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

 in 2014, Adam Goulder has over 30 years' experience within the maintenance engineering and asset management sectors including Pharmaceutical and Medical Devices manufacturing. As Head of Project Management and a Principal Consultant Adam oversees the management and implementation of enterprise asset management solutions to a wide range of organisations across the Pharmaceutical, Medical Devices, Healthcare, Logistics, Facilities Management, Utilities, Oil & Gas, and Transportation sectors. Adam is a Chartered Engineer, holds an MSc in Maintenance Engineering and Asset Management from the University of Manchester and is a member of the International Society of Pharmaceutical Engineers.

Cloud technology. Integrated digital web concept background | Image Credit: © kras99 - Stock.Adobe.com

According to the Cloud Industry Forum’s (CIF) 2023 annual report, 95% of businesses across the public, IT and technology, financial services, retail, and manufacturing sectors are now operating within the cloud, in one form or another (1). This figure highlights the rapid growth of the technology, which saw the global market value reach more than $569 billion in 2022 and is estimated to exceed $677 billion (2) in 2023 expanding at a compound annual growth rate o

Further findings from the survey also revealed that 55% of those polled are now operating a hybrid (cloud and on premise) approach, while “42% are embracing a cloud first strategy” with “96% saying their cloud strategy has delivered against expectations” (1).

Growth of the technology in the pharmaceutical industry is slower, however. Globally, uptake in the sector was valued at $4.8 billion in 2022, and reports suggest that growth will be around over 13% in 2023(3). While this growth does show acceptance of the technology by those working in the industry, it highlights that the sector is behind in its adoption compared to other major industries.Those companies in the sector that have transitioned to a cloud-based environment though have been reaping the benefits, which includes enhanced data analytics, reduced time required for innovation, and establishing standardized processes across sites.

While the benefits are well reported, these findings do raise the question, ‘Why are pharmaceutical companies reluctant to adopt cloud technologies?’

Several reasons are commonly given for why pharmaceutical companies don’t adopt the cloud. These reasons include regulatory compliance, data security, data privacy, costs, risk aversion, and data sovereignty.

The reality is that while there is a framework already in place to guide pharmaceutical companies around the implementation and use of cloud technologies, for example the International Society for Pharmaceutical Engineering’s (ISPE’s) Good Automated Manufacturing Practice (GAMP) guides, the industry’s hesitance to invest into new systems and its “late adopter” approach when onboarding new technology is slowing the sector’s widespread adoption of this hugely beneficial technology.

Data security as well as data privacy laws like the European Union’s (EU’s) General Data Protection Regulation (GDPR) or the US Health Insurance Portability and Accountability Act (HIPAA) demand that cloud providers are compliant with these laws. Requirements include consideration and controls related to geopolitical jurisdiction of data, and where they reside can provide compelling reasons for some multinational pharmaceutical companies to adopt the cloud and avoid the difficult decisions right now.

Though dependent on the benefits and risks of the overall program of work, cost will always play a part of a final decision to some greater or lesser degree. Pharmaceutical companies must ultimately ensure their products and services are compliant with regulations such as 

 (6), as well as others, and thus going with a legacy technology platform that is understood but less efficient or less flexible in the short term, may be perceived as less risky than adopting new technologies such as the cloud. The typical approach taken by many pharmaceutical companies has been to adopt the cloud where patient safety is not directly impacted and the systems that are deployed on them are of a lower risk (such as marketing, training), and only after a period of stable use, will a wider adoption to host production and patient safety critical systems occur.

With the qualification criteria of any patient safety system so stringent, delays to resolve issues or acceptance of defects often allowed in other industries are generally not permitted in the pharmaceutical sector. This added burden of resilience and efficacy often sways organizations from making the decision and postponing until confidence or circumstance force their hand.

Reasons behind the industry’s reluctance to widespread adoption of the cloud

The pharmaceutical industry’s hesitance to fully embrace cloud technologies, and digital transformation, can be boiled down to three concerns: regulatory, solution efficacy, and the underlying cost of validation.

It is not an understatement to say that adopting new systems can be a large undertaking, and just like any other organization, the switch can come at a significant cost, both in terms of the outright purchase, license, and support, but also the cost of integrating these into the existing business. These costs for example may include extended training, new hires, and their related onboarding, in addition to upgrading of existing infrastructure to allow the new systems to be able to work with each other. Furthermore, the industry’s need to manage risk and ensure their systems are verified and validated also demands significant time and a sizeable investment, adding to the challenge of the rapid adoption of digital technologies. Numbers can vary dramatically, but in the author’s experience between 25% and 40% of the overall software implementation budget for a cloud hosted solution is spent on the qualification and validation of the solution. This significant proportion of the overall project cost can at least delay the investment decision and at worst halt them altogether.

There is also the perceived risk with adopting new, “fresh out of the box” systems, and the associated effort in identifying the necessary tests and operational controls to ensure confidence and compliance of the system. These controls must ultimately ensure that any doubt in the systems efficacy is covered by reliable processes, procedures, and systems to mitigate the potential for failure.

As a result of this expansive effort and suitable controls, the pharmaceutical industry generally falls into the “late majority” technology adopter category by not utilizing new technology until it has proven its worth over time and thus has shown demonstrable reliability and extensive uptake in the market before doing so. This approach often results in staying locked in a technology path which “works” but which runs the risk in the long term of becoming out of date and a liability for future migration into the cloud.

Globally, cases exist of pharmaceutical companies operating on legacy and thus no longer supported infrastructure and systems—hoping that they continue to work until the decision to replace or upgrade is taken. As regulation advances, however, the assessment and subsequent decision to remain on these legacy platforms will become less likely until such time that a decision to move must be taken at all costs.

However, here are successful examples (7) of pharmaceutical companies utilizing cloud hosted systems in the development of drugs. In 2021 for example, UCB partnered with Microsoft, using its cloud and artificial intelligence (AI) solutions to improve the development of drugs in immunology and neurology. During the same year, Pfizer partnered with AWS to utilize machine learning and cloud capabilities to streamline its drug discovery and development efforts. It is therefore possible that the switch to cloud-based solutions can lead to significant benefits.

Other recent challenges facing the pharmaceutical industry

Like many sectors over the past few years, but more so for the pharmaceutical industry, the impact of COVID-19 has challenged the way in which business operates and tested processes and systems sometimes beyond their designed capabilities. This momentous challenge forced change and set deadlines beyond what was thought possible to an industry that measured success in delivery of drugs and vaccines in years not months that ultimately meant companies had to adapt far more quickly than what they would have historically done—with the cloud playing its part in enabling this rapid transformation.

Cloud-based systems allow organizations to securely capture and share clinical data far more rapidly. The unprecedented global health crisis prompted several changes within the industry that supported the acceleration of cloud-based operations and resulted in the delivery of vaccines around the world in record time. These included cloud-based remote R&D laboratories and supported secure collaborations and sharing of data between different research teams to streamline and accelerate the development phase of the program.

The cloud enables pharmaceutical companies to face such challenges as described above, head on, by supporting their regulatory compliance needs through the delivery of a secure and reliable platform that underpins and supports their validated systems. Reliable cloud-based systems provide scalable real-time monitoring, data analytics, and predictive maintenance that detects performance changes alerting support staff of potential problems before they become issues to end users.

Furthermore, auditing and security features inbuilt within cloud platforms ensure data are safe and secure, giving pharmaceutical companies the reassurance that their data are compliant and that the systems are capable of scaling and adapting to cope with the pharmaceutical businesses future needs. The next COVID event may be just around the corner, and business continuity plans and risk mitigation strategies should factor in those tools that provide support for scaling up to meet demand and secure collaboration when required.

Cloud computing allows for scalable and cost-effective storage resources that can also support a common platform streamlined validation approach. However, choosing the right partner to implement those systems, one who has the right level of expertise and experience is considered essential to save on the cost and onboarding and mitigate concerns when implementing a new cloud based digital system.

The right partner can support user and system requirements definition, testing, and qualification and validation activities, thereby reducing the operational impact on the pharmaceutical company. Following implementation, this transfer of responsibilities to the cloud platform provider reduces business overhead and time necessary to manage these complex systems. With less physical infrastructure, the responsibility for the pharmaceutical company should reduce, with the pharmaceutical company more able to focus efforts on the management of change and transition to cloud focused operations, thereby maximizing the benefits of security, accessibility, and integrity of data with an overall reduction in operational overhead.

While the benefits of widespread cloud adoption are clear in terms of efficiency, scalability, and collaboration and rewards achievable, the sector’s hesitant approach is clearly rooted in valid concerns around data security, regulatory compliance, cost, and the ability to partner with a knowledgeable and reputable service provider to successfully make the change happen.

However, the industry and pharmaceutical landscape is evolving, and several industry leaders have already recognized the potential that the cloud can have on the sector. It is anticipated that interest in cloud adoption within the industry will continue to grow in the coming years, which will pave the way for an industry that is secure, compliant, and has the ability to scale and adapt at pace to meet the challenges that will be presented in the future.

Cloud Industry Forum: Breaking New Ground with Cloud. 

Research Report (April 2023).
2. Fortune Business Insight. 

Cloud Computing Market Size, Share, and COVID-19 Impact Analysis, by Type, by Service, by Industry, and Regional Forecast, 2023–2030

. Market Report, May 2023.
3. Industry Research. 

Cloud Computing In Pharmaceutical Market in Pharmaceutical Industry Research Report 2023, Competitive Landscape, Market Size, Regional Status, and Prospect

Market Report, September 2023.
4. European Commission. 

Good Manufacturing Practice and Good Distribution Practice

. Guidance Document, Dec. 18, 2014 (updated Dec. 27, 2020).
6.

Electronic Records; Electronic Signatures

. March 20, 1997.
7. GlobalData. The Impact of Cloud Computing on the Pharmaceutical Industry. 

When referring to this article, please cite it as Goulder, A. Why Are Pharmaceutical Companies Reluctant to Adopt Cloud Technologies? 

Articles

Despite its understandable hesitancy, the pharma industry is facing a need for more widespread adoption of cloud-based solutions.

Why Are Pharmaceutical Companies Reluctant to Adopt Cloud Technologies?

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

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Between 10 and 17 May 2025, European eyes, and indeed eyes from all over the world, will be set on Basel, Switzerland for the 69th Eurovision Song Contest, where creativity and talent are celebrated in a multi-show spectacular! The first ever Eurovision Song Contest was held in 1956 in Lugano, Switzerland, and while there were only seven nations competing against each other for the inaugural competition, the Swiss came out on top and won (1).

The contest’s return to the country it was founded in, Switzerland, was too good an opportunity for Swiss pharma giant, Novartis, to miss. While it may seem an unusual pairing—Big Pharma with a music competition—the company is seeking to use this global platform to promote its broader campaign of “reimagining medicine, together” (2).

“Novartis is honoured to be an official partner of the 2025 Eurovision Song Contest in Basel—our home city. Both our organizations were born in Switzerland and believe deeply in the power of collaboration and bringing people together,” said Rob Kowalski, chief people & organization officer for Novartis, in a press release (3).

Indeed, the power of collaboration is a critically important for the bio/pharma industry—a detail that was proven during COVID-19 when collaborative efforts helped push therapeutic advances forward to the benefit of patients around the world. On a personal note, when reflecting on the fact that this is my last issue of 

, I must agree that working closely with many industry experts has been key to ensuring success throughout my various editorial roles over the years. And, as I prepare to depart my wonderful Pharmaceutical Technology Group colleagues for my next professional adventure, it will be the relationships and collaborations that I will celebrate most!

So, eagerly awaiting this year’s Eurovision Song Contest extravaganza, I wish Switzerland’s entry, Zoë Më, ‘bon chance’ for their song ‘Voyage’ as I set off to embark on my own new voyage with new collaborations.

Eurovision Song Contest. The Origins of Eurovision. 

Novartis. The 2025 Eurovision Song Contest. 

Eurovision Song Contest. Novartis Announced as ‘Official Partner’ for Basel 2025. Press Release, 31 Oct. 2024.

Felicity Thomas is Associate Editorial Director of PharmTech Group.

When referring to this article, please cite it as Thomas, F. A New “Voyage”. 

The power of collaboration is a critically important for the bio/pharma industry.

A New “Voyage”

Medical background. many capsule tablets or pills on blue table. Glass vials. Vaccine. Close up. Healthcare pharmacy and medicine concept with copy space Painkillers or prescription drugs consumption | Image Credit: ©taniasv - stock.adobe.com

The landscape of treatment for medical conditions and illnesses has become tailored and rich thanks to advances in personalized medicine, artificial intelligence (AI), and emerging modalities. Cell and gene therapies have been joined by messenger RNA (mRNA) vaccines in pushing innovation in the field of drug dosage forms. New manufacturing trends have also spurred the drive for new ways to deliver life-saving medicines.

“A confluence of innovative technologies is reshaping the healthcare market. Among these cutting-edge approaches, [AI], data analysis and management, blockchain technology, real-world data utilization, cybersecurity, and continuous manufacturing processes stand out as driving this paradigm shift,” says Jnanadeva Bhat, vice president at ACG Capsules (R&D). “These technological catalysts are not only bolstering medication delivery but also propelling forward the entire spectrum of development, packaging, and final product distribution to end consumers. Pharmaceutical industries are making up these newer technologies for innovation in healthcare.”

Tailoring dosage forms to individual patient needs is becoming a reality, confirms Ramesh Subramanian, chief commercial officer at Aragen Life Sciences. Treatment efficacy can be improved by customizing formulations based on genetic profiles and patient-specific requirements, which may minimize side effects, he emphasizes.

A shift in patient attitudes is also influencing innovation in dosage forms, according to Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette. “Compared with 10, or even five years ago, consumers are far more discerning about the types of drugs or individual ingredients they allow into their bodies,” says Verhaeghe. “This [change] is reflected in the demand for improved digestibility and convenience, personalized treatments in fields such as oncology, endocrinology, and infectious diseases, and especially in the recent ‘vegan revolution.’ The latter, in particular, has had implications for established drug formats like softgels. [Because] the traditional excipient of choice—animal-derived gelatin—is unsuitable for vegan or vegetarian applications, brands have turned to cutting-edge technologies, like first-of-its-kind hydroxypropyl pea starch…Such excipients are unlocking the potential to create high performance, planet-friendly plant-based drugs that are easy for consumers to swallow—both literally and metaphorically.”

Patient adherence is also making an impact on the development of dosage forms. “For decades, patient groups, including children, the elderly, and people who experience issues swallowing, have had no choice but to use medications that are inconvenient, difficult, or even dangerous to take. At best, this can lead to pill fatigue, and at worst complete non-adherence,” says Verhaeghe.

Permeability is also causing an impact on dosage form choice, according to Lisa Caralli, senior director, Scientific Advisory at Catalent. “Addressing permeability limitations for peptides and biomolecules has been an area of intense focus in recent years, with the modulation of tight junctions with excipients remaining a key approach,” she says. “First pass metabolic loss for small molecules will also drive the use of the injectable route, whereas pregastric delivery through the mouth with dosage forms such as orally disintegrating tablets remains an under-explored area to address this metabolic concern.”

Ishani Maharaj, application development specialist, pharma ingredients at Univar Solutions, also points to issues with API solubility and permeability as pushing the demand for improved formulation strategies. The use of solubility and permeation enhancing excipients allows for APIs with improved bioavailability and increased efficacy, she explains.

“To formulate these APIs as solid dosage forms, there have been promising strategies such as amorphous solid dispersions (ASDs), co-processed APIs, and lipid-based formulations (LBF),” continues Maharaj. “With the use of a lipid base delivery system consisting of a solvent, surfactant, and co-surfactant, a self-emulsifying delivery system can be formed in the digestive tract. This
[delivery system] allows improved dissolution of the drug within micelles and for better systemic absorption of the water-insoluble API. Choosing the right components of a lipid-based delivery system for a particular API can be complex. To address this, excipient manufacturers are now delivering ready-made lipid-based pre-concentrates to simplify this process for formulators.”

New technologies are also making an impact on dosage form development. Manali Dalvi, lead–White Papers & Publications at ACG, points to the integration of three-dimensional (3D) printing as one of the innovations creating new capsules that can be tailored to individual patients. “This breakthrough empowers manufacturers to effectively address the unique therapeutic needs of each patient,” says Dalvi. “Moreover, capsules also offer fresh perspectives on fixed dose combinations, introducing flexibility in the composition of capsule inner content. This versatility opens the door to a wide range of potential constituents—ranging from powders and pellets to semisolids and various liquid forms (solutions, suspensions, emulsions)—to be encapsulated within,” she notes. “As the field continues to advance, it has become imperative for pharmaceutical manufacturers to stand at the forefront of this transformative shift, driving innovation and personalized care forward.”

Developments in advanced and complex therapies have seen a surge in recent years. Bhat points to advances in genetics, molecular biology, and biotechnology as the drivers of these new treatments.

“Many researchers are eager to capitalize on these scientific breakthroughs,” asserts Bhat. “Complex therapies such as gene and cell therapies have the potential to offer advance treatment for the diseases that have been challenging to address with conventional medication. For example: cancer, heart disease, and cystic fibrosis. Many pharmaceutical companies have successfully developed and commercialized complex therapies, gaining the competitive edge in the sector, positioning themselves as leaders in medical innovation.”

Complex and advanced therapies often come with manufacturing and patient adherence challenges. How can industry meet these challenges?

The challenge of bioavailability is often seen in newly developed APIs, which exhibit poor solubility and where adequate dosing in a convenient dosage form is difficult, according to Verhaeghe. “This presents significant challenges, both in terms of manufacturing and end-user compliance,” he says. “But drug developers are fighting back with some truly ingenious approaches. One of the most exciting examples has been the expanded interest in specialized and co-processed excipients as processing aids and final-formulation ingredients. Cyclodextrins, for instance, have delivered great results in this area—their molecular encapsulation properties and affinity with complex molecules helps simplify formulations, increase solubility, and assure stability.”

Nick DiFranco, MEM, Global Market Manager, Novel Pharmaceutical Technologies at Lubrizol, agrees. “Complex therapeutics often involve challenges such as poor solubility or a high dose of drug. These challenges require efficient excipient technologies to solubilize compounds, control drug delivery without resulting in a tablet that’s too big to swallow, or avoid injections with extensive infusion times,” he says. “For example, if an oral tablet formulation is not optimized, patients may need to take tablets three or four times a day to achieve a desired therapeutic effect. Using excipients that enable high drug loading and/or control over release can increase the amount of drug per tablet while minimizing side effects, which reduces pill burden and offers huge benefits to patients. These excipient technologies don’t necessitate complex manufacturing techniques either.”

A multi-faceted approach can be used to address these challenges, according to Subramanian. “These innovations not only improve patient outcomes but also facilitate the development and commercialization of these advanced therapies,” he says. “Complex therapeutics often require specialized delivery systems, such as liposomes, nanoparticles, or microspheres that can improve drug stability, bioavailability, target specific tissues, and control release rates, enhancing the therapeutic effect.”

By way of example, Subramanian highlights nano-based formulations, 3D printing, and novel excipients as useful tools. “Nano-based formulations can enhance the therapeutic efficacy of complex drugs and reduce side effects,” he remarks. “3D printing is another technology that can help meet the dosage form requirements of complex therapies and bring formulation manufacturing closer to patients. [The technology] allows for precise control over the structure and composition of dosage forms and enables the creation of customized and patient-specific dosage forms, which is particularly valuable for complex therapies. The development of novel excipients can enhance the stability of complex therapeutics and improve their manufacturability. These excipients may be used to protect sensitive compounds or modify drug release profiles.”

Additionally, Subramanian points to quality by design as a tool in the development of complex dosage forms that uses a systematic approach to formulation to meet quality and performance requirements.

Filipe Gaspar, VP of Technology Intensification at Hovione, points to the company’s search for new technologies to deliver new modalities instead of technologies that come with limitations in formulation options, such as freeze drying. “Precise control over particle size and density, coupled with formulation design, is an enabler for high dose and low volume injections maximizing patient compliance,” he says. “At a much more mature phase is the use of respiratory delivery (inhalation and nasal) for biopharmaceuticals using spray drying technology which offers ample formulation options. Developing a highly efficient delivery device and product combination which ensures that an unskilled patient receives the intended effect is as important to address.”

The growth of the biologics market and patient-centric dosage forms have promoted the development of parenteral formulations and long-acting injectable products, according to Maharaj. “Injectable dosage forms are adequate when assessing the balance between benefit and inconvenience. The pursuit of convenient and reliable devices that can simplify injection procedures and give autonomy to patients can be a promising strategy to deliver such complex medicines in a patient-friendly way. Wearable devices such as a microneedle autoinjector could be a good candidate for delivering these larger molecules such as proteins, peptides, and monoclonal antibodies,” she says.

Delivering high-value biologics orally, however, will be a priority for the industry, continues Maharaj, because it is non-invasive. Delivery methods for biologics that are not readily absorbed after oral administration, however, will also be explored, she remarks.

“For example, monoclonal antibodies (mAbs) have a variety of potential therapeutic applications in autoimmune diseases and cancers. The dosage form remains a major obstacle for mAbs as frequent intravenous administration can reduce patient adherence,” says Maharaj. “Subcutaneous administration promises improved patient convenience and compliance due to the possibility of self-administration by patients, less visits to the hospital, and low healthcare costs.”

A push from regulators to develop advanced therapies also gives incentive for sponsor companies to invest in technologies and processes for complex therapies. FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME) allows for agency review of novel excipients, which “will foster development of excipients that may be useful in scenarios in which excipient manufacturers and drug developers have cited difficulty in using existing excipients” (1).

“Novel excipients can be the key to producing products with improved bioavailability and reduced side effects,” says Caralli. “For example, surfactant excipients are often used to solubilize molecules with low aqueous solubility, or to form emulsions. However, some of these excipients are known to cause a hypersensitivity reaction in some patients, therefore, by using alternative forms that do not induce this reaction could provide a better and safer patient experience. Another area is innovation in polymers used for amorphous systems: highly crystalline drug substances can be transformed into their amorphous state, and stabilized with polymers to improve in-vivo solubility, and therefore, bioavailability. Novel polymer systems that can be used at lower processing temperatures in hot melt extrusion may reduce drug degradation and improve processability.”

Technologies being adopted in laboratory hardware and data analytics are accelerating the development of dosage forms, according to Gaspar. “[Laboratory hardware] enables fast optimization, and [data analytics] transform the continuous accumulation of data (experience) into knowledge that can be multiplied for every new drug under development,” he says.

Gaspar points to continuous manufacturing of oral dosage forms as an example of a way to utilize data analytics because of the rich data environment and sophisticated process equipment and process analytical technology. “Scientists and engineers can interact with such a broad data environment and build sophisticated models that are normally used in control strategy definition, while also monitoring the manufacturing process not just with a few selected process parameters, but potentially with the full process data that can be analyzed by multi-variate methods to inform potential faults in real-time,” he notes. “During drug product development, it facilitates execution of extremely fast [design of experiments] and exploration of a design space.”

Caralli believes AI will play a pivotal role in drug dosage design. “[AI’s] ability to quickly synthesize current research will dramatically increase the speed of bringing new ideas into reality. [AI] could assess current dose design trends, based on patient populations and indication, allowing the optimization of drug administration, and ultimately increasing the rate at which drugs advance into the clinic,” she says.

However, Caralli cautions that AI-generated information may not be completely reliable. “Firstly, it may be detrimental to true innovation as it becomes easier to build on the ideas of others rather than generate new ones; and additionally, there is a need to override the natural impulse to publish studies showing what has been successful, versus what has not to avoid generating a biased data set. The industry may find itself becoming too trusting in the seemingly confident answers generated by AI, that it may not apply human skepticism, which is an important part of the scientific method,” she summarizes. “However, as the ability to identify trends through AI improves, the safety benefits to patients may ultimately outweigh the risks to innovation.”

1. FDA. Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME). 

®
Vol. 48, No. 3
March 2023
Pages: 12-14

When referring to this article, please cite it as Haigney, S. Reshaping Dosage Forms. 

Advancements in personalized medicine and other innovations are transforming the way dosage forms are viewed.

Reshaping Dosage Forms

Gayatri C.Patel, M.Pharm, PhD, is associate professor in the Department of Pharmaceutics & Pharmaceutical Technology, Ramanbhai Patel College of Pharmacy at the Charotar University of Science and Technology, Changa Campus, Changa- 388 421, Anand, Gujarat, India, gayatripatel.ph@charusat.ac.in, +91 2697 265162.

Divyangi Patel is a research scholar at Charotar University of Science and Technology, Ramanbhai Patel College of Pharmacy, Department of Pharmaceutics & Pharmaceutical Technology, CHARUSAT Campus, Changa-388421, Gujarat, India.

Round white pills and plastic pill bottle | Image Credit: © ironstealth - Stock.Adobe.com

Submitted: June 8, 2023.
Accepted: January 5, 2024.

Cefpodoxime proxetil (CFPD PRXL) is a third-generation cephalosporin antibiotic with broad-spectrum activity. However, its bitter taste often leads to poor patient compliance. This study aimed to develop a taste-masked drug resin complex (DRC) using the ion exchange resin Kyron T-114. Various variables, including resin ratio, pH, temperature, soaking time, and stirring time, were investigated for their impact on drug loading and taste reduction. A dispersible tablet was then formulated using the DRC and other pharmaceutical excipients. The formulated tablet underwent evaluation for weight variation, hardness, dimension uniformity, friability, content uniformity, wetting time, 

 drug release. Results demonstrated that the wetting and disintegration times of the tablets, as well as the 

 drug release, were comparable to those of the commercially available CFPD PRXL product. In conclusion, the developed method for taste masking CFPD PRXL and preparing orodispersible tablets proved to be simple, cost-effective, and potentially suitable for industrial application.

Cefpodoxime proxetil (CFPD PRXL) is a third-generation cephalosporin antibiotic with broad-spectrum activity commonly prescribed in both solid and liquid forms to treat various bacterial infections, including upper respiratory infections, ear infections, skin infections, and urinary tract infections (1–3). However, its extremely bitter taste poses a challenge for patient compliance, particularly among pediatric and geriatric populations. Solid dosage forms such as tablets are frequently used for these patients (1–3).

Ion exchange resins are solid, high-molecular weight polyelectrolytes that can reversibly and stoichiometrically exchange their mobile ions with the surrounding medium. These resins are available in various sizes and can be utilized to adsorb bitter cationic drugs onto weak cation exchange resins containing carboxylic acid. This interaction forms a complex that effectively masks the bitterness of active ingredients (4). Resinates can then be formulated into lozenges, chewing gum, suspensions, or dispersible tablets, effectively concealing the taste (3).

The binding of drugs to the resin can be achieved through repeated exposure or prolonged contact with the resin. By forming weak ionic bonds between the drugs and the oppositely charged resin substrates or resinates, the drug-resin complex (DRC) remains stable under salivary pH conditions, successfully masking the unpleasant taste and odor of the drugs.

The objective of this study was to incorporate the DRC into a dispersible tablet to enhance patient compliance (5–6). In a previous study, the preparation and evaluation of the DRC was performed using Kyron T-114, a weak acid derivative of methyl acrylic acid cross-linked polymer having a carboxylic acid functional group, which is responsible for its taste masking property for a pharmaceutical suspension; however, its use in tablet formulation was not investigated. Therefore, the specific objective of this present study was to develop and evaluate an orally disintegrating tablet (ODT) of CFPD PRXL using the optimized DRC that were utilized for suspension formulation (6).

 is a research scholar, both at Charotar University of Science and Technology, Ramanbhai Patel College of Pharmacy, Department of Pharmaceutics & Pharmaceutical Technology, CHARUSAT Campus, Changa-388421, Gujarat, India.


*To whom all correspondence should be addressed.


Vol. 48, No. 3
March 2024
Pages: 22–26

When referring to this article, please cite it as Patel, G.; Patel, D. Development of Taste-Masked Oral Dispersible Tablets of Cefpodoxime Proxetil. 

This study aimed to develop a taste-masked drug resin complex using the ion exchange resin Kyron T-114.

Development of Taste-Masked Oral Dispersible Tablets of Cefpodoxime Proxetil

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

3d illustration proteins with lymphocytes , t cells or cancer cells | Image credit: ©Design Cells - stock.adobe.com

Gamma-delta (γδ) T cells make up on average 4–5% of T cells found in human peripheral blood (1). Two different types predominate; one that is largely found in organs and tissues, and another found in blood. Unlike regular T cells, γδ-T cells function independent of the major histocompatibility complex (MHC) and recognize a wide variety of ligand molecules using multiple T-cell (TCR), innate (e.g., NKG2D), toll-like, and Fc (CD16) receptors. As a result, they are involved in immune responses against both pathogens and tumor cells, while also playing a role in homeostasis, wound healing, and aging.

Both autologous and allogeneic γδ T-cell immunotherapies are in development to treat a range of cancers. Stimulation and activation of the T cells prior to administration is common. While approaches are being pursued that use unmodified γδ T-cells because of their independent ability to identify cancer cells, many candidates in preclinical and clinical development also seek to boost their killing capability via genetic engineering and/or using a two-pronged strategy for increasing the susceptibility of the target cancer cells. Solutions include the use of combinations with chemotherapeutics or antibodies and active tumor modification with gene therapy.

According to William Ho, director, president, CEO, and co-founder of IN8bio, γδ T cells have the potential to address many challenges towards targeting different tumors, and when combined with chemotherapy or other therapies, that potential is magnified. This type of strategy, could, he believes, “make cell therapies a more central feature of the cancer armamentarium and provide potentially more lasting treatments.”

Several advantages vs. other cell therapies

Chimeric antigen receptor (CAR) T-cell therapies have been a fantastic advance in cancer treatment options, says Jeff Boyle, CSO of American Gene Technologies and spinout Addimmune. They are limited, however, by the need to have a differentiated antigen on the cell surface and “take all the breaks off of regular T cells,” which often results in off-target toxicity issues, he adds.

Gamma-delta T cells are not antigen-specific in the same manner, Boyle continues. “They recognize molecules via more of a pattern-recognition type of response that is not peptide-based and tend to be focused on entities arising from infection with fungi and bacteria, or carbohydrate entities,” he observes. That is an advantage because, Boyle explains, many of the same pathways upregulated during fungal and bacterial infections get upregulated in cancer as well. In addition, the broad targeting ability means γδ T-cell immunotherapies could possibly be generic, their MHC independence means there is greater potential for allogeneic therapies with reduced concerns of graft-versus host disease (GvHD) or host-versus-graft (HvG) rejection, and their different mechanism of action suggests they could have safer profiles.

More specifically, according to Ho, γδ T cells are “primordial innate anticancer cells that bridge the innate and adaptive branches of the immune system and present a formidable multi-tiered weapons package to directly recognize and immediately respond to a broad range of cancer-associated stress antigens with direct killing and release of inflammatory cytokines. In addition, γδ T cells can kill or amplify indirect killing mechanisms such as antibody-dependent cellular cytotoxicity through both CD16 and CD3 pathways, which sets up the potential for therapeutic synergy with cancer-target antibodies or bispecific engagers,” he observes.

Normal alpha-beta (αβ) T cells emerge following the initial innate immune response and recognize threat-specific peptides unique to the cancer, but the number and heterogeneity of tumor associated-antigens (TAAs) increases rapidly as the tumor grows and ultimately exceeds their ability to respond, says Ho. With their redundant stress-signaling pathway, γδ-T cells can overcome the complexity of tumor heterogeneity, he notes. Like natural killer (NK) cells, Ho adds, γδ-T cells can kill tumor cells very effectively, but because they are T cells, they can create an adaptive or memory response and are more persistent than NK cells. Furthermore, he points out that because normal cells do not express stress antigens, many of the toxicities of αβ T-cell therapies like cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or neurotoxicity, and GvHD may be avoided.

Patient-specific, autologous cell therapies have manufacturing and logistics challenges, but do not present concerns of potentially lethal GvHD. Off-the-shelf, allogeneic versions are potentially easier to produce more cost-effectively, would be immediately available, and because they come from healthy donors should be more robust from an activity- or tumor-killing standpoint, Ho comments. With allogeneically delivered αβ-T cells, however, potential lethal immune toxicities such as GvHD must be overcome through significant genetic editing.

The γδ T-cell, MHC-independent mechanism of action may obviate those risks, says Ho. He adds that γδ T-cell therapies have traditionally been known not to initiate GvHD. “Our data has not yet demonstrated a concerning safety signal with either of the autologous or allogeneic delivered products IN8bio is developing, including not having observed any CRS or ICANS to date,” he contends.

There are two important challenges to developing effective γδ T-cell therapies. They derive from the broad-natured activity of γδ-T cells, which is both a strength and a weakness, as they tend not to be as potent as desired at killing tumor cells, according to Boyle. Their killing capability is therefore often increased by increasing the activity of the γδ-T cells, and boosting the susceptibility of tumor cells to attack by these enhanced cells.

Ideally, Boyle observes, stimulation of the γδ-T cells occurs 

 prior to administration, which is then achieved in conjunction with another therapeutic agent of some kind (small molecule, antibody, gene therapy), that targets some of the tumor cells, the effect of which then spreads throughout the tumor.

Many different types of therapies based on cell types that occur naturally in the body are under development today. Designing optimum immunotherapies based on complex living cells that represent only a fraction of the highly complex immune system has limitations, however (1,2). Researchers do not yet fully understand the operations of different cells, making precise engineering a challenge. Undesirable cellular activities can result in off-target effects, for instance. The differences in patient cells due to genetic and environmental factors can, meanwhile, greatly impact the effectiveness of living cell therapies.

An alternative approach involves bottom-up construction of synthetic cells, such as “cell-like lipid-based compartments in the form of giant unilamellar vesicles,” in a step-by-step manner that allows for incorporation of defined functional capabilities and attributes (2). Such synthetic cells would thus be much simpler and perform only specific functions, potentially with greater potency and without concern of unwanted side effects.

To date most synthetic cells have been used in a laboratory setting for research applications, but some have been designed as potential drug-delivery systems and others that produce drug substances are being investigated as

treatments, including their implantation into tumors as anticancer therapies, their use to promote neuronal development, and a means to deliver insulin 

One recent paper reports the creation of immune-inspired synthetic cells (iiSCs) “that display an antigen-directed target specific cytotoxicity against cancerous cells” by incorporating aspects of NK, T, and B cells and adding a polyethylene glycol coating to prevent interactions with non-target cells (2). As a specific example, the researchers then immobilized immunoglobulins targeting leukemia cells onto the synthetic cells. While the system was built only to demonstrate the technology, the researchers believe that versions designed for 

application should be possible to make without too much difficulty given the charge-mediated assembly process employed (2).

Indeed, some believe that synthetic cells might prove to be optimal for the development and production of therapies for individuals or small patient populations, including on-demand, personalized cancer vaccines and drugs to treat rare infections (1). The ability to construct synthetic cells that are stable at room temperature would also facilitate eliminating the need for cold-chain management through their storage, transport, and delivery.

Regulatory clarity is still needed for treatments based on synthetic cells, however (1). While the guidelines for engineered cell therapies, such as CAR T-cell therapies, are applicable to some degree, synthetic cells are different and have unique aspects that will require specific guidance. To realize that goal will require close collaboration between developers of synthetic cell therapies and regulatory bodies such as the US Food and Drug Administration (1). Long-term security risks associated with development of synthetic cell therapies must also be considered and addressed (1).

1. Sampson, K.; Sorenson,C.; and Adamala, K. The FDA Needs to Get Ready to Evaluate Synthetic Cells, the Next Generation of Therapeutics. 

https://www.statnews.com/2022/07/26/fda-develop-framework-evaluate-synthetic-cells/

2. Bücher et al. Bottom-up Assembly of Target-specific Cytotoxic Synthetic Cells. 

The rarity of γδ-T cells in the immune milieu creates a third important challenge to developing γδ-T-cell therapies, notes Ho. Because they encompass approximately 5% of the total lymphocyte, or white-blood-cell population, obtaining sufficient cells to formulate multiple doses requires significant cell expansion.

Fortunately, though, the ability to grow γδ-T cells in large numbers is easier than growing standard effector T cells, according to Boyle. “Standard T cells once activated immediately begin upregulating all systems and processes, and it is necessary to shut those down in order to maintain effectiveness after longer periods of expansion. That is not an issue with γδ-T cells, which means it is much less difficult to maintain effectiveness during expansion compared to other types of T cells,” he explains.

Developing allogeneic and autologous treatments at IN8bio

IN8bio is a clinical-stage company with two active programs in glioblastoma (GBM) and hematologic malignancies. The GBM program has progressed to a Phase II study, and the company is completing its Phase I study in hematologic malignancies. “Our philosophy is to create a cancer therapy that achieves durability, tolerability, and addresses tumor heterogeneity to achieve the goal of our mission ... Cancer Zero, or the safe elimination of all cancer cells in every patient battling the disease,” Ho remarks.

That mission is being implemented, according to Ho, by coordinating γδ T-cell therapy with other therapies available to patients to ensure that cancer cells are attacked when they are at their lowest in numbers and are the most vulnerable. “With their unique status as cells that sit at the nexus of the adaptive and innate immune systems, γδ T cells address the critical concerns limiting the utility of cell therapies in solid tumors (i.e., durability, addressing tumor heterogeneity, and safety) and have demonstrated less potential for immune toxicities like CRS or ICANS than traditional αβ T-cell therapies,” he comments.

Specifically, IN8bio has developed proprietary technologies for the expansion, activation, and genetic engineering of γδ-T cells. The company has created γδ-T cells that are chemotherapy-resistant for treatment of solid tumors using autologous cells and plans on doing the same with allogeneic cells, according to Ho. For leukemia patients, it has optimized methods for expanding and activating γδ T cells 

 from allogeneic donors without additional modification. IN8bio is also working to create non-signaling CAR-T (nsCAR) therapies out of γδ T cells that allow them to distinguish between tumor cells and healthy tissue, thus avoiding many of the on-target, but off-tumor toxicities reported with αβ CAR T-cell therapies.

Another area of development for IN8bio is the creation of induced pluripotent stem cell (iPSC)-derived γδ T cells to allow the potential production of cell banks with multiple billions of cells, Ho says. Finally, the company is also investigating opportunities for combining γδ T cells with other novel therapies to maximize their potential as immunotherapies.

“IN8bio has unique expertise based on the seminal work of our CSO, Dr. Lawrence Lamb, who has studied γδ T cells for nearly three decades. His research has led to our unique capability in isolating, expanding, and activating these cells to maximize their efficacy, as well as modifying them into the variety of modalities possible with γδ T cells,” Ho says. He adds that through optimization efforts, the company has reduced the manufacturing time and cost and limited manufacturing failures for its autologous products.

One specific clinical program mentioned by Ho is IN8bio’s Vd2+ γδ T-cell program. He notes that this particular type of γδ T cell is prone to exhaustion or death during the expansion and engineering process. “Their production at scale requires some finesse, and thus we are the only group to date that has brought genetically modified Vd2+ γδ-T cells to patients in the clinic through the FDA,” he comments. The company also intends to demonstrate the utility and risk: benefit ratio of both its autologous and allogeneic γδ T-cell therapies in its Phase II INB-400 trial.

Leveraging gene therapy at American Gene Technologies

The γδ T-cell therapy program at American Gene Technologies has been reduced in scope for the past 18 months as the company has focused on developing solutions for human immunodeficiency virus (HIV) infections. The company recently announced the spinout of its HIV-related assets to a new company (Addimmune). Once the spinout is completed, American Gene Technologies will be continuing with a different executive team and renewing its focus on γδ T-cell therapy.

American Gene Technology’s approach involves activation of a large number of highly purified γδ T cells 

 combined with administration of a gene therapy designed to make the target tumor cells hyper-sensitive to the γδ-T cells. “

 tumor targeting using a gene therapy makes it possible to add molecular mechanisms within the tumor that make is susceptible to the specific type of γδ-T cells that we are administering,” Boyle explains.

Gene therapy as a combination treatment was selected, Boyle says, because it creates the opportunity to make one type of γδ T-cell therapy broadly applicable to many different tumor targets. “We can lock down the expansion and activation of the γδ T cells and then use those cells for different cancer treatments by changing the tumor-targeting ability of the gene therapy,” he notes.

In addition, gene therapy provides molecular control of expression within the tumor through selection of different knockdowns, according to Boyle. Use of a small-molecule as an adjunct treatment is problematic, he believes, because these treatments are delivered systemically, which increases the chances for off-target effects. Antibodies as adjuncts, however, are more promising from Boyd’s perspective, particularly as antibody-based technologies continue to advance.

1. Ling Ma; Yanmin Feng; and Zishan Zhou. A Close Look at Current γδ T-cell Immunotherapy. 

Cynthia A. Challener, PhD, is a contributing editor to 

®
Vol. 48, No. 3
March 2024
Pages: 16-18

When referring to this article, please cite it as Challener, C. A. Development of Gamma-Delta T-Cell Therapies. 

Activation and expansion are essential for success in both autologous and allogeneic therapies.

Development of Gamma-Delta T-Cell Therapies

Amin Ziaie, QRM Merck & Co., Inc, PRST, the Technological University Dublin.

Anne Greene, PhD, is director PRST, Technological University Dublin.

Martin J. Lipa, PhD, martin.lipa@prst.ie, is a senior research fellow at Pharmaceutical Regulatory Science Team.


This article was peer-reviewed by a member of 

Submitted: September 8, 2023
Accepted: January 19, 2024

Business woman holding checked icon on virtual screen. Business process automation, quality assurance management, certification, digital transformation. Service guarantee, Validation concept.| Image Credit: ©Atomic62 Studio - stock.adobe.com

In 2020, the International Council for Harmonisation (ICH) published a concept paper (1) that outlined a limited revision to the published guideline ICH Q9 

 (2) to address the fact that “the benefits of QRM [quality risk management], as envisaged by ICH Q9, have not yet been fully realized.”

Arguably, despite the publication of the companion ICH guidelines in the first decade of the 21st century, ICH Q9 (2) and ICH Q10 

(3), there are still numerous challenges in enhancing manufacturing operations, which lead to quality issues and drug shortages. Even with significant efforts in QRM by both the industry and regulators, there are signs that unmitigated risks persist within the pharmaceutical industry, resulting in quality defects as reported by Kevin O’Donnell, Market Compliance Manager at the Health Products Regulatory Authority (HPRA) in Ireland, who observed that the number of total quality defects reported to the Irish regulator between 2002 and 2021 had increased by more than 10-fold (4). In addition, a survey of chief quality officers of 30 global pharmaceutical companies found that the benefits envisioned by ICH Q10 have generally not been realized, and in some cases the situation was slightly worse or more complex (5).

FDA’s 2019 Drug Shortage Report underscored the ongoing problem of drug shortages in the United States, suggesting manufacturers might prioritize cost reduction over quality investment because quality is not viewed as a competitive marketplace advantage (6). Concurrently, the US Senate Committee on Homeland Security drew attention to the escalating trend of essential medication shortages, impacting a broad spectrum of products from emergency hospital drugs to over-the-counter remedies. By the end of 2022, drug shortages reached a new peak. This crisis was rooted in various factors, such as an overreliance on foreign sources for active ingredient, a lack of domestic manufacturing capacity, and insufficient supply chain visibility into all the companies involved, leading to a misleading appearance of supplier diversity. These shortages have profound cascading effects on patient care (7).

As a tangible step to help address some of these challenges, a targeted revision of ICH Q9 was approved. ICH Q9(R1) was published in January 2023 (8), superseding the original ICH Q9 guidance issued in 2005 (2). This revision narrowly focused on the following four topics deemed critical to advance the competency and effectiveness of the industry in risk management:

high levels of subjectivity in risk assessments and QRM outputs

lack of understanding into what constitutes formality in QRM work

lack of clarity on risk-based decision-making.

The ICH Q9(R1) concept paper further suggested risk review and hazard identification as two additional points to be addressed.

Considering the topic of subjectivity, the ICH Q9(R1) Concept Paper (1) noted the challenge associated with subjectivity as follows:

“High levels of subjectivity in risk assessments and in QRM outputs—the reasons for this can include highly subjective risk scoring methods and differences in how risks are assessed and how hazards, risk, and harms are perceived by different stakeholders. This can lead to varying levels of effectiveness in the management of risks. While subjectivity cannot be completely eliminated from risk assessment and QRM activities, it may be controlled using well recognized strategies, including addressing bias and behavioral factors.”

The Concept Paper further went on to describe potential benefits of addressing subjectivity and suggests:

“Less subjective risk assessments to support manufacturing processes should lead to fewer quality defects that could present risks to patients. Recalls are required every year to protect patients from the real and/or potential risks presented by defects in medicines, leading in some cases to shortages of important medicines. Less subjective risk assessments should also lead to more science-based manufacturing operations, control strategies, and validation activities, resulting in the potential for reduced costs and the possibility to free up resources for other necessary activities. ICH Q8, Q10, and Q11 expect science- and risk-based applications, and revising ICH Q9 to address subjectivity in QRM more explicitly will help enable/accelerate the continued implementation of Q8, Q10, Q11 (and Q12), because of the foundational relevance of QRM.”

Drivers to reduce subjectivity are compelling when one considers the opportunity to reduce defects (and, in turn, recalls). Reduced defects will ultimately lead to reduced costs and resources, and further realization of the goals of a modern PQS. Indeed, one could argue that subjectivity casts a long shadow over many facets of the pharmaceutical business not just QRM. This paper provides an introductory exploration into the topic of subjectivity in QRM by:

reviewing contemporary QRM literature on subjectivity

creating a shared understanding of subjectivity for QRM

examining how subjectivity is addressed in the original Q9 guidance, and comparing it to the revised guidance.

Subjectivity: insights from contemporary QRM-related literature

The emphasis on subjectivity in ICH Q9(R1) is not surprising when one reviews contemporary literature on the topic published since the 2005 release of ICH Q9. Notably, H. Gregg Claycamp, the Regulatory Rapporteur of the original ICH Q9 guidance document, published a paper in 2018 entitled “Controlling Subjectivity in Risk-based Decision Making: The Benefits of Multi-criteria Decision Analysis” (9). In this paper, in addition to brief discussions on subjectivity inherent in risk assessment and risk management, and linking subjectivity and uncertainty, Claycamp proposed that the problem with subjectivity in QRM stems from two elements as follows:

“A failure to recognize where and when subjectivity enters and might create problems in risk assessment and risk-based decision-making.

“A failure to implement control on subjectivity where it is known
to occur.”

Several other papers have further highlighted the challenges posed by subjectivity, including a paper by ICH Q9(R1) rapporteur Kevin O’Donnell (10). This paper discusses elements of subjectivity and uncertainty such as the impact of human heuristics, which are cognitive behaviors that can introduce bias and errors in judgment during activities like brainstorming and probability estimation. It suggests incorporating design elements into QRM tools to counteract the adverse effects of heuristics and reduce guesswork. Practical strategies and cognitive approaches are presented to improve the accuracy of risk analyses and enhance the outcomes of QRM exercises. These insights can be valuable to facilitators in achieving more accurate risk assessments.

In a follow up paper (11), O’Donnell discusses the significance of risk communication in the QRM process, highlighting potential challenges of subjectivity and uncertainty in this activity. Stakeholders’ individual perceptions can lead to subjective differences in risk judgments, introducing uncertainty in risk management outcomes. To address these issues, O’Donnell suggests adopting a more rigorous approach to risk communication. Practical strategies based on research from experimental psychology and uncertainty analysis to improve risk communication and reduce subjectivity and uncertainty are presented. These strategies include stakeholder selection, employee roles in risk communication, and essential information to be communicated within pharmaceutical companies.

In a 2016 publication (12), authors Vesper and O’Donnell highlight multiple issues encountered 10 years after the publication of ICH Q9. One of the issues discussed was the relationship between risk and uncertainty, with risk defined as the “effect of uncertainty on achieving one’s objectives.” Subjectivity in risk assessment can emerge due to differences in perceptions, values, and experiences among stakeholders. This subjectivity influences the evaluation of potential harms, probabilities, and severities in the QRM process. This may be compounded by groupthink during risk assessment activities, leading to difficulties in reaching consensus on risk acceptability and appropriate courses of action. Vesper and O’Donnell emphasize the importance of addressing subjectivity and uncertainty in risk assessment and offer strategies to do so. These strategies include fostering diverse team composition, using key words in scales, acknowledging uncertainty, and relying on validated data. Additionally, this publication suggests integrating good science into risk assessments and documenting current controls before assigning ratings to failure modes or hazards.

A 2018 paper by Emma Ramnarine and Kevin O’Donnell (13) emphasizes the role of subjectivity during risk assessment activities and how subjectivity can negatively impact the state of control and the delivery of products with consistent quality throughout their commercial life.

In addition to QRM-related literature that directly highlights subjectivity, related research by Valerie Mulholland explores the impact subjectivity plays in effective risk-based decision-making. In a paper on Key Decision Review Points (14), Mulholland proposes that each decision within a QRM process has the potential to be sub-optimal due to subjectivity (among other causes). Furthermore, in another paper from the same four-paper series focused on uncertainty (15), Mulholland discusses the presence of high uncertainty, which poses significant challenges in decision-making. In some cases, the risk itself may be uncertainty. Uncertainty can arise from various sources, including variability in data, lack of knowledge, and ambiguity in interpretations. Decision-making under uncertainty may rely on different mental abilities and competencies compared to evidence-based decision-making. Overall, addressing uncertainty in risk management requires a thoughtful and strategic approach, acknowledging the interconnectedness of risk and subjectivity.

Considering these articles in aggregate, the authors of this paper suggest that Claycamp’s 2018 assertion that the problem with subjectivity in QRM arises from two elements (9) captures the essence of an important theme across this literature. The authors propose restating these two challenges more simply as follows:

knowing what to do about it when it does.

In the opinion of the authors, creating a common understanding of subjectivity is a prerequisite for both of these challenges and is an important need for the industry and those involved in the practice of QRM, as discussed in the next section.

Subjectivity: seeking a common understanding

This article explores the emergence of subjectivity in ICH Q9 (R1).

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