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A “Plan, Prevent, Prove” Approach

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. 

Articles

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

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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

While high levels of subjectivity were identified as an issue, it is notable that neither ICH Q9 (2), the ICH Q9(R1) Concept Paper (1), nor ICH Q9(R1) (8) provide a definition for subjectivity. In the opinion of the authors of this paper, this lack of a common operational definition and/or associated examples poses the risk of an inconsistent comprehension and understanding of what subjectivity is. Therefore, establishing a common definition of subjectivity as it pertains to QRM is important.

Basic definitions of the word subjectivity exist, including the following
dictionary entries:

“The quality of being based on or influenced by personal feelings, tastes, or opinions” (Cambridge Dictionary)

“The influence of personal beliefs or feelings, rather than facts” (Oxford Dictionary).

While these definitions certainly provide a good starting point, the world of QRM has many different challenges, including:

leading-edge science and new types of therapies

expectations for speed (e.g., product development in response to a pandemic or other market pressures)

human behaviors (e.g., expert opinion, heuristics, bias) multi-step QRM process with many different participants over a long-time horizon.

It is difficult to recognize when subjectivity enters QRM and influences outputs that may affect product quality and patient outcomes. The authors suggest this is an important topic for future study. Notwithstanding, the lack of a definition for subjectivity ICH Q9(R1) does offer important clues by its use of other language, in particular language that evokes objectivity as the antidote for subjectivity in a scientific setting, as explored in next section.

Subjectivity: a closer examination of its emergence in ICH Q9(R1)

While ICH Q9(R1) (8) does not expressly define subjectivity, an examination of it in comparison to the 2005 version of ICH Q9 (2) reveals the emergence of the term subjectivity, which appears 10 times in the revised document in contrast to the lack of being mentioned in the original.

Furthermore, the authors have observed that the language in ICH Q9(R1) includes concepts related to subjectivity- and objectivity as its antonym, for example:

terms which invoke scientific facts which suggests minimizing subjectivity (e.g., evidence, data, information, knowledge)

knowledge management (KM) as a means to manage and deliver scientific knowledge to QRM and risk-based decision-making processes.

A simple comparison of the two documents was conducted by the authors to evaluate the frequency of relevant terms in each ICH Q9 and ICH Q9(R1), the results are presented in 

Table I: Frequency of subjectivity-related terms in International Council for Harmonisation (ICH) Q9(R1) and ICH Q9. KM is knowledge management.

As can be seen by the comparison, there is a significant increase in subjectivity related concepts in ICH Q9(R1). The authors believe this signifies a proactive desire to address subjectivity. By incorporating these related concepts, the revised guideline emphasizes the importance of basing risk assessments on objective evidence and data-driven insights. This shift toward more objective decision-making that is evidence-based, while seeking to minimize the influence of subjectivity enhances the reliability of risk analyses and risk management at large.

Subjectivity emerges in ICH Q9(R1) (8) as a concept that must be addressed to improve the effectiveness of risk management, and in turn the pharmaceutical quality system. In fact, O’Donnell challenges “can an organization do effective Risk-based Decision-making if its risk assessments are highly subjective?” (16). As mentioned by experts, acknowledging and addressing subjectivity are crucial for making informed and effective risk-based decisions, ultimately leading to improved product quality, patient safety, and product availability. Indeed, subjectivity casts a long shadow on QRM and, by extension, the pharmaceutical industry as a whole.

Updates included in the revision to ICH Q9(R1) reflect the growing recognition of the significance of subjectivity in risk management within the pharmaceutical industry. By incorporating language related to bias, evidence, data, information, knowledge, and knowledge management, the revised guideline appears positioned to enhance the objectivity and reliability of risk assessments. These changes included in ICH Q9(R1) provide an opportunity to shine a light on this issue by emphasizing the need to address subjectivity and its connection to business outcomes and patient safety.

However, while subjectivity has emerged as important in ICH Q9(R1), significant work remains to develop a clear and shared understanding of what subjectivity is, when subjectivity might exist and what to do about it when it does. These topics will be the focus of future research by the authors. Such research is also expected to explore subjectivity in other industries and study best practices. In addition, it is anticipated that training on this topic, and exploring emerging technologies and methods, would be beneficial.

The views expressed in this article are those of the authors and are not necessarily those of any organizations with which the authors are affiliated.

ICH. Final Concept Paper ICH Q9(R1): Quality Risk Management. 2020. 

https://database.ich.org/sites/default/files/Q9%20Guideline.pdf

. (ICH, 2008). https://database.ich.org/sites/default/files/Q10%20Guideline.pdf (accessed: Aug. 28, 2023).

O’Donnell, K. Quality Risk Management–An Update on the Ongoing Revision of ICH Q9 ‘Delivering Value and Resilience using QRM’ [Conference Proceeding]. in PDA Ireland, Dublin, Ireland, September 2022.

Ramnarine, E. Solving the Continual Improvement and Innovation Challenge for the Benefit of Patients: How an Effective Pharmaceutical Quality System (PQS) and Risk-Based Approach Could Transform Post-Approval Change (PAC) Management. 2021. DOI: 10.21427/960F-8S69.

https://www.fda.gov/drugs/drug-shortages/report-drug-shortages-root-causes-and-potential-solutions

Peters, G. Risk of Drug Shortages-United States Senate Committee- Homeland Security & Governmental Affairs Report. 2023. 

https://www.hsgac.senate.gov/wp-content/uploads/2023-03-20-HSGAC-Majority-Draft-Drug-Shortages-Report.pdf

https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf

Claycamp, G. Controlling Subjectivity in Risk-based Decision Making: The Benefits of Multi-criteria Decision Analysis. DIT Academic Press, 2018.

O’Donnell, K. Strategies for Addressing the Problems of Subjectivity and Uncertainty in Quality Risk Management Exercises Part I-The Role of Human Heuristics. 

O’Donnell, K. Strategies for Addressing the Problems of Subjectivity and Uncertainty in Quality Risk Management–Part 2 Risk Communication and Perception Issues. 

Vesper, J. and O’Donnell, K. Current Challenges in Implementing Quality Risk Management. 

https://ispe.org/pharmaceutical-engineering/ispeak/current-challenges-implementing-quality-risk-management

Ramnarine, E. and O’Donnell, K. Demonstrating Pharmaceutical Quality System Effectiveness and Driving Continual Improvement: Evidence-based Risk Reduction.

 72 (3), pp. 338–345, May 2018, DOI: 10.5731/pdajpst.2017.008524.

Mulholland, V. and Greene, A. Improving Risk Based Decision Making Effectiveness: A Case for Risk Decision Review Points (KDRPs) In The Quality Risk Management Process. 

Mulholland, V. and Greene, A. Improving Risk Based Decision Making Effectiveness: Addressing Uncertainty. 

O’Donnell, K. ICH Q9(R1) and Some Personal Thoughts about Implementing the New Guidance [Conference Proceeding]. in TU Dublin, PRST Conference, Dublin, Ireland, June 2023.

Amin Ziaie, QRM Merck & Co., Inc, PRST; Anne Greene is director PRST; and Marty Lipa, PhD, PRST; all at the Technological University Dublin.

®
Vol. 48, No. 3
March 2024
Pages: 30-33

When referring to this article, please cite it as Ziaie, A.; Green, A.; and Lipa, M. Shining a Light on the Long Shadow of Subjectivity in Quality Risk Management. 

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

Shining a Light on the Long Shadow of Subjectivity in Quality Risk Management

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

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All drugs are subjected to regulatory scrutiny during the full development lifecycle because, whichever way a drug is administered, it should always be effective and, most importantly, safe for the end-user. The requirement for safety, however, is ever more pressing for parenteral products, as these drugs are administered either directly into the bloodstream or into other delicate mucus membranes.

Focusing on parenteral drug manufacturing in particular, a critical step that ensures sterility and contaminant-free results is fill/finish. “Following drug development and production, fill/finish is the next step in the process—and crucial for getting the drug into the required container and making it ready for distribution,” confirms Andreas Mattern, vice-president Strategy and Global Product Management Pharma at Syntegon.

“Fill/finish manufacturing entails the process of aseptically filling and sealing products, in this case pharmaceutical products, ensuring that precision, sterility, and compliance with regulatory standards are meticulously followed,” concurs Carlos Quintero, director, Industry Services—PMMI (the Association for Packaging and Processing Technologies). “This is critical to ensure safety, efficacy, and shelf life.”

It is imperative for both bio/pharma manufacturers and any contract service providers, such as contract manufacturing organizations, to pay close attention to fill/finish processes, making sure there is the utmost sterility while also being robust and reliable, notes Mattern. “Filling and closing are especially demanding [because] the drug and its container come into contact with many different parts of equipment,” he adds. “To date, some of these processes still require manual intervention from operators, which makes them even more prone to contamination.”

In 2022, a key regulatory revision was released—the European Union’s Good Manufacturing Practice Annex 1 revision (1)—that has far-reaching consequences for sterile filling operations, not just within the EU but for the global bio/pharma industry, Mattern reveals. “The specifications affect the manufacturing processes of all drugs imported into the EU,” he says.

“Among the major challenges of the new Annex 1 is the separation of the aseptic process area from the operator environment,” Mattern continues. “Pharmaceutical manufacturers therefore require at least restricted access barrier systems (RABS) for the approval of new products.”

As a result of these new regulatory requirements, there is now high demand for new machines and barrier technology upgrades, Mattern explains. “In the case of older machines, the question is whether to upgrade or invest in a completely new line with pre-installed barrier technology,” he says.

The revised Annex 1 also clearly sets out the requirements for air flow, Mattern specifies. “Unidirectional air flow is mandatory for open isolators and RABS in all class A areas and should not be interrupted between the air inlet and the open product. Yet this uninterrupted flow is not possible everywhere,” he says.

“A typical exception is the filling needle together with the filling needle holder, which must be positioned exactly above the open, sterilized packaging material in order to achieve loss-free filling,” Mattern states. “It is expected that these components are aerodynamically designed to minimize turbulences and that these items can be sterilized separately and installed aseptically.”

As alluded to earlier, the revised regulatory requirements are leading to the need for new technologies to be used in fill/finish processes. A further elaboration on this matter is highlighted in the second chapter of Annex 1 (1), where automation and robotic systems are penned as appropriate technologies, confirms Mattern. “By using these technologies, gloves and human intervention in barrier systems can be reduced to an absolute minimum or even eliminated,” he says.

Just a decade ago, the primary focus for bio/pharma research companies and manufacturers was large-batch blockbusters or traditional drugs, remarks Andreas Mattern, vice-president Strategy and Global Product Management Pharma at Syntegon. “Today, these medicines continue to make an important contribution to human health. Some of them, such as blood thinners, painkillers, or insulin, have become an indispensable part of the drugstore shelf. They are produced on lines in 24-hour operations,” he says. “Further new drugs in this realm (e.g., a high-dose injectable version of the incretin mimetic semaglutide) will continue to push the need for high-speed production.”

However, there is an apparent drive towards more niche areas. “Special and often personalized medications are now available to cure or at least delay some life-threatening illnesses. Cellular and molecular biotechnology has been accompanied by a revolution in pharmaceutical manufacturing: while high-speed, high-throughput lines used to be in the greatest demand, more and more pharmaceutical companies are now investing in the development and commercialization of small-volume medicines, which have very different production and filling requirements,” Mattern asserts.

“The increasing prevalence of advanced therapy medicinal products, such as cell and gene therapies and bioengineered tissue products, shows that the industry is specializing steadily,” Mattern continues. “These drugs are not manufactured on huge lines. Instead, the focus is on what is commonly known as small batch production.”

“The issue of gloves presents many challenges, which are acknowledged in separate paragraphs,” Mattern continues. “For example, gloves are to be additionally tested in operation during longer campaigns—which is not possible with the glove testing equipment used to date without risking the integrity of the sterile room. A switch to gloveless systems with robotics that handle these manipulations is already possible.”

Additionally, in conjunction with robotic filling lines, artificial intelligence (AI)-influenced line controls and automation will be able to offer faster scalability and increased flexibility for manufacturers, remarks Quintero. “Automation and AI are always accelerating the rate of precision, quality control, and efficiency of the fill and finish-seal process in manufacturing,” he says. “This has a huge impact on reducing contamination risks and the overall effectiveness and performance of the lines.”

Another pressing issue for the bio/pharma industry and its stakeholders is sustainability. More sustainable equipment and processes are needed across the board in bio/pharma manufacturing to ensure various reporting requirements can be met, which is something that technology providers, such as Syntegon, can help with, notes Mattern.

In terms of the sustainability of fill/finish manufacturing, Quintero anticipates a marked and quick change in the coming years. “Fill/finish manufacturing most likely will rapidly evolve into a zero-waste process and will incorporate more and more, sustainable renewable energy sources,” he states.

Furthermore, the drive towards automation of fill/finish processes will continue into the future as humans remain to be the main source of contamination, Mattern adds. “While drugs are becoming more and more complex, and as such expensive, separating pharmaceuticals from operators has been gaining attention throughout the industry for some years—a topic that is still becoming more pressing when considering small and even micro batch filling of highly potent substances,” he says. “Hence, automation and digitalization will play an increasingly crucial role.”

“While it is not easy to integrate what is known as ‘Industry 4.0’ into complete pharmaceutical manufacturing operations, many individual solutions are already available,” he summarizes. “The main question here is how to make use of the enormous amounts of data generated by fill/finish (and other pharmaceutical) processes every day.”

1. EC. Annex 1 Manufacture of Sterile Medicinal Products, 

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

When referring to this article, please cite it as Thomas, F. Automating the Future of Fill/Finish. 

Given the criticality of fill/finish processes, it is clear that automation is the next technological step.

Automating the Future of Fill/Finish

Cheryl Barton is director of PharmaVision, 

In February 2024, the National Institute for Health and Care Excellence (NICE) recommended AbbVie’s Tepkinly (epcoritamab) as the first injectable bispecific antibody for certain blood cancers (1). Unlike existing chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies do not require cell collection and engineering and, unlike monoclonal antibodies, they provide a dual functionality, selectively targeting two different epitopes/receptors resulting in enhanced clinical efficacy with low intrinsic toxicity and immunogenicity (2). In May 2021, the US Food and Drug Administration issued final guidance on bispecific antibody development providing greater clarity for drug developers and fuelling significant investment in recent years (3).

Big Pharma, including AbbVie, Johnson and Johnson, Regeneron Pharmaceutical, and Sanofi, have bispecific antibodies in development (

). In addition, the industry has also forged partnerships with academic institutes and innovative biotech’s in this field including, Jazz Pharmaceuticals/MD Anderson Cancer Center (2023), ONK Therapeutics/NATA Biosciences (2023), F-star/Takeda (2022), Gilead Sciences/MacroGenics (2022), AbbVie/Genmab (2020), and BeiGene/Zymworks (2018) (4–10).

To date, three bispecific antibodies have received regulatory approval, Amgen’s Blincyto (blinatumomab), Chugai’s Hemlibra (emicizumab), and Roche’s Vabysmo (faricimab), and many more are under clinical development (

). Two European biotech’s, Affimed and Merus, are leading the field in bispecific antibodies and have developed proprietary technology to generate several products that are in clinical development.

Bispecific antibodies under clinical development.

Affimed harnessing the potential of the innate immune system

Affimed N.V. (Nasdaq: AFMD), a German-based immune-oncology company, is utilizing its proprietary Redirected Optimized Cell Killing (ROCK) platform to generate customized innate cell engager (ICE) molecules that can activate immune cells to target tumour cells (11). The high-affinity bivalent ICE molecules, bind to natural killer (NK) cells via CD16A without inducing non-specific NK-cell activation or cell death. The bivalent interaction of the ICE molecules with CD16A triggers antibody-dependent cell-mediated cytotoxicity (ADCC) (12).

Affimed’s lead bispecific antibodies include:

 a bispecific antibody targeting CD30 on cancer cells and CD16a on innate immune cells being developed to treat Hodgkin lymphoma (HL). Affimed has initiated a Phase II study, LuminICE-203, evaluating acimtamig in combination with alloNK an allogeneic NK cell from Artiva Biotherapeutics, in patients with recurrent/refractory HL (13).

 a bispecific antibody targeting epidermal growth factor receptor (EGFR) and CD16a as a monotherapy and in combination with anti-programmed death 1 (PD-1) in solid tumours in Phase Ib and I/IIa, respectively (14).

 a bispecific antibody targeting CD123 and CD16a, a monotherapy for the treatment of acute myeloid leukaemia (AML) in Phase I.

Affimed has forged strategic alliances with Artiva Biotherapeutics to develop acimtamig; Genentech, Roivant Sciences, and Roche on the development of novel ICEs, as well as the MD Anderson Cancer Center and Leukaemia Lymphoma Society (15).

In January 2024, Adi Hoess stepped down as CEO and management board member, and Andreas Harstrick was appointed interim CEO, who will be supported by Annalisa Jenkins. The company is undergoing a strategic restructure to reduce headcount by up to 50%, and extending its cash position into mid-2025 as it focuses on advancing its clinical programmes (16). Earlier the same month, the company sold AbCheck, its wholly owned subsidiary to Ampersand Biomedicines, and the US$6 million (€5.5 million) proceeds will support ongoing clinical development activities (17).

Merus, a Netherlands-based biopharmaceutical company, is utilizing its proprietary technology platform Multiclonics, to develop full-length human immunoglobulin G (IgG) bispecific (Biclonics) and trispecific (Triclonics) antibodies with long half-lives and low immunogenicity. The Multiclonics platform allows the rapid generation of bivalent and trivalent IgG species with the desired multifunctionality using patented DEKK dimerization technology. DEKK introduces lysine side chains into the heavy chains (L351D and L368E in one heavy chain and L351K and T366K in the other) to form stable constructs (18).

Merus’ lead bispecific antibodies include:

 a bispecific antibody targeting Herceptin 2/3 (HER2/HER3) receptors which is being evaluated in Phase II trials as a single agent in Neureguline 1 fusion-positive (NRG1+) in non-small cell lung cancer (NSCLC) and advanced pancreatic ductal adenocarcinoma (PDAC) (19).

 a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (c-MET); has also shown promising results as a single agent in patients with head and neck squamous cell carcinoma (HNSCC) and in combination with osimertinib in non-small cell lung cancer (NSCLC) in Phase II trials (20).

 a bispecific antibody targeting EGFR and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in Phase I/II as a monotherapy for patients with previously treated HNSCC (21).

Affimed has signed strategic alliances with Incyte Corporation to develop NCA33890, a novel TGFBr2xPD-1 bispecific antibody, and Loxo Oncology at Eli Lilly, to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies utilizing Merus’ Biclonics platform and proprietary CD3 panel (22). In August 2023, Merus closed a public offering and raised US$172 million (€158 million) to advance its clinical development programmes, resulting in a cash, cash equivalent, and marketable securities position of US$446 million (€411 million), as of 30 Sep. 2023 (22).

Challenges and future opportunities in bispecific antibodies

The clinical approval of different bispecific antibodies demonstrates the significant therapeutic potential of this novel class of biologicals (23). However, they also present unique challenges concerning the production of high quality proteins due to heavy- and short-chain misparing issues, and the generation of antibody fragments and aggregated molecules that require additional purification steps when scaling up manufacturing processes (24). Biotech, pharma, and clinical manufacturing organizations have made significant progress in overcoming these obstacles through the development of novel linker and stability engineering platforms as well as the efficient expression and production of bispecific antibodies using bacteria and mammalian systems. In addition, advances in downstream purification processes have increased the industry’s capacity to scale up the cost-effective production of these novel proteins which will enable them to reach their full potential as a complementary approach to conventional therapies over the years ahead (25).

1. Cision News. NICE Recommends Subcutaneous Treatment Option Tepkinly (epcoritamab) for Eligible* Adults with Aggressive Form of Blood Cancer After Two or More Lines of Systemic Therapy. Press Release, 1 Feb. 2024.
2. Carter P.; Lazar G. Next Generation Antibody Drugs: The Pursuit of the ‘High-Hanging Fruit’. 

, 17, 197–223.
3. Sheridan, C. Bispecific Antibodies Poised to Deliver Wave of Cancer Therapies. 

Bispecific Antibody Development Programs, Guidance for Industry

. Guidance Document (FDA, May 2021).
5. Jazz Pharmaceuticals. Jazz Pharmaceuticals and MD Anderson Announce Five-Year Collaboration to Evaluate Zanidatamab in HER2-Expressing Cancers. News Release. 7 Nov. 2023.
6. ONK Therapeutics. ONK Therapeutics and NAYA Biosciences Announce a Research Partnership to Advance Combination Therapy of Optimally Engineered Off-the-Shelf Natural Killer Cell Therapies and FLEX-NK™ Bispecific Antibodies. News Release, 16 Dec. 2023.
7. F-star. F-star Therapeutics Announces a License Agreement with Takeda for a Novel Next-Generation Immuno-oncology Bispecific Antibody. News Release, 20 July 2022.
8. Gilead. Gilead and MacroGenics Announce Oncology Collaboration to Develop Bispecific Antibodies. Press Release, 17 Oct. 2022.
9. Genmab. Genmab and AbbVie Announce Broad Oncology Collaboration. News Release, 10 June 2020.
10. BeiGene. Zymeworks and BeiGene Announce License and Collaboration Agreement for Zymeworks’ HER2-Targeted Therapeutic Candidates, ZW25 and ZW49, in Asia-Pacific and Research and License Agreement for Zymeworks’ Azymetric™ and EFECT™ Platforms Globally. News Release, 27 Nov. 2018.
11. Ellwanger, K.; Reusch, U.; Fucek, I.; et al. Redirected Optimized Cell Killing (ROCK®): A Highly Versatile Multispecific Fit-for-Purpose Antibody Platform for Engaging Innate Immunity. 

, 11 (5), 899–918.
12. Affimed. ICE® Molecules: A Novel Approach for Directing the Innate Immune System to Attack. 

 (accessed 19 Feb. 2024).
13. NIH. A Phase 2, Open-Label, Multi-Center Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD-30 Positive Peripheral T-Cell Lymphoma. 

 (accessed 19 Feb. 2024).
14. Reusch, U.; Damrat, M.; Wingert, S.; et al. AFM24, a Bispecific EGFR/CD16A Innate Cell Engager with the Potential to Overcome Resistance to Current Targeted Treatments for EGFR-Positive Malignancies. Poster presented at American Association for Cancer Research (AACR). Annual Meeting. 22–24 June 2020. Virtual. Poster 5659.
15. Affimed. Harnessing the Potential of the Innate Immune System for Oncology. Company Presentation, January 2024.
16. Affimed. Affimed Announces Leadership Change and Organizational Restructuring. Press Release, 8 Jan. 2024.
17. Affimed. Affimed Announces Sale of Wholly-Owned Subsidiary AbCheck. Press Release, 3 Jan. 2024.
18. De Nardis, C.; Hendriks, L.J.A.; Poirier, E.; et al. A New Approach for Generating Bispecific Antibodies Based on a Common Light Chain Format and the Stable Architecture of Human Immunoglobulin G1. 

, 292 (35), 14706–14717.
19. Merus. Merus Announces Two Clinical Abstracts on Zenocutuzumab (Zeno) in NRG1-fusion (NRG1+) Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer (PDAC) Selected for Presentation at the ESMO Congress 2023. News Release, 28 July 2023.
20. Merus. Merus Presents Interim Data on MCLA-129 at ESMO Asia Congress 2023. News Release, 2 Dec. 2023.
21. Merus. Merus’ Petosemtamab Interim Data Demonstrates Clinically Meaningful Activity in Previously Treated Head and Neck Squamous Cell Carcinoma (HNSCC). News Release. 17 April 2023.
22. Merus. Merus Announces Financial Results for the Third Quarter 2023 and Provides Business Update. News Release, 2 Nov. 2023.
23. Segués, A.; Huang, S.; Sijts, A.; et al. Opportunities and Challenges of Bi-specific Antibodies. 

, 369, 45–70.
24. Li, H.; Er Saw, P.; Song, E. Challenges and Strategies for Next-Generation Bispecific Antibody-Based Antitumor Therapeutics. 

, 17, 451–461.
25. Wang, Q.; Chen, Y.; Park, J.; et al. Design and Production of Bispecific Antibodies. 

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

Novel genetic engineering technologies are transforming the design and manufacture of bispecific antibodies, which are emerging as a promising new class of biologics.

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