at Agilent Technologies, has stated that “every regulated company is going to be using multiple software platforms across their production quality control environments, and they are going to generate huge volumes of GxP [good manufacturing practice] data, so implementing data integrity controls across all those individual software systems is very time consuming. It requires specialist skills, and it requires dedicated support. But you can protect the integrity of that data by keeping your software platforms up to date using the latest security and technical controls that automate workflows to try to minimize human contact. Due to ageing software platforms, companies tend to implement hybrid solutions where they develop and wrap around workarounds, but it still leaves them with an element of data integrity risk. This is more susceptible to human error and deliberate falsification, and that’s really where a lot of the recent data integrity warning letters come from” (2). 

Wright went on to enumerate some of these common issues that appear to have played a role in the high-profile example of Laronde (3). Wright empathized, “Data integrity is a key part of any regulatory inspection. I remember going through my first data integrity inspection in 2013, and it really revolutionized the way I look at the laboratory and the way I prepare for inspections… [problems are] deliberate use of generic logons to protect the identity of people who are falsifying data, scientists having additional privileges that they don’t need to perform their role, [and] performance screening analysis before an official analysis. One of the biggest ones though is manipulation and falsifying by changing integration or integration events to make failing batches pass. [Or] deleting or hiding official sample data to avoid stoppages with the need to document the failure, then perform an investigation, and then retest. The last but most important is audit trails. Some companies have deliberately chosen not to activate the audit functionality. Other companies give their users privileges so that they can manipulate their information within the audit trail so they can cover up cases of falsification” (2). 

Wright concluded on a positive note. “So, these are some of the common problems that have been cited in recent warning letters, but they can all be avoided if you keep your software up to date, and if you use all those technical and security controls that are available which have been specifically designed into those software platforms to protect the data. So, if you use your software correctly, you can be data integrity compliant” (2). 

While Wright might be optimistic, the human element will have the last word. Reporting from STAT and The Boston Globe made public a story that is surprisingly common but underacknowledged. In this case, the story made headlines partly because of the therapeutic promise surrounding the approach, but mostly because of the high market valuation involved.

As reported, the company noticed difficulties reproducing results in their preclinical data in a pivotal anti-obesity therapy aimed at competing with Wegovy and Mounjaro, partly because of a lack of detailed record keeping. “It underpinned the enormous $440 million the biotech raised in a 2021 Series B funding round, according to four people with knowledge of its plans, as well as a slide from an internal slide deck, which valued the company at over $1 billion” (3). 

A star researcher, Cifuentes-Rojas, was presenting data “that was perfect. Anybody who works in in vivo [animal research] knows that’s not possible,’ said Jane van Heteren, an ex-Laronde employee who worked on the same team as Cifuentes-Rojas… Cifuentes-Rojas’ chart showed the protein levels starting at zero—an impossibility, because unless the mice were seriously ill, they would naturally produce GLP-1 of their own, van Heteren said. In an attempt to pinpoint why, she sought out Cifuentes-Rojas’ raw data, first in the company’s electronic lab notebook system and then from Cifuentes-Rojas herself. But there was no data in the company’s digital records, and Cifuentes-Rojas declined to share any with her colleague.” 

The emphasis here is that a sister company to the obviously successful company, Moderna, fell prey to the one bad apple syndrome. Reporting goes on to say that “Initially, the manufacturing staff came under scrutiny…. [as] one batch might be 60% pure eRNA, another might be 80%. That was initially cited as the reason why scientists were getting different preclinical results, but three former manufacturing team members said it was a red herring, because none of the data produced at Laronde showed a clear relationship between how much eRNA was in a batch and how well it performed inside of cells or mice” (3). 

The journey of data integrity depends fundamentally on the integrity of the people involved. A software platform can be made rigorously regulatory compliant, as long as operators’ intentions and personal integrity are in synch with that goal. 

1. Spivey, C. Gene Quantification, Introspection and RNA Meditations, Conference, February 2002, Cambridge Healthtech Institute. 

2. Playter, G. Unpacking the Science Behind Data Integrity, Drug Digest Interview with Page Kane and Garry Wright. 

3. DeAngelis, A. and Cross, R. The Inside Story of How Data Integrity Issues Roiled a Biotech Seen as ‘Moderna 2.0’. 

When referring to this article, please cite it as Spivey, C. Good Practices for Data Integrity. 

Automation can be balanced with operator oversight.

Good Practices for Data Integrity

On June 23, 2023, Eppendorf Group announced that it is awarding its Young European Investigators 2023 research prize to Maurice Michel, PhD, of the Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden. Michel was selected by an independent jury chaired by Prof. Reinhard Jahn, emeritus director, Max Planck Institute for Biophysical Chemistry, Göttingen. This marks the 28th time that Eppendorf has bestowed this award. Finalists included Alicia Michael, PhD, of the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, and Adel Al Jord, PhD, from Collège de France.

Michel’s research delves into artificial functions of DNA repair enzymes for the treatment of disease. Through his research he has shown that binding of a small molecule to the active site of a DNA repair enzyme not only increases the molecule’s activity, but also prompts it to carry out a reaction not found in the free protein, leading to enhanced DNA repair after oxidative damage.

Maurice Michel, PhD, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden

“These ground-breaking discoveries may have far-reaching applications in the treatment of cancer or age-related degeneration,” said the judges on the awards jury, according to an Eppendorf company press release.

Michel is also heavily involved in Target 2035, an international federation of biomedical scientists from the public and private sectors, dedicated to develop a pharmacological tool for every human protein. The federation has generated much interest from legacy companies in general, and increasingly big pharma in particular, as it pushes into previously uncharted drug discovery terrain.

Announced in a recent Target 2035 article in a medicinal chemistry journal: “The goals of Target 2035 can only be accomplished by expanding hit-finding approaches beyond traditional methods. This is especially true for un/understudied proteins that have no link to disease. Traditional hit-finding methods tend to be prohibitively resource-intensive and limited to large private sector entities” (1).

“During the past year Target 2035 launched two Public Private partnerships (PPPs), Critical Assessment of Computational Hit-finding Experiments (CACHE), and Open Chemistry Networks (OCN) … Because CACHE is a prospective hit-finding exercise, where predicted compounds are procured and tested using biophysical and biochemical methods, the metric of success is hit rate, diversity, and drug likeness rather than binding pose or docking score,” the article explains (1).

“It is an immense honor and I feel humbled to be awarded with the 2023 Eppendorf Award,” said Michel in the company press release. “This would not have been possible without the contribution and spirit of many scientists, be it colleagues or collaborators, as well as mentors and an incredible family I call mine. The award recognizes the potential of manipulating enzymatic functions in living cells at will. Using small-molecule organocatalysts, we installed new biochemical reactions within an enzyme and have thus succeeded in rewriting the base excision repair pathway … Rerouting or reducing oxidative DNA damage depending on individual needs could serve as a new strategy for the development of the precision therapeutics of the future.”

The award ceremony took place on June 22, 2023, at the Advanced Training Center of the European Molecular Biology Laboratory in Heidelberg, Germany. Further information on application modalities, selection criteria and previous winners of the Eppendorf Award for Young European Investigators can be found at 

1. Arrowsmith C.;Ackloo, S.; Antolin, A .; et al. Target 2035—An Update on Private Sector Contributions. 

The prestigious award, worth €20,000 (US$22,000), goes to Maurice Michel of the Science for Life Laboratory at Karolinska Institutet, Stockholm, Sweden. 