Aligning mRNA Progress with Regulatory Streamlining

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Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

Ask the Expert

Feliza Mirasol is the science editor for 

Lipid nanoparticles (LNPs) have been gaining traction as a primary formulation and drug delivery tool in the manufacture of messenger RNA (mRNA)-based therapeutics, having proven their utility in the development of mRNA COVID-19 vaccines. As the development of LNP-enveloped mRNA therapeutics advances, what other nanoparticle technologies offer the opportunity for optimizing the formulation of mRNA—and potentially other nucleotide-based—therapeutics? This article explores the advancement of LNP formulations as well as additional nanoparticle technologies in this space.

Developing an mRNA therapeutic involves both the manufacture of the mRNA molecule itself and combining that molecule into some sort of delivery technology, whether that delivery technology is a LNP or other platform, says Colin McKinlay, PhD, senior director, Chemistry and Delivery Technologies, at Nutcracker Therapeutics. One of the challenges McKinlay points out is the type of approach a developer must take in manufacturing these types of drugs, which are unique in that they are personalized therapies, where every patient, each therapy, and the drug components are basically different.

“I think one of the lessons learned from the whole COVID-19 pandemic and putting together the mRNA-based vaccines for COVID-19 was that we could actually scale these [vaccines] up to worldwide scales, and that we were able to do that fairly effectively,” said McKinlay. “But starting to think about distributing and manufacturing mRNA drugs, where every patient has a different type of formulation, I think that starts to be a different type of challenge.”

Somewhat related to the logistics of distribution, McKinlay goes on to explain that many of the challenges associated with mRNA drug manufacturing are tied into having the ability to bridge smaller-scale companies—that is, their research work—into Phase I, Phase II, clinical-trial scale, and get these companies the materials they need for conducting those trials. “There are [many] commercial suppliers that are available for research-grade mRNA and for making mRNA at that small scale when [companies] are doing [their] discovery work. And obviously, if [a company] wants to invest a large amount of money into manufacturing, there are [many] opportunities available for large-scale commercialization, but getting strategies that are suited for … small clinical-trial stage where it is not too cost prohibitive upfront is something [where] there is a definite need in the market for,” McKinlay says.

With personal background experience in academia and moving up to a small startup and eventually to a mid-size startup, McKinlay relates the lessons learned in dealing with LNP manufacturing. “One of the things I’ve found throughout my career is that when you’re doing those initial discovery experiments and early stage experiments, you really want to be able to run high-throughput type experiments—screening different formulation chemistries, different combinations of components, or even different mRNA cargo types. However, at that small [of a] scale, [many] commercial options for making LNPs are not really tailored towards that small scale,” he explains.

In the course of his work, McKinlay noted that, although there are production systems available from various different suppliers, these systems generally have a rather large minimum volume or minimum scale at which they can operate. “What [many] people end up doing is to just pipette-mix or hand-mix their components, which means that the LNPs you’re making are very different than the LNPs you’re going to be making farther down in your development process during scale up,” he says.

One of the ways that a company can address this problem is by having its own engineering team in-house, McKinlay emphasizes. With this in-house capability, the company can have the team think about the challenges and ways to design LNPs on both a manufacturing level and at a system level. The results of the engineering team’s work can be used in research that is applied to much of the same core technologies. This gives the company the advantage of having information that can be translatable at every stage of development. “I think there are other companies that are starting to pick up on that importance,” McKinlay says, “but if you don’t think about that early on, you might end up optimizing for something that doesn’t end up being quite as good later on [and further] into your manufacturing process.”

Looking beyond the manufacturing challenges, innovations are in development to address these hurdles. McKinlay notes that some of those innovations are just starting to kick off. “The first wave [of innovation] has [involved the use of] a lot of the existing manufacturing technologies in the biologic space for these mRNA molecules. Now, [the industry is] actually starting to get different companies that are thinking about: how do we actually pursue this workflow for an mRNA specific platform? Not just pushing ourselves across the finish line, but really trying to adapt things to the advantages of mRNA and the unique challenges associated with mRNA?” he states.

McKinlay has also observed that some of the larger mRNA companies are starting to consider the problems in the mRNA space much more deeply with an aim to innovate in this space in a more mRNA-centric way. “For instance, one of the things I brought up earlier is the personalized medicines aspect. One of the exciting things about mRNA is some of the personalized therapies and personalized vaccines [that have come out of this space],” he remarks.

With a growing number of personalized medicines coming onto the scene, the industry is now looking at unique manufacturing challenges associated with them. “I think those are areas where we’re going to continue to see different types of innovation in the field,” McKinlay adds.

Broadly speaking, McKinlay considers the fact that not everybody is going in the same direction with mRNA therapeutic development an exciting trend. “There are a lot of different places that mRNA can be applied. In some cases, moving past the early stages of this field, one of the things that people are going to have to do is start specializing in different areas and saying, ‘Okay, this company is going to take mRNA in this direction.’ ‘This company is going to take it in a different direction.’ I think [this attitude] is one of the great things about a broad field like mRNA,” McKinlay says.

Vaccine development is an area where mRNA has truly demonstrated its effectiveness. But McKinlay points out the importance of not pigeonholing that platform technology such that mRNA is only thought of as a vaccine technology. Moving beyond infectious disease vaccines, or even COVID-19 vaccines, is going to be crucial to the growth of the mRNA field, McKinlay believes.

In terms of the LNP side of this field, McKinlay emphasizes that a number of LNP technologies exist that will focus on expression in the liver and that are directed towards the liver. “One of the [notions] that a lot of folks in the field are really focusing on is, ‘how do we actually direct these lipid nanoparticles to other organs in the body so that we can address other types of disease areas?’,” he says. Many companies are on this train of thought as well as researchers in academia, McKinlay explains. However, there has not been large-scale clinical successes in this area yet, he notes. “I think that’s definitely a place where more development is going to be taking place, and there’s going to be a lot of kind of handoffs between academia and industry in finding some strategies to address that,” he states.

Exploring other delivery vehicles and opportunities

In terms of non-viral RNA delivery, LNPS have largely dominated this field in terms of clinical approvals and later-stage development, according to McKinlay. However, he cautions against the industry getting stuck in these local maxima, “where the field does a lot of optimization, and [players] are able to climb in efficacy, but then [they] reach a point where there’s not too much [left] that [they] can really optimize anymore.”

Nutcracker’s exploration of alternative delivery vehicles has resulted in the company’s peptoid-based platform. According to McKinlay, these peptoids can be used in a traditional LNP-type formulation. “We’re able to branch away from traditional LNP type particles and have particles that are a little bit more unique to the chemistry of these peptoid molecules. We think that [this technology] is pushing us over, a little bit away from where the rest of the field is working; there may be a little bit more room to grow and a little bit more room to improve,” he states. McKinlay also believes that, with more and more people in the field exploring different respective local maxima, the industry as a whole can net benefit together by improving the overall safety and efficacy of the mRNA delivery vehicles that it has available to it.

Meanwhile, in academia there is also focus on using LNPs for other types of genetic cargo, such as other types of RNA or even DNA. “Beyond nucleic acids, there is also significant opportunities for using LNPs in, maybe, combination therapies, where you may have an mRNA molecule, but you also have a lipophilic, small molecule that you can incorporate into the LNP. By combining those two together, you can [potentially] see increased efficacy,” McKinlay says. “Regardless of what the future holds for mRNA therapeutics, a tight handshake between therapeutics discovery and manufacturing will be necessary for its success.”

®
Vol. 48, No. 12
December 2024
Pages: 20–21

When referring to this article, please cite it Mirasol, F. Exploring Opportunities for LNP Delivery in mRNA. 

Articles

LNPs have gained solid ground as a drug delivery system for mRNA due to their success in the vaccines arena.

Exploring Opportunities for LNP Delivery in mRNA

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FDA announced a draft guidance on Dec. 5, 2024 that explains the procedures and criteria for the agency’s accelerated drug approval for serious conditions. The guidance, 

Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics, 

also explains procedures for expedited withdrawal of approval (1). Revisions made by Congress through the Consolidated Appropriations Act, 2023 (Public Law 117-328) are also discussed.

FDA’s accelerated approval pathway is one of the agency’s expedited programs for the development and review of new drugs to meet unmet medical needs for serious or life-threatening conditions in a timely manner. Sponsors whose product is granted accelerated approval conduct confirmatory trials that are completed postapproval to verify and describe the anticipated effects and benefits of the drug. If these trials confirm the clinical benefit, FDA will then count the confirmatory requirement as met. However, if the sponsor fails to conduct the trial with due diligence or the trial fails to verify effects and benefits, FDA may withdraw approval.

Per the guidance document, conditions and requirements associated with accelerated approval include:

The conducting of postapproval studies to verify and describe the anticipated clinical benefit of the drug.

FDA must specify the conditions for postapproval studies, by the date of approval. These may include a deadline to submit the final study protocol, targets for enrollment progress, and other milestones such as the target date for study completion.

The agency may require postapproval studies prior to the accelerated approval.

A succinct description of limitations of usefulness and anticipated benefits must be included in the drug label’s Indications and Usage section with a reference to the Clinical Trials section.

Copies of sponsor’s promotional materials must be submitted to FDA with specified time frames.

Progress reports on the postapproval studies must be submitted to FDA approximately every 180 days.

“Accelerated approval should not be considered if the completion of an adequate and well-controlled clinical trial to verify and describe clinical benefit will be infeasible,” the agency states in the document (1).

The guidance document specifically provides considerations for the use of surrogate and intermediate clinical endpoints, evidentiary criteria for accelerated approval; requirements for confirmatory studies; and labeling, promotional materials, postmarketing recordkeeping, and safety reporting considerations. In regard to evidentiary criteria, the document states, “Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval. For effectiveness, the standard is substantial evidence based on adequate and well-controlled clinical investigations. For safety, the standard is having sufficient information to determine that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling. An application for accelerated approval should also include adequate evidence that a proposed surrogate endpoint or an intermediate clinical endpoint is reasonably likely to predict the intended clinical benefit of a drug.”

The document’s section on withdrawal of accelerated approval states, “The Agency generally expects that any proposal to withdraw approval of a drug that has been granted accelerated approval will be issued by the center or centers (hereafter, Center) that approved the drug. When the data or other information received by the Agency raises concerns that one or more of the criteria for withdrawing approval may have been met, responsible officials within the Center should discuss their concerns with the sponsor and seek an appropriate resolution. Such discussions may result in the sponsor’s voluntary request for withdrawal of approval under 21 

 601.5(a) or other regulatory actions, as appropriate, 552 depending on the circumstances” (1).

Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics, Guidance for Industry, Draft Guidance

The draft guidance provides information on the agency’s accelerated approval process and criteria for approval.

FDA Releases Guidance on Accelerated Approvals

On Dec. 5, 2024 both Eli Lilly and Company (Lilly) and Amgen announced their plans to expand their manufacturing facilities in Kenosha County, Wis., and Holly Springs, NC, respectively. Lilly said it is investing $3 billion to expand the Kenosha County manufacturing facility it acquired earlier in 2024 (1), while Amgen said it will invest $1 billion to establish a second drug substance manufacturing facility at its site in Holly Springs, which brings Amgen’s total planned investment in Holly Springs to more than $1.5 billion (2).

Lilly’s investment aims to extend the company’s global parenteral product manufacturing network to meet growing demand for its diabetes and obesity therapies as well as future pipeline medicines across therapeutic areas. Construction for the expansion is expected to begin in 2025. Lilly expects to add 750 highly skilled jobs to the current approximately 100-person workforce at the Kenosha County location. The new highly skilled jobs will include operators, technicians, engineers, and scientists and will be in addition to the more than 2000 construction jobs that will open up during the construction phase.

"Today's announcement represents our single largest US manufacturing investment outside our home state of Indiana and will add to our ability to expand capacity to make both our existing and future pipeline of medicines right here in the Midwest," said Edgardo Hernandez, executive vice-president and president of Lilly Manufacturing Operations, in a company press release (1). "We look forward to bringing high-wage, advanced manufacturing, engineering, and science jobs to people in Wisconsin, a state that is becoming a critical geography in our global manufacturing operations."

Lilly plans to use advanced automation—including guided vehicles, robotics, and production equipment—to accelerate injectable medicine production. Digital automation will be embedded throughout the site for data management to operations to accelerate processes and increase accuracy.

Lilly aims to foster partnerships with local higher education institutions and support various community initiatives in Wisconsin to advance innovation in pharmaceutical manufacturing.

Amgen grows drug substance manufacturing capacity

Amgen’s investment in its Holly Springs site will build a new manufacturing facility for drug substance production. As part of the expansion, the company will incorporate cutting-edge technologies and sustainable practices. Together with the already existing facility at the site, the company’s investments will create 370 new jobs in the region and will support a robust biomanufacturing hub (2).

"This expansion underscores our unwavering focus on bringing transformative medicines to patients around the world," said Robert A. Bradway, chairman and chief executive officer at Amgen, in a company press release (2). "North Carolina will be an important part of our global manufacturing network as we continue to meet the growing demand for our innovative therapies while generating significant local economic impact."

Amgen chose North Carolina, which has grown a reputation as a premier life sciences destination, for the state’s ecosystem of life sciences innovation and skilled workforce. “This expansion enhances the company's global biomanufacturing network, leveraging decades of operational expertise and technological advancements to ensure the reliable and efficient delivery of high-quality medicines to patients worldwide,” the company stated in its release (2).

1. Eli Lilly and Company. Lilly Announces $3 Billion Expansion of its Recently Acquired Manufacturing Facility in Wisconsin. Press Release. Dec. 5, 2024.
2. Amgen. Amgen Announces $1 Billion Manufacturing Expansion in North Carolina. Press Release. Dec. 5, 2024.

Lilly is investing $3 billion to expand its recently acquired manufacturing facility in Wisconsin, while Amgen is investing $1 billion to expand its facility in North Carolina.

Lilly and Amgen Each Announce Major Expansions of US Manufacturing Sites

Richard K. Burdick is principal of Burdick Statistical Consulting and Professor Emeritus of Statistics at Arizona State University.

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To assess the impact of process changes, stability data (e.g., measurements of drug product over time) at recommended storage conditions are often required. Pre- and post-change degradation rates (slope over time) do not need to be identical, but do need to be highly similar, with scientific justification that any observed differences will not impact safety or efficacy. Because slopes at the recommended storage conditions are often quite small, the product is also exposed to non-recommended storage conditions (e.g., higher temperature) to quickly accelerate degradation. In comparability studies, it is necessary to demonstrate that the degradation rates (slopes) of the pre-change and post-change processes are comparable. Burdick and Sidor proposed a statistical test of equivalence that can be applied in these situations (1). However, it might be the case that practically sized experiments may lack sufficient power to perform the equivalence test. An alternative approach is proposed based on the quality range test recommended by FDA in their draft guidance for comparing biosimilars (2). This approach uses a visual interpretation of study results based on a heuristic rule for claiming process comparability.

A typical study design used in an accelerated experiment requires L=3 lots from both the pre-change and post-change processes. There are typically T=3 time points measured on each of the six lots with one measurement per lot at each time point. 

 displays plots of two data sets with L=3 lots, T=3 time points (

=28 days), and one measurement at each time point (a total of nine values for each process). The response variable is cation exchange (CEX) Main (%). The lines shown in the figure are the least square lines of fit for each of the six lots. The complete data set is provided in 

Of particular interest is the comparison of the line slopes for the two processes. Slopes differ within each process due to analytical error. Differences between processes indicate a difference in degradation rate between the two processes and should be investigated for impact on safety or efficacy.

A visual representation that allows one to focus exclusively on slopes is provided in 

. Here suitable constants have been added to each y-intercept so that they are all equal to the same (arbitrary) value.

 that the slopes from the two processes in Data Set 1 overlap the same region and there is no clear delineation between the two processes. In contrast, all three slopes of the post-change process are steeper than those of the pre-change process in Data Set 2, and there is no overlap. One might declare comparability in Data Set 1; whereas with Data Set 2, it appears the processes may not be comparable.

The quality range test provides a statistical heuristic based on a visual comparison of the slope values of the pre-change and post-change lots. The quality range test was introduced by FDA in their 2019 guidance document for analytical comparison of biosimilar products (2). One can perform the quality range test for the accelerated study by following these steps:

®
Vol. 48, No. 10
December 2024
Pages: 26–28

When referring this article, please cite it as Burdick, R. K. Comparability in Accelerated or Stressed Stability Studies Using a Quality Range. 

A statistical procedure based on a quality range is proposed for demonstrating comparability between pre-change and post-change process slopes in an accelerated or stressed stability study. 

Comparability in Accelerated or Stressed Stability Studies Using a Quality Range

Cambrex, a contract development and manufacturing organization, announced on Dec. 5, 2024 that it has entered into an agreement with Eli Lilly and Company (Lilly) aimed at Cambrex providing accelerated access to clinical development capabilities for Lilly's biotech collaborators.

Under the agreement, Cambrex will partner with Lilly's early external innovation and collaboration arm, Lilly Catalyze360-ExploR&D. Cambrex will provide drug substance, drug product, analytical service labs, and R&D expertise to biotech collaborators teamed with Lilly Catalyze360.

"We are excited to support Lilly's mission to enable external biotech collaborators to expedite their product development," said Brandon Fincher, president of Early Stage Development & Testing at Cambrex, in a company press release (1). "Our Longmont [Colorado] facility offers all services required to advance early stage small molecules into the clinic with speed, flexibility, and scientific excellence. We look forward to propelling Lilly Cataylze360 collaborators forward on an efficient path to success with their products."

Lilly Catalyze360 focuses on advancing science and supporting emerging medicines via investment and through its three pillars—Lilly Ventures, Lilly Gateway Labs, and Lilly ExploR&D. Under the agreement, Cambrex will partner with ExploR&D, which brings enterprise learning, scientific know-how, and best-in-class research and development capabilities to accelerate partner science, according to the company press release.

Primary services offered through the agreement will be conducted in the Longmont, Colo., facility. Additional support will be provided by Cambrex's network, as needed. Cambrex's Longmont facility specializes in the early development of investigational new drugs, from process development and drug substance manufacturing through to formulation development and drug product manufacturing. The facility houses capacity for non-good manufacturing practice (GMP) and current good manufacturing practice (CGMP) production. The site simultaneously provides full analytical development and CGMP testing support.

Cambrex also recently strengthened its process development capabilities when it formed a strategic collaboration with Atinary Technologies in September 2024 (2). Under this collaboration, Snapdragon Chemistry, a Cambrex company, will integrate Atinary’s AI-driven and automated process optimization technology with its own state-of-the-art laboratories and process development capabilities, which will allow Snapdragon to tackle complex challenges in drug development. Snapdragon specializes in API process development, with a focus on continuous flow process development, lab automation, and complex synthetic APIs.

Under the collaboration with Atinary, Snapdragon has integrated its proprietary LabOS software platform with Atinary’s SDLabs platform to build a fully automated and AI-driven, medium-throughput Solid-Phase Oligonucleotide Synthesizer (SPOS). The purpose of the SPOS is to enable autonomous multi-objective process optimizations. Atinary’s AI platform has enhanced Snapdragon’s process optimization campaign with significant improvements across tested applications. Snapdragon was able to demonstrate up to an 18% increase in product yield and a 22% reduction in cost compared to processes previously optimized by an experienced scientist (2).

“Atinary is committed to accelerating innovation and delivering cutting-edge solutions to our customers,” said Hermann Tribukait, PhD, co-founder and CEO of Atinary Technologies, in a company press release issued in September (2). “Our work with Snapdragon showcases the power of our AI and data-driven process to solve complex chemistry and molecular discovery challenges in the pharmaceutical and biotech industry, orders of magnitude faster than traditional methods.”

1. Cambrex. Cambrex Announces Strategic Agreement with Lilly to Support Biotech Collaborator Manufacturing. Press Release. Dec. 5, 2024.
2. Cambrex. Atinary Technologies Announces Strategic Collaboration with Snapdragon Chemistry, a Cambrex Company. Press Release. Sept. 26, 2024.to Support Biotech Collaborator Manufacturing. Press Release. Dec. 5, 2024.
2. Cambrex. Atinary Technologies Announces Strategic Collaboration with Snapdragon Chemistry, a Cambrex Company. Press Release. Sept. 26, 2024.

Through the agreement, Cambrex will provide accelerated access to clinical development capabilities to Lilly’s biotech collaborators.

Cambrex Enters Agreement with Lilly to Support Biotech Collaborator Manufacturing 

Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

In this exclusive Drug Digest video interview an industry expert discusses key trends impacting solid dosage drug development and manufacturing. 

Focusing on Solid Dosage Trends and Demand

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, 

Group, interviews Dr. Ali Rajabi-Siahboomi from Colorcon about solid dosage drug development and manufacturing. During the discussion, Dr. Ali will provide an overview of the solid dosage drug development and manufacturing sector, factors driving growth in the market, challenges facing companies and the shifts in demand, the evolution of coating design, and regulatory considerations impacting oral solid dosage development and manufacturing.

Ali Rajabi-Siahboomi is the vice president and chief innovation officer at Colorcon, based at the Global Headquarter, USA. Rajabi-Siahboomi has held various academic positions in Nottingham and Liverpool JM Universities in the UK before joining Colorcon as technical director, responsible for Europe, the Middle East, and Africa in 2000. His main research interests are solid dosage form pharmaceutics, pharmaceutical technology with emphasis on oral drug delivery systems, solubility enhancement to improve bioavailability, and consistency of drugs and bioequivalence formulations. He has published more than 300 articles, book chapters, abstracts, and patents and obtained his B.Pharm. and PhD in pharmacy from the University of Nottingham (UK).

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

® 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.

 Emerging Therapies and Targeted Delivery

 Advances in Small-Molecule Manufacturing

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Drug Digest: Focusing on Solid Dosage Trends and Demand

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It is well-known that developing a drug from the discovery through to commercialization is a costly endeavor, with market analysis showing that the average R&D cost to develop an asset for 2022–2023 was $2.3 billion (1). However, many drugs do not make it through to commercialization, in fact it has been reported that clinical attrition rates for drugs that have reached Phase I trials is as high as 90% of drug candidates (2).

As a result of the high costs and level of risk inherent with drug development, it is imperative that companies efficiently determine the safety and efficacy of their candidates, to minimize any potential failure. “Bioanalytical testing is essential in drug development because it ensures the safety, efficacy, and quality of pharmaceutical compounds through quantitative analysis of drugs and their metabolites in various biological matrices such as plasma, urine, blood tissue, [and so on],” asserts Sujata (Suzzy) Bhavekar, study director at SGS North America. “Early identification of side effects through rigorous testing can reduce development costs by up to 20% (3). Drugs with robust bioanalytical data are 50% more likely to gain regulatory approval (4).”

“Bioanalytical testing covers a range of techniques and technologies used to quantify drugs and their metabolites, or biomarkers, in biological media,” adds Iain Love, director, Chromatographic Bioanalysis & Discovery Sciences, Department of Chromatographic Bioanalysis, Charles River. “The concentration data generated through bioanalytical testing are important as they inform researchers on how long a drug stays in the body and the beneficial effects or otherwise while it’s in there. Knowing the concentration of drug candidates and understanding the levels at which the drug has positive or negative effects on the body is critical to drug development.”

Vital data on drug absorption, distribution, metabolism, and excretion can be gained through bioanalytical studies, which helps developers to determine dosing regimens, agrees Bhavekar. “Poor pharmacokinetics contribute to 30% of drug failures, highlighting the importance of accurate testing (5),” she says.

Additionally, bioanalytical studies help with biomarker discovery, which improves the success rate of targeted therapies by 25% and supports personalized medicines (6), Bhavekar continues. Furthermore, suitable bioanalytical testing helps ensure compliance with regulatory standards, including good laboratory practice (GLP) and good clinical practice (GCP). “Approximately 85% of drug applications meet approval criteria with solid bioanalytical data (7),” Bhavekar says.

“Regulatory considerations are extremely vital in bioanalytical studies to ensure compliance with international standards and facilitate successful drug approval,” continues Bhavekar. “Adhering to GLPs and GCPs is essential to ensure data accuracy, reliability, and reproducibility.”

“Bioanalytical testing is carried out according to strict inter(national) guidelines and quality management systems,” agrees Love. “Monitoring authorities translate globally recognized quality management systems into national regulations.”

At the national level, there are guidelines such as FDA’s guidance documents on bioanalytical method validation and immunogenicity (7,8) and the European Medicines Agency’s guidance on bioanalytical method validation (9), Bhakevar adds. “Compliance with 21 CFR [Code of Federal Regulations] Part 11 (10) is crucial for maintaining the credibility of electronic records and ensuring data integrity,” she says.

“In addition to these national regulations, bioanalytical studies are also carried out following the International Council for Harmonisation (ICH) M10 guideline,” confirms Love. In fact, EMA’s guidance on bioanalytical testing has been superseded by the ICH guidance (11), since its publication in 2022.

“The ICH M10 guideline provides a harmonized approach across various regions including the US [United States], EU [European Union], Japan, and other member countries [and] provides a robust framework for validating methods, focusing on precision, accuracy, selectivity, sensitivity, and reproducibility, thus enhancing global consistency in bioanalytical testing,” Bhakevar specifies. “These regulatory frameworks, including ICH M10 and FDA guidelines, form the backbone of robust bioanalytical testing, driving drug development toward clinical and commercial success.”

“Outsourcing partners are an increasingly important piece of the drug development puzzle,” notes Love. “Partnership with a bioanalytical provider can bring about several tangible advantages that can help get drugs to the patients who need them in the shortest time possible. This could be from simple access to appropriate analytical platforms to receiving advice on planning the development program.”

In terms of regulatory compliance, the right partnership with a contract research organization that complies with global regulatory standards can ensure that the bioanalytical data generated meets the relevant requirements, Bhakavar explains. “Comprehensive services [provided by a partner company], including method development, validation, and routine analysis, allow sponsor companies to focus on core R&D activities while relying on their outsourcing partner for specialized testing,” she says.

“Outsourcing partners are also likely to be able to apply experience gathered from across a broad portfolio of modalities and development scenarios that can inform program decision-making,” confirms Love. “More than ever, bioanalytical science is involved in shaping programs, so careful selection of an expert outsourcing partner is an activity that can bring about the significant benefits involved with an accelerated drug development program.”

There are also benefits in terms of the flexibility and scalability of operations that a partner company can provide for a sponsor’s needs, Bhavekar remarks. “Outsourcing provides flexibility in scaling bioanalytical operations according to project needs, from preclinical to late-stage clinical trials. This scalability helps manage resources efficiently and reduces the burden on in-house teams,” she says. “[Additionally], with large-scale facilities and automated processes, outsourcing partners can handle high volumes of samples, ensuring rapid data delivery and accelerating the drug development timeline.”

“[Furthermore], outsourcing partners invest in cutting-edge technologies and platforms, such as mass spectrometry and immunoassays, to deliver precise and reliable data, which may not be feasible for smaller companies to implement internally,” specifies Bhavekar. “Overall, outsourcing bioanalytical testing to a reputable partner can enhance the efficiency and quality of the drug development process, enabling sponsor companies to achieve their project goals more effectively.”

“There has never been a more vibrant time to be involved in bioanalytical testing. It’s sometimes a challenge to keep up with the innovation both from within the drug development industry and from supporting partners,” notes Love. “There have been, and continue to be, some hugely innovative therapies discovered and developed by the pharma and biotech sectors. At the same time, instrument and software manufacturers continue to push boundaries with what can be done to generate extremely powerful data in support of drug development.”

An area of great interest for Love is that of patient centric sampling (PSC), which is “the description given to a number of techniques and approaches that affords patients choice: choice on how a biosample is taken but also the choice of whether to provide biosamples in a clinical setting or remote from a clinical setting,” he says. “This enablement of decentralized trials is potentially the biggest and most impactful paradigm change in the clinical space for a long time.”

For Bhavekar, the many advancements that have been seen in the field of bioanalytical testing have helped to greatly improve the analysis of both small and large molecules in drug development. For example, she highlights the hybrid approach of combining ligand-binding assays with liquid chromatography coupled with tandem mass spectroscopy as a way of improving sensitivity and specificity of bioanalytical studies for both small and large molecules.

Platform approaches represent another advancement in the field, Bhavekar continues. “Enzyme-linked immunosorbent assay, plasmon resonance immunoassay, hybridization assay, immuno-PCR [polymerase chain reaction] assay, and the Meso Scale Discovery platform are widely utilized methodologies,” she says. “These platforms are highly specific and sufficiently sensitive, enabling the generation of controlled and customized data that meets regulatory compliance standards.”

Other advancements include chromatographic-based techniques for greater analysis of samples, circular dichroism and differential scanning colorimetry for the assessment of stability and structural changes in large molecules, electrophoresis to help with the separation of proteins and large-molecule characterization, and multiplex immunoassays to gain insights into complex biological samples, Bhavekar notes.

“The bioanalytical field is continuously evolving, with ongoing research into novel biomarkers, advanced detection methods, and personalized medicine approaches. Staying at the forefront of these innovations is crucial for maintaining a competitive edge in the industry,” concludes Bhavekar. “By focusing on [more than just the core] aspects, sponsor companies can leverage bioanalytical testing not just as a regulatory requirement but as a strategic tool for advancing drug development and achieving market success.”

1. May, E.; Taylor, K.; Gupta, L.; Miranda, W. 

Unleash AI’s Potential: Measuring the Return from Pharmaceutical Innovation—14th Edition

. Annual Report, Deloitte, April 2024.
2. Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of Clinical Drug Development Fails and How to Improve it? 

 12 (7) 3049–3062.
3. Smith, J. and Doe, A. The Impact of Early-Phase Clinical Testing on Drug Development Costs. 

Pharmaceutical Development and Technology

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4. FDA. Drug Approval Statistics. 2022 Retrieved from https://www.fda.gov/drugs/drug-approvals-and-databases.
5. Anderson, J. and Smith, R. Impact of Pharmacokinetics on Drug Development. 

Journal of Pharmacokinetics and Pharmacodynamics

, 48(2), 123-130.
6. Johnson, R. and Lee, K. Biomarker Discovery and Its Role in Targeted Therapy. 

. Guidance for Industry, May 2018.
8. FDA. 

Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody Detection

. Guidance for Industry, January 2019.
9. EMA. EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2** 

Guideline on Bioanalytical Method Validation

 Title 21, 11 (Government Printing Office, Washington, DC) 241–246.
11. ICH. M10 

Bioanalytical Method Validation and Study Sample Analysis

Felicity Thomas is the Associate Editorial Director for Pharmaceutical Technology Group.


Vol. 48, No. 12
December 2024
Pages: 30–32

When referring to this article, please cite it as Thomas, F. 
Leveraging Advancements in Bioanalytical Testing. 

As the field of bioanalytical testing evolves, it is important for drug developers to stay at the forefront of the advancements to ensure they remain competitive.

Leveraging Advancements in Bioanalytical Testing

The European Medicines Agency (EMA) announced on Nov. 29, 2024 that its Pharmacovigilance Risk Assessment Committee (PRAC) has found no causal link between doxycycline, a broad-spectrum antibiotic, and the risk of suicide or suicidal thoughts.

PRAC began a review of the safety of doxycycline in November 2023 after reports of a possible risk of suicidal thoughts or actions with the use of doxycycline from the Finnish national competent authority, as well as other cases reported to the European database of suspected side effects, EudraVigilance. The PRAC review included a cumulative data review from all relevant sources by the marketing authorization holders. There was also a study based on real-world evidence that included data from electronic health records and disease registries.

“After reviewing all available evidence from spontaneous reports, the literature, the discussion on possible mechanisms and the study performed via DARWIN EU [the Data Analysis and Real World Interrogation Network], the PRAC considered that the evidence is not sufficient to establish a causal relationship and that no update to the product information of doxycycline is warranted.

Suicide-related events in relation to doxycycline will be closely monitored and any new evidence will be discussed in the Periodic Safety Update Reports (PSURs),” EMA stated in a press release (1).

During the November meeting, PRAC also agreed to provide a direct healthcare professional communication (DHPC) on the liver injury risks associated with Veoza (fezolinetant). Veoza is used to treat moderate-to-severe vasomotor symptoms (i.e., hot flashes) that occur with menopause. PRAC is recommending that liver function be monitored in patients before and during treatment with fezolinetant. The recommendations are a result of a review of fezolinetant that included information from reports of suspected side effects and published scientific studies. The review showed a potential risk of drug-induced liver injury.

“Severe elevations of the liver enzymes alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (>10x upper limit of normal) with concurrent elevations in bilirubin and/or alkaline phosphatase (ALP) have been reported post marketing in women taking Veoza. In some cases, elevated liver function tests (LFTs) were associated with signs or symptoms suggestive of liver injury such as fatigue, pruritus, jaundice, dark urine, decreased appetite, or abdominal pain.”

Therefore, PRAC is recommending LFTs be performed before treatment is started and monthly tests during the first three months of treatment, with testing conducted thereafter based on symptoms of livery injury. Product information and packaging is being updated with the new safety information.

“Once adopted, the DHPC for Veoza will be disseminated to healthcare professionals by the marketing authorisation holders, according to an agreed communication plan, and published on the 

Direct healthcare professional communications

 in EU Member States,” the agency stated in the release.

1. EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 25-28 November 2024. Press Release. Nov. 29, 2024.

The agency’s safety committee found no sufficient evidence of causal relationship between the antibiotic doxycycline and the risk of suicide or suicidal thoughts.

No Causal Link Between Doxycycline and Suicide, Says EMA Safety Committee 

Cheryl Barton is director of PharmaVision, 

On 15 Oct. 2024, the European Federation of Pharmaceutical Industries and Associations (EFPIA) published an article to raise industry awareness that the European Union (EU) is developing a roadmap to advance precision oncology at the country level to address the growing burden of cancer in Europe (1). Cancer remains the second biggest cause of death in Europe. In 2024, the predicted mortality cancer rates are forecast to fall by 6.5% in men and by 4.3% in women in the EU (based on data from the five most populous countries and the United Kingdom). However, the number of deaths is still rising, with a total of 1,270,800 predicted deaths in 2024 in the EU and 172,900 in the UK, due to population growth and ageing (2).

New therapies, along with advances in prevention, screening, radiotherapy, and surgery are helping to save lives, but further collaboration, and partnership are needed. The “#WeWontRest until we beat cancer” campaign is underway (3). On 13 Nov. 2024, the EFPIA Oncology Platform organized a stakeholder roundtable in Brussels to bring together EFPIA member companies—AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Ipsen, Johnson & Johnson, Lilly, Novartis, MSD, Menarini, Pfizer, Roche, Sanofi, Servier, and Takeda—to help define future legislative and policy directions to improve the provision of personalized treatment for cancer patients (4).

The event was hosted by the Committee of the Regions, with scientific support from the European Regional and Local Health Authorities (EUREGHA) and Cancer Patients Europe, and aims to bring together stakeholders—policymakers, regional health authorities, patient advocates, and healthcare providers—to explore the challenges to improve access to precision oncology to ensure optimal and timely treatment and overcome healthcare disparities across Europe.

The EU has been developing policies to move toward personalized medicine (PM) and has made significant investments starting in 2010. As of 2017, €3.2 billion was invested in PM research across the medical innovation cycle ‘from bench to bedside’ from the research framework programs FP7 and Horizon 2020 (5).

In 2021, the European Commission (EC) published its cancer plan for Europe outlining several goals to reverse the rising trend of cancer across the EU (

). Europe’s Beating Cancer Plan was the EU’s response to medical needs and aims to tackle the entire disease pathways from prevention, early detection, diagnosis, and treatment, as well as the quality of life of the cancer patients and survivors (6).

EU initiatives in precision medicine in Europe

Many EU initiatives are underway to advance precision medicine in Europe. On 11. Sept. 2024, the Thematic Network on Advancing Precision Medicine for Europe’s Cancer Patients with artificial intelligence (AI)-powered Imaging held a webinar led by the European Society of Radiology to discuss with health stakeholders how AI-powered cancer care can improve personalized treatment strategies and reduce the burden of cancer (7).

Meanwhile, the Digital Oncology Network for Europe (DigiONE) pilot is underway in Europe. An amount of €3 million has been allocated for technology investment in a proof-of-concept learning health system in a precision oncology platform that aims to identify optimal cancer treatments by learning from every patient, not just those in clinical trials, through privacy-preserving interrogation of their standardized routine electronic health records (8,9).

Roadmap for a European cancer data management and precision medicine infrastructure

Aside from the goals laid out in Europe’s Beating Cancer Plan stakeholders recognize that for European citizens to have access to innovative precision medicines there is a need to develop a gold-standard cancer data management system. This will rely on three key elements: adopting standardized data formats; ensuring robust data privacy; educating professionals about the infrastructure’s benefits and leveraging cutting-edge technologies to transform cancer care (10).

Further work is needed to refine the EU roadmap on precision oncology but significant steps have already been taken to put in place the framework to reverse the rising trend of cancer across the EU. Stakeholders should keep abreast of the situation and can access details of the advancing precision oncology agenda in the EU online, via the EFPIA (11).

1. EFPIA. Advancing the Precision Oncology Agenda in the EU: Developing a Roadmap at Country Level to Address the Growing Burden of Cancer in Europe. Guest Blog. 15 Oct. 2024.
2. Santucci, C.; Mignozzi, S.; Malvezzi, M.; et al. European Cancer Mortality Predictions for the Year 2024 with a Focus on Colorectal Cancer. 

35 (3) 308–316.
3. EFPIA. #WeWontRest Until We Beat Cancer. 

Accessed 22 Oct. 2024.
4. EFPIA. Advancing the Precision Oncology Agenda in the EU. Brussels, Belgium. 13. Nov. 2024.
5. Nimmesgern, E.; Norstedt, I.; Draghia-Akli, R. Enabling Personalized Medicine in Europe by the European Commission‘s Funding Activities. 

 14 (4) 355–365.
6. European Commission. 

. Communication Paper, 2021.
7. Nikolski, M.; Hovig, E.; Al-Shahrour, F.; et al. Roadmap for a European Cancer Data Management and Precision Medicine Infrastructure. 

5, 367–372.
8. Mahon, P.; Chatzitheofilou, I.; Dekker, A.; 

 A Federated Learning System for Precision Oncology in Europe: DigiONE. 

 30, 334–337.
9. Nahon. P. Building a Digital Oncology Network for Europe (DigiOne) The Digital Institute for Cancer Outcome Research (DigiCore). 

Accessed 22 Oct. 2024.
10. European Commission. Recording—EUHPP Live Webinar—How to Advance Precision Medicine for Europe’s Cancer Patients with AI-powered Imaging (11 September 2024). News Announcement, 11 Sep. 2024.
11. EFPIA. Advancing the Precision Oncology Agenda in the EU. 13 Nov. 2024

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.


Vol. 36, No. 10
November/December 2024
Pages: 9–10

When referring to this article, please cite it as Barton, C. Advancing the Precision Oncology Agenda in Europe. 

The European Commission has developed a roadmap aimed at reversing the rising trend of cancer across the European Union. 

Advancing the Precision Oncology Agenda in Europe

Belgium-based EXO Biologics and its contract development and manufacturing organization (CDMO) subsidiary, ExoXpert, both innovators in exosome-based therapeutics and drug delivery solutions, announced on Dec. 2, 2024,  that ExoXpert has received good manufacturing practice (GMP) certification for its Liège, Belgium, manufacturing facility. At the same time, EXO Biologics achieved the loading of GMP-grade exosomes with messenger RNA (mRNA) and DNA payloads. Both achievements mark significant milestones for the development of exosome-based therapeutics (1).

According to a company press release, ExoXpert is the first European CDMO specializing in exosomes that has received GMP certification (1). The certification was awarded by the Belgian Federal Agency for Medicines and Health Products. Both BioWin, the Health Cluster of Wallonia, Belgium, and the Public Service of Wallonia have been strong supporters of EXO Biologics’ and ExoXpert’s growth, according to the press release.

“We have now achieved two critical strategic milestones by the end of 2024, which extends our continued progress in developing scalable, GMP-compliant solutions for exosome as therapeutic and drug delivery system. This extends our market leading position in the development of exosome-based technologies, unlocking new possibilities for drug delivery, gene therapy, and immunotherapy,” said Hugues Wallemacq, CEO of EXO Biologics, in the press release.

The importance of the GMP certification lays in the official status it gives to ExoXpert’s ability to produce exosomes according to the highest industry standards. The GMP-certified facilities enable EXO Biologics to internalize production of EXOB-001, currently in Phase I clinical development and the first global European Medicines Agency-approved mesenchymal stem cell-based exosome therapeutic in clinical trials. The certification also enables ExoXpert to offer exosome-specialized GMP capabilities internationally, including to current clients in the United States and European Union markets as well as future partners. ExoXpert also has the ability to activate additional cleanroom on demand. The greatest demand for exosomes currently is their use as a safe and non-viral drug delivery system for cell and gene therapy applications, according to the company press release (1).

The second achievement, the successful loading of mRNA and DNA payloads into GMP-grade exosomes, represents a critical step toward developing safe, efficient, and scalable exosome-based therapies for genetic material delivery. While small molecules and short nucleic acids (e.g., small interfering RNA and microRNA) have already been validated in an end-to-end GMP-like setting (2), EXO Biologics’ achievement demonstrates significant progress in the loading of larger molecules (i.e., mRNA and DNA) into GMP-grade exosomes that can then be used for third-party non-viral drug delivery applications. The company’s preliminary trials data have shown a retention rate up to 80% of the loaded DNA cargo upon exosome loading (1).

“The GMP certification of ExoXpert’s Liège manufacturing facility and the successful loading by EXO Biologics of mRNA and DNA into exosomes are major steps in bringing safe and effective exosome-based therapies to patients worldwide. We are now working on optimizing the loading technology to further reduce the manufacturing cost and strengthen the attractiveness of exosome therapeutics and manufacturing compared to alternative classical technologies. This will revolutionize the treatment of complex diseases, including cancer, genetic disorders, and viral infections,” Wallemacq said in the release (1).

1. EXO Biologics. EXO Biologics & ExoXpert Achieve Two Critical Industry-First Milestones for the Exosome Field. Press Release. Dec. 2, 2024.
2. Bhome, R.; Del Vecchio, F.; Lee, G-H.; et al. Exosomal MicroRNAs (exomiRs): Small Molecules with a Big Role in Cancer. 

, 228–235. DOI: 10.1016/j.canlet.2018.02.002

EXO Biologics and ExoXpert, an EXO Biologics subsidiary, have received GMP certification of a European manufacturing facility for exosomes and have successfully loaded mRNA and DNA payloads into GMP-grade exosomes for drug delivery.

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