Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

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

Bridge made of colorful blocks on violet background, flat lay. Connection, relationships and deal concept | Image Credit: © New Africa - stock.adobe.com

At the beginning of 2023, inflation represented a significant thorn in the side of global economies and exacerbated the challenges raised by the tumultuous preceding 12 months—encompassing the tail end of the COVID-19 pandemic, the war in Ukraine, and skyrocketing energy prices. Despite inflation moving in the right (downward) direction across Europe, it is still a lingering issue for the continent and is negatively impacting European economies (1,2).

For the bio/pharma industry—an industry well known for its ability to weather economic turmoil with reasonable safety—the latest global economic challenges have raised significant concerns. In Europe, moving into 2024 there will be additional factors at play, such as an increased drive to digitalization, a focus on sustainability, and a shortage of skilled personnel, meaning that bio/pharma companies will need to adapt over the coming months.

“The pandemic, inflation, geopolitics, new therapeutic modalities, evolving ways of working, and EU [European Union] regulatory changes, have conspired to have major implications for the pharma industry,” reports Romuald Braun, managing partner, MAIN5, a European consulting firm specializing in organizational and digitally enabled change in Life Sciences.

“The most notable fallout,” Braun says, “has been rising operational complexity (e.g., the need to manage diverse product portfolios and supply chains); increasing risk around balancing global demand, supply chain disruptions, and new modalities; the need to adapt to technological changes; rising capital costs (investing in new technologies and facilities); variable cost increases (addressing inflation and supply chain challenges); and the need to seize every opportunity for savings through optimized operations.”

In concurrence, Jordan Schmitting, senior research analyst, The Josh Bersin Company—research, advisory, and education on the trends, technologies, and best practices for the new world of work—confirms that the evolving geopolitical, economic, and regulatory conditions have put European pharma companies’ supply chains and profit margins under pressure throughout 2023.

“However,” Schmitting adds, “digitization and biotechnology were perhaps the most defining trends within the industry, shaping the future of not only how treatments are discovered, developed, manufactured, and distributed, but the types of treatments being explored.”

An increased integration of digital technologies is being seen within the bio/pharma industry, agrees Braun. “This [integration] includes the use of AI [artificial intelligence], big data analytics, and digital health platforms to improve efficiency and outcomes,” he says. “Digital transformation now extends to adoption of ‘Generative AI’, as companies strive to be more data and insight driven, moving away from dependence on static documents.”

Furthermore, the use of cloud-based systems to ease information exchange and data management will be seen, Braun continues. “Breaking down data silos is essential to enable advanced analytics and faster decision-making—as long as data governance and data quality are prioritized so that teams can trust the insights being surfaced,” he states.

Along with changes in data collection, however, comes an increased focus on data privacy and the general data protection regulation, adds Kate Coleman, vice president of Quality and Compliance at Arriello—a consultancy and solutions provider of risk management and compliance services to the pharma industry. “Again, these topics were raised repeatedly in 2023, not just in the context of medicine but also in the broader social context, and the importance of data protection is a conversation that will continue into 2024,” she notes.

“AI has gathered pace and is a consistent talking point as it is now recognized as a powerful tool in many areas across the pharmaceutical industry including drug development, writing, data analysis, translations, and pharmacovigilance activity to name a few,” remarks Coleman. “AI has the potential to radically change how we do things in the industry, and everyone will need to increase their understanding of this powerful technology to understand both its strengths and weaknesses.”

For Beena Wood, senior vice president of Safety and Medical, ArisGlobal—the creator of the LifeSphere technology platform and provider of global patient treatment solutions—there has been crucial technological innovation that is now providing all bio/pharma companies access to AI and machine learning (ML). “AI/ML can now be applied to a broad range of connected data—including a broader range of standardized, reliable real‑world data—to enable advanced analytics and powerful, timely insights,” she says. “This will inspire new treatment/care innovation with the interests of patients right at the heart.”

Patient-centricity will become an intense focus for bio/pharma companies in 2024 because of several converging factors, according to Wood. “First, the status quo is being challenged increasingly by empowered patients who now know and expect more,” she specifies. “Second, [there is] accelerated delivery of personalized therapies, geared to the needs of smaller patient populations and individuals. Meanwhile, regulatory mandates are now prioritizing patient concerns and considerations right from development phase and throughout the treatment lifecycle.”

Braun concurs that patient centricity will be a huge topic for companies moving forward and points out that patients’ needs and outcomes will remain important for companies. “Personalized medicine, patient engagement, and real-world evidence will guide decision-making,” he states.

“The increased focus on personalized medicine, gene therapies, and other advanced therapeutics combined with discussions on treatment costs have raised questions that will need to be considered for the viability of future innovative pharmaceutical products,” emphasizes Coleman. “Many high-profile agreements have been reported in 2023, and the topic of cost benefit analysis for innovative therapies will be ongoing in the next year.”

Another focus for bio/pharma companies in the future will be embracing more sustainable practices, something that is being expected from customers and patients. “Companies will be increasingly investing in green initiatives, implementing eco-friendly manufacturing practices, and adopting sustainable packaging solutions,” says Preeya Beczek, principal consultant at Beczek.com, a regulatory affairs and compliance consultancy.

“Increasing efforts will need to be made to reduce waste generation, minimize water consumption, and decrease greenhouse gas emissions,” Beczek continues. “These changes will need to be measurable so that achievements against targets can be demonstrated through key performance indicators over time.”

As the climate crisis is becoming more apparent to the world, an issue that will only be more heightened in the coming years, the bio/pharma industry is finding itself in a difficult position, states Coleman. Simply due to the nature of the bio/pharma industry—manufacturing and distributing products around the world—it is a major contributor to the global carbon footprint, she stresses.

“The pharma industry is also highly regulated, which means significant change is neither easy nor fast,” Coleman says. “To really combat the impact that the pharma industry has on the environment, the risks and impacts from the industry need to be fully identified across all activities from sourcing of raw materials, shipment, transport, manufacture, distribution, and management of waste to identify a full and holistic plan for change that can reduce the impact on the environment and on the planet. When mitigation actions are identified that will improve the carbon footprint, such as reverting to stainless steel rather than single use plastics, the regulators will need to assist companies with balancing the risks between impact on patients, impact on employees, and impact on the environment as a whole.”

There are numerous environmental, social, and corporate governance (ESG) challenges facing the bio/pharma industry, confirms Braun. “These [challenges] include reducing carbon footprint and promoting sustainable practices; ensuring ethical sourcing and minimizing environmental impact across the supply chain; balancing profit with patient needs to ensure patient access and affordability; more responsible drug development (ethical research and innovation); diversity and inclusion considerations, promoting a diverse workforce and equitable practices,” he notes.

“Moreover, there will be changes to what needs to be reported on, and how, under the EU’s Corporate Sustainability Reporting Directive (CSRD),” Braun stresses. “From 2024, almost 50,000 companies are subject to mandatory sustainability reporting, including non-EU companies with subsidiaries operating within the EU or listed on EU-regulated markets.”

An increasing role of technology and innovation, such as AI, robotics, and automated processes, combined with newer therapeutic modalities and personalized medicines in the bio/pharma industry is changing the skills and expertise required, emphasizes Coleman. “For example, roles such as the Qualified Person have changed significantly when considering ATMPs [advanced therapy medicinal products] where the QC [quality control] tests and timelines for batch review and release to market have been either significantly reduced or removed completely,” she says.

Schmitting also alludes to a misalignment of roles and skills across all talent segments of the bio/pharma industry caused by rapid evolution of the industry’s requirements as a result of trends like AI, automation, digitization, and big data. “These forces are changing the nature of work not only in manufacturing and distribution, but across the entire pharma value chain, including R&D,” she says. “Take AI-driven platforms, for example, which is a research innovation fundamentally changing the methods and timescale of specialized therapy discovery and development.”

However, the technological innovation being seen within the bio/pharma industry could also help to attract the younger generation to the sector, Beczek remarks. The skills gained with a more technologically advanced bio/pharma industry can also be transferrable should the potential employee wish to change their role, she adds. “Harnessing the tech-savvy power of this younger generation could help the industry see new possibilities and pathways to drive change forward,” Beczek states.

Additionally, as biologicals and molecular technologies become more present within industry, the skillsets required to deal with these are changing and are not necessarily easily acquired, Braun stresses. To manage this issue, Braun anticipates there will be an increase in M&A activity and a rise in the use of external services to plug gaps.

“Lower-skill labour in production facilities is a challenge too, not least as 24/7 continuous production increases,” Braun says. “To address these shortages and contain costs, pharma companies will need to continue streamlining processes, harnessing automation and applying AI as appropriate.”

Potential options for bio/pharma companies to deal with the skills shortage is to collaborate with academic institutions, industry associations, and research centres to pool talent, Braun continues. To attract and retain skilled professionals, companies should develop a more compelling employer value proposition and offer continuous learning opportunities for existing employees, such as upskilling in digital technologies, and so forth, he adds.

Beczek believes in a two-pronged approach to tackle the skills shortage. “Start at the higher education level and actively recruit seasoned medical experts in the key therapeutic areas to join innovative companies as clinical development leaders, medical experts to drive product strategy at a disease level,” she explains.

There also needs to be different pathways offered in addition to the standard three- to four-year full-time qualifications pursued at an academic institution, according to Beczek. “There are a handful of settings that offer young adults a life sciences path via apprenticeships with an opportunity to balance hands-on work and study including a salary. This is the way forward,” she says.

“The academic institutions do appear to recognize the change in the industry and proactive measures have been taken at this level to ensure graduates are more equipped to deal with the demands of the reality of working in a high technology environment,” specifies Coleman. “However, one element that this cohort lack is the practical experience needed to develop into quality resources that can support this ever-changing industry.”

Moving into 2024, Braun expects that bio/pharma companies will continue to be cost-conscious and the industry transformation with new modalities gaining prominence will persist. “Pharma companies will need to invest in R&D to harness these [therapeutic] innovations effectively,” he says.

Adoption of digital technologies will accelerate, and companies will need to invest in digital capabilities to keep up with opportunities, Braun adds. “AI/ML will move from a prototyping or pilot phase towards larger use cases, presenting new challenges for validation and data integrity,” he says. “As the pace of change accelerates, IT must be much closer to the business than previously.”

There is heightened pressure on bio/pharma companies to control costs, maximize the value of investments, and optimize their strategic focus, while also maintaining the highest levels of patient safety and stakeholder confidence, adds Wood. “In pharmacovigilance and agency reporting, large language models/ChatGPT-like Generative AI tools are poised to deliver up to 80% productivity gains for certain work processes, compared with 20–50% improvements with previous-generation technologies,” she states. “No company can afford to let that kind of opportunity pass them by. The appetite is there, and proof-of-concepts are well underway now.”

However, with the various therapeutic and technological advancements, companies will also need to ensure they keep abreast of regulatory updates. “The EU’s regulatory changes will continue to impact the industry. Companies must stay informed about evolving regulations related to clinical trials, medical devices, and AI applications. Compliance and adaptation are key,” Braun reports.

Coleman also points to the regulatory landscape, which will be a focus in 2024 as the existing pharmaceutical regulation will be replaced. “The main objectives of the revision are aligned with the points mentioned previously, and it is intended that the revised EU pharmaceutical regulation will address innovation and technological advancements in the industry, align manufacturing of medicinal products with the European Green Deal related to climate change, and make medicines in Europe more affordable, accessible, and available to patients that need them,” she summarizes. “The changes are intended to make the industry and its regulation more agile, and more appropriate for the world we live in now.”

The regulatory updates are aligned with the rise in biotech innovation, drive to reduce time-to-market, and increased focus on patient needs, meaning that the bio/pharma industry has no choice but to change the way it operates, asserts Wood. “Leading players have realized that if they want different outcomes, they can’t keep doing things the way they’ve always done,” she says. “They need to be smarter, and more informed by the latest data, if they want to honour their commitment to patient centricity, and to safe, agile innovation.

All the trends discussed have a massive impact on the bio/pharma industry because of the many moving parts involved, adds Beczek. “The crucial part is that teams will have to increasingly work across functions not just in R&D but also closely with commercial, medical affairs, in country affiliates, with industry experts and healthcare professionals, expanding the end-to-end value chain of strategy and operations,” she concludes.

1. Guerrera, F. Europe Faces Dirtier Inflation Fight than US. 

, 6 Sep. 2023.
2. Smith-Meyer, B. High Interest Rates Have Hit Growth More than Expected, EU Says. 

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.


Vol. 36, No. 1
January 2024
Pages: 10–12, 16

When referring to this article, please cite it as Thomas, F. Bridging Gaps and Investing in Change. 

Articles

European bio/pharma companies have no choice but to invest and adapt to the evolving industry needs.

Bridging Gaps and Investing in Change

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

We have to stick to the facts. a group of scientists working together in a lab.| Image credit: © Courtney H/peopleimages.com - stock.adobe.com

® survey audience members to see what has remained the same and what has shifted, regarding pharmaceutical workforce attitudes toward their jobs, their current employers, and the general direction the industry is heading. The industry’s response to COVID-19 has had the most significant measurable impact on the way both business and manufacturing processes were managed in the past two or three surveys. In 2023, the largest observable shift was brought about by the steady emergence of advanced therapeutic medicinal products (ATMPs). The last half of 2023 was a watershed moment for pharmaceuticals, given the industry saw the first set of approvals for gene edited therapies, as well as for a self-amplifying messenger RNA vaccine. But everyone experienced the year through the lens of the products and activities their own company sells. In this way, one can say of pharmaceutical manufacture, “All happy families are alike; each unhappy family is unhappy in its own way” (1). Let’s examine survey responses to see what these differences might be founded upon (2). There is a gulf between survey responses such as “struggling industry full of scientific brains lacking leadership, mentoring, and training” or “Party’s over–hunker down, folks,” to “Aside from a few ‘deplorables’, the industry is in good condition’’, “volatile, encouraging, innovative, nerve-wracking”, or “Incredible advances and treatment options.”

As the sugar rush of COVID-19 response funding wore off, so too did the number of hours workers put in on average. Hours worked returned to pre-pandemic levels, based on earlier survey results (see 

). This finding was somewhat surprising given conversations held during conferences, but there was perhaps some confirmation bias during conferences, versus survey results. It’s easier in a survey to say ‘I’m not working as hard’ compared with a network contact you are used to doing business with. The final question of the survey asks, “If you could describe the 2023 bio/pharma industry in five words or fewer, what would you say?” And this is where the quote from Tolstoy can most readily be explored.

Figure 1: COVID-19 measures. | Image credit: © 

Figure 2: Are working hours rising or falling? | Image credit: © 

Opinions about the post-pandemic industry were largely positively oriented, from “post-COVID readjustment” and “the 2023 bio/pharma industry has benefitted greatly from covid restrictions.” Responses ranged from “consolidation after covid pandemic rush” to “Great come back after covid.” But some were bleak in their appraisal, with “Pandemic stress, Supply chain collapse” and “Post-pandemic blues” being somewhat frequent responses.

Naturally, one can suppose the technologies and services most involved in the pandemic response, such as vaccine manufacture and distribution, were/are the respondents going through the deepest readjustment phase. One of the features of the pandemic was that it forced everyone to communicate more quickly, clearly, and completely. This seems to have remained.

Karolina Makovskyte, head of Business Development at Caszyme, said, “One positive aspect of CRISPR-Cas technology is the emergence of a more active dialogue about gene editing regulations, particularly in Europe. It is also somewhat linked to another positive aspect, which is increased exploration of the technology by new industries, seeking ways to integrate CRISPR-Cas into their activities.”

Satisfaction with pay in 2023 didn’t move to any great degree versus historical years (see 

). Perhaps the timing of the survey influenced a type of survival-driven satisfaction, as the last half of the year saw several companies markedly reduce workforce numbers as part of restructuring efforts. Pfizer axed approximately 900 staff, as their Covid vaccine reported $1.31 billion in sales, a 70% decline from the year before. “Wall Street had expected $1.53 in revenue. Paxlovid suffered an even sharper drop, with revenue of just $202 million—97% down from last year” (3). Not a big reduction but still significant for a company that sold $100 Billion in product for the first time in 2022. Grifols, a Spanish company specializing in blood plasma therapies, trimmed its operations in the United States by cutting approximately 2300 positions (which amounts to approximately 8.5% of its global workforce). Takeda braced for competitive threats with cuts of nearly 1400 staff, to prepare for generic competition to its diabetes drug Actos. Thermo Fisher Scientific adjusted to changing demands through a series of workforce cuts totally nearly 1300 staff, mainly due to decreased demand for COVID-19 testing products and “evolving economic conditions.” Genentech, Biogen, Catalent, and Amgen also witnessed significant workforce diminutions, while Novavax, Emergent BioSolutions, and Bristol Myers Squibb, round out the list (4).

Figure 3: Salary satisfaction. | Image credit: © 

, job security hit its highest levels during the height of the COVID-19 pandemic. While the survey questions don’t allow enough depth to explored in detail, going back to the Tolstoy metaphor, the workers feeling most secure are likely the staff working on the most promising new advanced therapeutic medicinal products (ATMPs), as this is clearly where the excitement and major new investments are being ploughed into. For example, RoslinCT will manufacture Vertex Pharmaceuticals’ CRISPR-based gene therapy, Casgevy, recently approved for treating sickle cell disease and β thalassemia (5). Novo Nordisk is also planning a US$2.3 billion investment in new French facilities, partly to facilitate extra capacity for glucagon-like peptide-1 products (6). One of the survey respondents summed up the entire industry with the words “Sustained growth with new therapies” while another simply stated “Vaccines, proteins, blood, tissues.”

Figure 4: How secure do you feel in your job? | Image credit: © 

Similarly, optimism about future performance was also peaked during the pandemic.Somewhat alluding to the Tolstoy metaphor and also the COVID-19 sugar rush, Barbara Ryan, founder, Barbara Ryan Advisors commented, “It is interesting, however, because the market remains highly bifurcated—companies with good data are able to finance, and often the aftermarket performance is quite positive, as the deals are viewed as a clearing-event lifting the financing overhang. As of press time, there had only been 11 biotech IPOs this year, in contrast to more than 100 each in 2020 and 2021. Sadly, however, too many companies went public in 2020 and 2021 that were at a far-too-early stage in their development (i.e., preclinical, Phase I trials) to be public companies; they were not sufficiently funded to proof-of-concept data. This is where the real pain is” (7). Ryan went on to round out her assessment of the industry, ending on a highly positive note. “The innovation renaissance is alive and well, with record numbers of FDA new drug approvals in each of the past several years. M&A continues to be another bright spot. Beginning in 2025, large pharma will be losing exclusivity for products currently representing over $350 billion in revenue, leaving a huge growth gap that needs to be filled through M&As, licensing, and partnering. Dealmaking has always been a key pillar of the industry’s growth strategies. More good news: according to EY’s Annual Fire Power Report, large pharma has a record $1.4 trillion to fund deals. There have been a total of 30 public biotech acquisitions this year, and 15 of these were above $1 billion each, which surpasses the number in any year for the past 10. As we wind down 2023, the hope will be for rate relief in the year ahead—and substantially improved biotech performance.”And as if on que, the Federal Reserve just suggested three cuts to interest rates in 2024, sending the DOW into record territory by rising 1.4%, to close at 37,090.24 (8).

Pharmaceutical Technology/Pharmaceutical Technology Europe Employment Survey

Q.ai Contributor Group, Pfizer Layoffs Confirmed as Vaccine Manufacturer Drives For Cost Savings. 

Buntz, B. 10 Major Pharma and Biotech Companies that Downsized in 2023. 

Mirasol, F. RoslinCT to Manufacture CRISPR-Based Gene Therapy Casgevy, 

Mirasol, F, Novo Nordisk to Make Multi-Billion Dollar Investment in Expansion of Production Facilities in France, 

Ryan, B. Will Calendar Change Bring an End to Run of Volatility in Biotech? 

Mena, B.; Wallace, A. Buchwald, E. Dow Surges to New Record as Fed Signals Three Rate Cuts in 2024. 

Chris Spivey is the editorial director of 

When referring to this article, please cite it as Spivey, C. New Therapies Cry Out for New Skills. 

There are positive indications for future growth.

New Therapies Cry Out for New Skills

Kelley Waldron, PhD, is business unit manager, Quality and Manufacturing Science Consulting, at ValSource.

Tiffany Baker, MBA, is senior consultant at ValSource.

concept of auditing and evaluating quality and efficiency of personnel ,business document evaluation process ,inspection of business finance tax documents ,Data analysis reports growth results | Image credit: © chaylek - stock.adobe.com

In 2009, the pharmaceutical and biopharmaceutical industry’s quality risk management (QRM) journey was still in its infancy. The industry had begun performing risk assessments, lots of risk assessments. Consider, for example, this December 2009 quote from Roche’s Wallace Torres in 

: “[following the initiation of the company’s QRM program], we performed more than 100,000 full FMEA [failure mode and effects] analyses worldwide in the first year” (1). Industry has since learned that excessive numbers of risk assessments can bog down the system and minimize the value that can be extracted from the assessments. Thankfully, with the release of the International Council for Harmonisation’s (ICH) Q9(R1), industry can better plan what risk assessments are needed, when, why, and how (2).

As is often the case, the pharmaceutical industry was not the first to learn this lesson. ISO 14971, “Medical devices—Application of risk management for medical devices,” first described the use of a risk management plan for device risk management in 2007 and has retained this requirement through each subsequent revision. Among other things, this standard obliges medical device developers and manufacturers to define a plan for risk management activities throughout the product lifecycle. As noted by ISO 14971, “a risk management plan is required because (a) an organized approach is essential for good risk management, (b) the plan provides the roadmap for risk management, [and] (c) the plan encourages objectivity and helps prevent essential elements from being forgotten” (3).Similarly, validation master plans, in use throughout industry for many years, are designed to achieve the same goals.

The requirements for a risk management plan in ISO 14971 read like what one might envision as a QRM procedure for the pharmaceutical and biopharmaceutical industries. Roles and responsibilities are defined and delineated, the scope of the plan with regard to the product lifecycle is outlined, a governance structure and associated processes are established, risk and residual risk acceptance criteria are defined, and requirements and data sources for the use of production and post-production information (similar to the risk review phase of the ICH Q9(R1) lifecycle) are described. In addition to these standard requirements, ISO 14971 notes that the risk management plan may be used to define milestones, plan risk management activities, and outline risk tools to be employed for the various activities. In this way, the risk management plan has an inherently flexible structure with the goal of better enabling the organization to plan for what risk management activities must be done to align with certain product-realization goals (3).

While ICH Q9(R1) does not explicitly address the use of a risk management plan, the QRM lifecycle begins with a “QRM Initiation” step, the primary focus of which is a process of gathering the information needed to begin a risk assessment and continue throughout the remaining lifecycle stages (2). Considering the learnings from ISO 14971, this initiation step can be enhanced through an outline of strategic goals for the QRM program and a detailed plan on how the firm intends to reach them. While the first version of ICH Q9 paid little attention to planning and organization, the current version of ICH Q9 highlights the application of thoughtful and objective decision-making throughout the QRM lifecycle, including the often overlooked “QRM Initiation” step.

The historic lack of emphasis on QRM planning is a plausible reason why the industry has struggled with the administration of the QRM program and the creation of myriad risk assessments with no holistic vision. The lack of strategic planning could also contribute to a siloed approach to QRM application and risk assessment performance. By outlining overarching objectives for the QRM program, the use of a risk management plan can enable the pharmaceutical and biopharmaceutical industries to spend less time “doing QRM” and more time managing risk to the patient. This plan would be a living document over time to demonstrate the current state of the program, as well as updating the future of QRM implementation. Depending on the firm’s level of maturity and experience with QRM, strategic objectives for the QRM program may include:

Hire/develop QRM experts to enable the implementation of the program and the risk assessment portfolio

Author QRM policy, procedures, and work instructions

Design and implement role-based QRM training

Integrate QRM principles and practices into quality and operational systems

Define and create portfolio of living risk assessments.

To distinguish from the medical device risk management plan and the clinical/medical risk management plans in use for drugs with unique risk profiles, and to capitalize on the familiarity with validation master plans, such a plan is best termed a QRM Master Plan. The remainder of this article focuses primarily on the last bullet listed above—the creation of a living risk assessment library.

Two more welcomed additions to the 2023 ICH Q9(R1) include an expansion on the concept of risk-based decision making and the acknowledgement, in the context of QRM formality, that under certain circumstances only a portion of the complete QRM lifecycle needs to be applied. For example, one might apply the risk assessment portion of the QRM lifecycle to help determine a commensurate depth of investigation for a process deviation or complaint, or to evaluate the appropriate frequency for preventive maintenance, calibration, or self-inspection. These applications of QRM do not necessarily require the totality of the lifecycle to be followed; rather, a risk assessment may be conducted to facilitate a decision without continuing into the risk reduction, risk acceptance, and risk review portions of the lifecycle. It is therefore necessary for firms to distinguish between living risk assessments, which follow the full breath of the QRM lifecycle and are generally more formal in nature, and ad hoc risk assessments, which may only address a portion or portions of the lifecycle and are generally (but not always) less formal in nature, depending on the risk question. This alleviates some of the administrative burden of a QRM program by focusing energy and resources (particularly within risk review) on the applicable portions of the lifecycle.

Living risk assessments should represent the core of the QRM program. These are performed on a product, process, or system, with the objectives of understanding the associated risks, controlling them to an acceptable level, and reviewing the risks in light of changing conditions to evaluate the continued relevance of the identified risks and the effectiveness of risk controls. Ad hoc risk assessments are likely to be performed as part of an integrated quality system to support risk-based decision making within specific contexts. These risk assessments need not be subject to risk review, but are often the input into the review of living risk assessments. Many companies struggle as they attempt to review risk assessments intended for risk-based decision making rather than for the QRM lifecycle, because related decisions have been taken and resultant next steps enacted. A mature QRM program addresses and embraces both types of risk assessments.

It follows, of course, that the products manufactured by a firm, as well as the facilities where these processes occur, should be subject to the full rigors of the QRM lifecycle, and therefore have living risk assessments associated with them. These represent the most direct link to the patient and should be continually evaluated in a QRM framework throughout their lifecycle. The question then becomes, what living risk assessments are necessary to ensure that risks to the patient are fully understood and controlled?

QRM Master Plan–proactively designing the portfolio of living risk assessments

A mature QRM program would have a clear picture of the minimum scope required to achieve holistic risk knowledge and would have established a QRM Master Plan to achieve this. For example, a firm may elect to use the approach commonly employed by medical devices, with one risk assessment (and QRM lifecycle initiation) each for the product, process, and use. Such a living risk assessment library might leverage platform processes and technologies and similarities in design and construction to cover the totality of product considerations and would be mindful to the myriad regulatory requirements and expectations for topics to be evaluated through QRM. An example of a complete living risk assessment library for current good manufacturing practice (CGMP) operations is provided in 

 Example of an optimized living risk assessment library for current good manufacturing practice (CGMP) operations. FIGURE IS COURTESY OF THE AUTHORS.

Some firms may already have an established portfolio of living risk assessments and be seeking to close gaps with new or changed regulatory requirements, expansion of product lines, or process variations.This is common, for example, with companies that manufacture sterile products as they seek to align with the updated Annex 1 requirements in the European Union. In this instance, the scope of the QRM Master Plan may be limited to the development of living risk assessments to support the contamination control strategy (CCS) as required by the Annex (4). To address the breadth of aseptic activities and information flow necessary to enable the CCS, a firm may focus their QRM Master Plan on three separate risk assessments: one focused on classifying interventions into the critical zone (ISO 5/Grade A), one focused on assessing hazards associated with all manufacturing and support processes, and one focused on assessing hazards associated with the classified areas of the facility and colocated clean utility distribution systems (drop points). Given the more narrow scope of this sort of QRM Master Plan, more detailed information such as the applicable risk question and QRM tool to be employed may be included, as illustrated in 

 Example of an optimized living risk assessment library to support the contamination control strategy (CCS). QRM is quality risk management. FIGURE IS COURTESY OF THE AUTHORS.

While the scope and contents of a QRM Master Plan may vary based on a firm’s level of QRM maturity and specific objectives, the critical thinking and planning necessary to compose the plan will serve as a guidepost for the organization’s activities, mobilizing personnel toward a common goal.

. The purpose section of the QRM Master Plan should describe the goal and intent of the plan. Depending on the individual firm’s current level of risk maturity and specific objectives, the goals might differ. For example, less mature firms may elect to focus on the development of a QRM process, governance structure, and training, while more mature firms may wish to focus on expanding an existing QRM program to additional aspects of the quality system. Similarly, some firms may need to develop living risk assessments only on a certain topic (such as contamination control) while others may need to develop the holistic risk library from scratch.

. The scope section should describe the boundaries of the QRM Master Plan and should use exclusionary language where necessary to describe elements or areas that are out of scope. This section may include, for example:

the site (or sites, buildings, etc.) to which the QRM Master Plan applies

products, product lines, and/or
systems to which the plan applies

product lifecycle phases to which the plan applies (e.g., development through Phase I,
commercial only, etc.)

types of risks covered by the plan (e.g., contamination related risks)

quality system elements included in the plan, if any (e.g., change control, deviation management, etc.)

It is recommended that the QRM Master Plan cover a timeframe spanning one to three years, enabling both short-term “quick wins” as well as longer-term strategic objectives to be outlined.

. This section of the QRM Master Plan should outline the roles and responsibilities for those working or interacting with the QRM program. Many firms have experienced success with the use of a responsibility assignment (RACI) matrix, which maps each role to a given activity according to whether they are Responsible, Accountable, Consulted, and/or Informed. The responsibilities and tactics or activities outlined in this section should directly correlate to the content of the plan; that is, all activities within the plan should be assigned to a specific role, and each responsibility listed should likewise have specific actions associated with it. This practice ensures clarity is provided to both the readers and users of the plan (

 Example responsibility assignment (RACI) matrix for quality risk management (QRM) Master Plan. FIGURE IS COURTESY OF THE AUTHORS. 

. The bulk of the QRM Master Plan should include a discussion of objectives and activities that will be completed under the plan, as discussed in the prior sections. This activities list can be composed both of new assessments to be performed in addition to risk review of existing assessments. Where many activities comprise the QRM Master Plan, it may be prudent to prioritize work using a risk-based approach, such that all stakeholders will understand the rationale for the cadence of tasks. One example of such a risk-based prioritization tool might involve the ranking of each activity for the criticality of the topic and the complexity of the effort (see 

 Example of topic criticality ranking criteria, for quality risk management (QRM) activity prioritization. FIGURE IS COURTESY OF THE AUTHORS.

 Example of effort/complexity ranking criteria, for quality risk management (QRM) activity prioritization. FIGURE IS COURTESY OF THE AUTHORS.

The intersection of the individual rankings for topic criticality and effort complexity can then located in the prioritization matrix to determine the relative priority of the activity (

 Example of QRM activity prioritization matrix. FIGURE IS COURTESY OF THE AUTHORS.

The relative priority of each QRM activity can be used, in addition to an analysis of activity interdependencies, critical path identification, and other considerations, to determine an appropriate timeframe for completion. This enables the firm to allocate resources toward the most appropriate activities to enhance QRM maturity and deliver a direct benefit to the patient. An example activity list using the above principles is shown in 

 Example activity list for quality risk management (QRM) Master Plan. FIGURE IS COURTESY OF THE AUTHORS.

A thoughtfully constructed QRM Master Plan translates the strategy established by leadership into actionable, prioritized tasks and enables a risk-based approach to the “QRM Initiation” step of the ICH Q9(R1) lifecycle, thereby ensuring the organization remains centered upon the things that matter most—protection of the patient.

Cox, B. Roche Builds Quality Risk Management Program in Response to Viracept Crisis. 

ISO 14971.“Medical Devices–Application of Risk Management to
Medical Devices.” 2019.

EC. Annex 1: Manufacture of Sterile Medicinal Products. 

Baseman, H. and Long, M. Risk Management of Microbial Contamination Control in Aseptic Processing and Interventions Risk Assessment Model (IREM): The Use of Critical Thinking to Make Informed Decisions. In 

Contamination Control in Healthcare Product Manufacturing

, Vol. 3, eds. Russell Madsen and Jeanne Moldenhauer, 341-404. Bethesda: PDA/DHI, 2014.

When referring to this article, please cite it as Waldron, K and Baker, T. Developing an Optimized Risk Assessment Portfolio—The Quality Risk Management Master Plan. 

A thoughtfully constructed QRM Master Plan translates the strategy and enables a risk-based approach. 

Developing an Optimized Risk Assessment Portfolio—The Quality Risk Management Master Plan

Cheryl Barton is director of PharmaVision, 

Cells and biological chain abstract concept. chemical molecule wallpaper | Image Credit: © Rosianna - Stock.adobe.com

Belgium-based Orionis Biosciences is a clinical-stage life science company developing conditionally acting medicines for cancer and other diseases. Its pipeline includes molecular glue drug modalities and targeted cytokine immunotherapies. Its proprietary allosteric molecular glues, Allo-Glues, are monovalent molecules that can target protein degradation (TPD) modulation, by inhibiting or promoting intracellular signals. Orionis’ agnostic Allo-Glues can be used to target proteins in hard-to-treat diseases, such as oncology and organ transplant rejection (1).

Molecular glues were first discovered in plants such as Arabidopsis thalian where they were found to stick proteins together (1). In 1971, researchers at Sandoz observed that Sandimmune could induce neo-protein-protein associations and impact protein degradation, and in 1983 Astellas (formerly Fujisawa) identified tacrolimus (FK506). Both agents have since been approved for use in patients to prevent organ transplant rejection (2).

Today, the most widely used molecular glues are monovalent small molecules (<500 Da) that bind to the surface of an E3 ligase receptor or DCAF15 to modulate protein degradation via the proteasome (3). However, biopharma companies have been actively screening for agents that can TPD and several classes have emerged including natural glues (e.g., FKBp12 F36V, FKBP12 PK1012, Rapamycin, Synstab A, Taxol), synthetic bifunctional glues (e.g., DDB1 Cereblon CK1a, Lenalidomide, Indisulam, Thalidomide), as well as novel proteolysis-targeting chimera (PROTAC) glues (e.g., ARV-110) and tacrolimus analogues (e.g., CEP250 FKBP12 and WD8002) (3,4).

Several molecular glues—Sandimmune, Tacrolimus, Sirolimus, Thalidomide, lenalidomide, Taxotere—have already demonstrated good immunosuppressive efficacy and tolerability in solid tumours and as gene therapies for acute leukaemia (3,5).

Orionis has several Allo-Glue programmes that focus on cancer and immunology targets, and and initiated a Phase I trial in November 2023 with its lead candidate, ORB‑011, a cis-targeted interferon for the treatment of patients with advanced solid tumours (6).

Big Pharma, including Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Merck & Co, and Novartis, have molecular glue programmes in development and forged collaborations with leaders in this field (

). For example, Orionis Biosciences has forged partnerships with Novartis and Genentech (7,8), and Austrian-based Proxygen has initiated collaborations with Merck & Co./MSD and Boehringer Ingelheim in multiple targets (9,10). In the United States, Nurix Therapeutics has teamed up with Seagen to combine TPD and antibody-drug conjugation (ADC) in cancer therapeutics (11).

Companies leading the field in molecular glues.

Competition is intensifying, and several Chinese and US biopharma companies are also working in this field and have products in preclinical and early clinical development. These include:

China-based Degron Therapeutics has raised US$34.5 million (€31.5 million) in venture capital and has more than 20 projects of unique molecular glue degraders (MGDs) targeting IKZF1 and IKZF3 using its proprietary GlueXplorer platform. The company expects to file an investigational new drug (IND) in 2024 for its lead programme.

US-based C4 Therapeutics (a spin-out from the Dana-Farber Cancer Institute) has developed its proprietary TORPEDO platform and developed MonoDAC and BiDAC degraders. Its lead candidate CFT7455 is currently in a Phase I/II clinical trial for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. In 2021, CFT7455 received an orphan drug designation from the US Food and Drug Administration (FDA) for multiple myeloma (13).

US-based Nurix Therapeutics is developing a Bruton Tyrosine Kinase (BTK) degrader, NX-5948 and NX-2129 in haematological cancer. Nurix has built DELigase, an integrated discovery platform to identify and advance novel drug candidates that can modulate proteins within the cell.

US-based Seed Therapeutics plans to file an IND in the US in 2024 for RBM30 in oncology and has several other agents in preclinical development that target neurodegeneration, immunology, and antivirals and has established an R&D collaboration with Eli Lily (14).

US-based BioTheryx in May 2023 presented new data on bifunctional degraders of CDK4/6 and SOS1 degraders. BTX-9341 for HER.

US-based Magnet Biomedicine is applying its proprietary TrueGlue technology to discover new indication-agnostic treatments and has attracted US$50 million (€46 million) Series A funding to move its pipeline forward.

US-based Monte Rosa Therapeutics has developed the QuEEN (Quantitative and Engineered Elimination of Neosubstances) targeting degrons on the surface of therapeutically relevant proteins that act as ubiquitin ligase recognition signals.

US-based Triana Biomedicines identifying novel E3 ligases. In January 2023, it was named the most promising new company in BioSpace’s NextGen 2023.

TPD using molecular glues has proven to be a powerful method for targeting traditionally undruggable proteins (15). Several molecular glues have received regulatory approval and many more are under clinical evaluation for a multitude of disease targets (14,16). Big Pharma have invested in this area, and biotech start-ups have attracted investor attention. Over the next few years, molecular advances in artificial intelligence and genetic tools will help drive the discovery and validation of novel bifunctional agents that could change the way pharma modulates protein interactions. Until then, pharma and private investors will have to wait patiently to see if Orionis Biosciences and its Chinese, European, and US-competitors can overcome the off-target effects of first-generation therapies and provide a more targeted approach to protein degradation and generate small-molecule proximity-inducing reagents, such as PROTACs and other unique molecular glues to treat cancers and other diseases (17,18).

1. Orionis Bioscience. Engaging the Powers of Nature with Precision Drug Design. 

, Accessed 7 Dec. 2023.
2. Schreiber, S.L. The Rise of Molecular Glues. 

; 184(1):3–9.
3. Alabi, S. Novel Mechanisms of Molecular Glue-Induced Protein Degradation 

; 60(31):2371–2373.
4. Di Stasi, A.; Tey, S.-K.; Dotti, G.; et al. Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy. 

; 365:1673–1683.
5. Békés, M.; Langley, D.R.; Crews, C.M. PROTAC Targeted Protein Degraders: The Past is Prologue. 

; 21:181–200.
6. Orionis Bioscience. Orionis Bioscience, Announces First Patient Dosed in Phase 1 Clinical Trial of ORB-011 in Patients with Advanced Solid Tumors. News release, 15 Nov. 2023.
7. Orionis Bioscience. Genentech Sticks Molecular Glue Deal with Orionis for $47M Upfront. News release, 10 Sept. 2023.
8. Orionis Bioscience. Novartis-Partnered Orionis Secures $55M to Push Cytokine Program into the Clinic. News release, 19 Oct. 2022.
9. Proxygen. Proxygen Announces Collaboration and License Agreements with MSD. News release, 5 April 2023.
10. Proxygen. Boehringer Ingelheim Collaborates with Proxygene. News release, 7 Dec. 2020
11. Nurix Therapeutics. Nurix Announces Strategic Collaboration with Seagen Combining Industry Leading Technologies of Targeted Protein Degradation and Antibody-Drug Conjugation to Advance an Innovative New Class of Cancer Therapeutics. News release, 7 Sept 2023.
12. Sasso, J. ACS Webinar on Molecular Glues and Targeted Protein Degradation. Webinar, 12 Oct. 2022
13. C4 Therapeutics. C4 Therapeutics Announces FDA Orphan Drug Designation for CFT7455 for the Treatment of Multiple Myeloma. News release. 11 Aug. 2021.
14. Seed Therapeutics. Pipeline. SeedTherapeutics.com, Accessed 7 Dec. 2023.
15. Fan, A.T.; Boyle, B.T.; Ferguson, F.M. A New Avenue for Molecular Glues: Rapid Discovery of an NFKB1 Degrader. 

;30(4):340–342.
16. Dewey, J.A.; Delalande, C.; Azizi, S.-A.; et al. Molecular Glue Discovery: Current and Future Approaches. 

;66(14):9278–9296.
17. Sternicki, L.M.; Poulsen, S.A. Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation. 

. doi: 10.1021/acs.analchem.3c03853.
18. Zhang, D.; Lin, P.; Lin, J. Molecular Glues Targeting GSPT1 in Cancers: A Potent Therapy 

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


Vol. 35, No. 9
September 2023
Pages: 18–19, 22

When referring to this article, please cite it as Barton, C. Harnessing the Power of Oncolytic Viruses. 

Novel molecular glues are transforming targeted protein degradation.

Frontrunners in Molecular Glues

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

While many stem-cell therapies remain at the preclinical stage, several are progressing through the clinic toward late-stage trials. Developing successful treatments based on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in part depends on creating effective formulations in which cell viability is maintained during cryopreservation, storage and handling, shipment, and reconstitution prior to delivery to the patient. Excipients, therefore, play an important role in bringing novel cell therapies to the market.

Buffers, stabilizers, and cryoprotectants

As with most biologic drug products, the predominant excipient in cell therapy formulations is the buffered saline solution. In this case, the saline solution is an osmotically balanced water solution designed to keep the cells from drying out and dying, according to Ryan Guest, senior CMC translation consultant for eXmoor pharma.

In addition to physiological saline, Carole Nicco, CSO at BioSenic notes that other isotonic solutions containing chemical substances present in blood, such as Ringer’s lactate, are also used to help maintain the electrolyte balance and keep the cells stable, sterile, and viable with proliferative capacity until their application. Furthermore, these isotonic solutions offer chemical easy systemic and local application, according to Nicco.

Classically, most formulations will also have protein to balance the solution as a buffer or reservoir for smaller molecules and enable transport via active protein transporters on cell membranes, Guest notes. The standard is an albumin (0.5–2.5%), such as human serum albumin. Albumin constitutes 50–75% of the colloidal osmotic pressure of blood (1–3) and performs a very similar role in MSC and iPSC formulations, Guest says. More specifically, albumin is a useful component in cell therapy formulations for balancing water availability during product hold times, cryopreservation, and thawing prior to product administration.

In fact, Guest observes that the presence of an equivalent protein in cell therapy formulations is predicted to have a significant impact on cell survival. In MSCs, for instance, the absence of an appropriate protein can reduce viable recovery by 20–40%, he comments.

The other important excipients for cell therapy products are cryoprotectants, given that the majority of these treatments are cropreserved. The cryopreservation of MSC- and iPSC-based therapies using 2–10% dimethyl sulfoxide (DMSO) in solutions containing a high content of serum is a common procedure, Nicco observes. She adds that while DMSO has been used to reduce the formation of ice in cells stored in liquid nitrogen since 1959, it is toxic, resulting in undesired clinical and biological side effects. Serum also introduces variation and safety risks.

“There is, consequently,” Nicco says, “a move toward solutions containing bio-preservation media free of DMSO, serum, and other proteins, optimized for the preservation and distribution of these products at low temperatures, either in cold (2–8 °C) or cryopreserved conditions (-70 °C to -196 °C).” The new excipients, she explains, eliminate toxicity issues as well as the need for human product excipients (serums, proteins) that can induce a risk of contamination to the drug product. Complex formulations involving dextran-40, lactobionate, sucrose, mannitol, glucose, adenosine, and/or glutathione are examples, according to Guest.

Intended application key driver of excipient choice

The type of stem cell therapy generally does not impact the choice of excipients, although Guest does note that some iPSCs can be more acutely sensitive to the final formulation, hold times, and routes of administration. For example, anucleated products, specifically designed to deliver payloads, have a reduced capability to produce proteins or perform cellular repair. Nicco adds that iPSCs and cells differentiated from them are commonly multicellular systems, which she says also makes them more sensitive to the stresses of freezing and thawing than single cells.

Overall, however, similar types of excipients are used for the preservation of cell-based therapies, regardless of the cell type or method of manipulation, according to Nicco. “It is the route of administration, the need for transport, and the storage temperature that influence the choice of excipients,” she states.

Special applications, for instance, such as therapies for artificial skins and wound healing may have specific properties or additional ingredients for sealing the wounds, Guest notes. Hence, the excipients or scaffolds are part of these therapies. Dosage size is another important factor, he adds. “Larger doses need to take into account any toxic side effects of the excipients, such as DMSO, and may place maximal limits upon the total volume of excipients to be administered,” he observes.

Always consider the route of administration and freezing requirements

One of the most critical issues for cell therapy manufacturers is the maintenance of the cells in an appropriate medium/excipient from the end of the culture until the time of administration to the patient. “Not only should the medium keep the cells viable with their properties intact, but the route of administration must also be taken into account,” Nicco states. She adds that a good excipient “is solvent-free and suitable for fresh or frozen suspensions of living cells formulated in a proprietary formulation adapted to the route of administration, such as intravenous, intra-articular, or intracranial.”

In addition to understanding the delivery mechanism, Guest stresses the importance of considering the container and dose when choosing excipients. The next important factor, he says, is whether the cell therapy product will be supplied frozen, as that will require selection of a cryoprotectant. Formulation development experiments should then be designed carefully to optimize potency while taking into consideration hold periods and freeze/thaw steps and eliminating or otherwise minimizing the use of diluents and wash steps. In addition, Guest recommends evaluating existing administration formulations, containers, equipment, and protocols to minimize the need for new or changes to clinical practices.

An important component of any formulation strategy is consideration of the raw materials.For excipients intended for use in cell therapy products, Guest emphasizes the need to identify available good manufacturing practice (GMP)-suitable sources with acceptable lot-to-lot controls that will enable a reproducible product formulation. It is also critical, he says, to confirm the material is suitable for the manufacturing process and will be available to meet manufacturing demand for the cell therapy throughout its product life cycle.

Equally important, Guest observes, is to ensure the availability of suitable cellular material and drug product for designing formulation experiments. Understanding the patient group and the intended administration route are essential, meanwhile, for identifying potential side effects of any excipients.

Compendial excipients are generally preferred, Guest continues, due to the risk that novel or untested solutions will require significant development to ensure the material does not impact upon the therapeutic benefit of the cellular material. In addition, all materials including excipients must be suitable for the intended route of administration and present minimal risk of inducing toxicity, immune reactions, or the transfer of adventitious agents.

Assessing formulation stability and quality

Controlling cellular material from the point of “optimal” donor selection to manufacturing under GMP conditions, commercialization, and application is critical for ensuring the quality, safety, and efficacy of the final drug product. While MSCs used as starting materials for production of advanced therapy medicinal products can only be isolated in authorized centers using globally standardized processes, the optimal conditions for culturing isolated MSCs are not standardized. That poses a major challenge in controlling their quality and therapeutic properties, Nicco contends.

It is, therefore, essential to control the cell sources (e.g., bone marrow, umbilical cord, and adipose tissue), cell density in culture, duration of culture, and cell engineering and composition of culture media and implement in-process quality controls that ensure cell efficacy and safety at all stages of manual and automated manufacturing processes, including cryopreservation, use of cell banks, and transport systems. “Ultimately, the stability and quality of the cell therapy product and the excipients it contains must always be evaluated against reference samples submitted to the same storage facility,” emphasizes Nicco.

Complicating this situation is the fact that it can be difficult to find reliable mode-of-action potency methods for cell-based therapies, according to Guest. “Often both 

 models are required to confirm the suitability of the formulation,” he says.

In addition, formulation strategy, hold times, cryopreservation, and thawing are intrinsically linked, and it can be difficult to determine the impact of each component of the formulation, Guest observes. “Doing so requires carefully designed experiments and suitable analytical methods that assess not only the impact of formulation changes and freezing and thawing processes, but downstream biological mechanisms such as apoptosis and necrosis, which require time in a suitable cell-culture facility or 

 models to optimize formulations,” he explains.

“A further difficulty rests with the fact that viability determinations are often tied to the analytical methods, the technicians performing them, and whether biological mechanisms of apoptosis and true cell recoveries are accounted for in the testing strategy,” Guest comments. Therefore, it is important for cell therapy developers relying on external testing laboratories to ensure those outsourcing partners have the proper understanding, expertise, and capabilities needed for appropriate and comprehensive testing.

Advances in cell therapy formulation science underway

The cell therapy field is expanding at a rapid rate, and technology is advancing to support the increasing breadth of treatments under development. That includes formulation science and the development of enhanced excipient solutions. Cryoprotectants developed through biomimicry of natural antifreeze proteins to replace DMSO and serum protein-based media are one example highlighted by Nicco.

More work is to be done in this area, however. “There is a clear unmet need for the discovery and development of novel cryoprotectants that can either replace or reduce the required amounts of current gold standards formulated to protect and treat challenging sample types such as MSCs and, even more, iPSC multicellular systems. This multivariate problem is complex, with multiple mechanisms of damage to be addressed and subtle differences between cell types and freezing methods. Combining high-throughput testing with iterative computational algorithms is key to optimizing protocols and excipient formulations to preserve emerging cell-based therapies,” Nicco comments.

Guest, meanwhile, predicts that as the cell therapy field advances, clinical practice will naturally standardize formulation, delivery, and routes of administration through product safety and efficacy data. “That will include the use of animal-free or recombinant excipients and other fit-for-purpose additives developed through the use of artificial intelligence to minimize cytotoxicity while improving stability and hold times,” he states.

Nicco is also confident that the combination of new technologies such as intelligent library design, computational modeling, rapid screening assays, and advances in genomics will lead to a better understanding of the structure-function relationships between drug and excipient. “That greater understanding will lead to more effective and efficient excipients that afford higher-performing cell therapies and ultimately benefit both cell therapy developers and patients,” she concludes.

Valerio, C.; Theocharidou, E.; Davenport, A.; Agarwal, B. Human Albumin Solution for Patients with Cirrhosis and Acute on Chronic Liver Failure: Beyond Simple Volume Expansion. 

 Mar 8;8(7):345-54. doi: 10.4254/wjh.v8.i7.345. PMID: 26981172; PMCID: PMC4779163.

Buffers, stabilizers, and cryoprotectants play major roles in cell therapy formulations.

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