The use of quality-by-design (QbD) principles, supported by standard processes and tools, are well established across industry for delivering enhanced understanding of pharmaceutical drug product and manufacturing processes as well as ensuring regulatory expectations are met. A key pillar of QbD is quality risk management (QRM), which positions risk assessments at the intersection of numerous pharmaceutical processes, acting as a lynchpin, driving control strategy development, technology transfer, supporting regulatory submissions and lifecycle management of manufacturing processes. The primary objective of this article is to explore the use of digital risk assessment platforms and their advantages.

Risk assessments are an essential element within the QbD framework and play a vital role in identifying and controlling product quality risks across the product life cycle. Risk assessments systematically dissect both product and process designs based on potential hazards, aiming to identify risks and quantify their criticality to craft effective risk mitigation and control strategies. Moreover, they help to prioritize the experimental strategy focusing on the process steps with a high number of critical parameters to establish the optimal modeling strategy. The overarching goal of a risk assessment is to provide decision-makers with a comprehensive understanding of the drug product and manufacturing process, facilitating informed decision-making and the implementation of risk mitigation strategies. There are various risk management techniques described in International Council for Harmonisation (ICH) Q9, including basic risk management facilitation methods, failure mode and effects (criticality) analysis (FMEA and FMECA), fault tree analysis (FTA), hazard analysis and critical control points (HACCP), hazard operability analysis (HAZOP), and preliminary hazard analysis (PHA). FMEA, in particular, is a widely used tool for identifying, assessing, and analyzing risks used to prioritize work packages to ensure the development of safe and effective medicines.

Traditional risk assessment workflows using spreadsheets or word-processors can be laborious and have limited capacity to connect with the vast volumes of data generated by organizations, including product specific understanding. This leads to challenges with leveraging prior knowledge, which in turn can result in unwanted inconsistencies between risk assessments for a single product or across multiple products of the same modality. While these risk assessments are acknowledged for their inherent value, they are limited in scalability and susceptible to human errors. The resource-intensive nature of these assessments results in the generation of large datasets that prove complex to maintain and analyze using traditional techniques, leading to knowledge silos.

In response to the evolving landscape, pharmaceutical companies have developed risk assessments embedded with prior knowledge, often stored in a collection of spreadsheets and written report templates. However, these encounter the same challenges that extend beyond their effectiveness, posing limitations on knowledge sharing. The current paradigm of risk assessments operating primarily in this traditional, siloed, unintegrated format results in significant challenges associated with collaborative risk management across disciplines, groups, and even regulatory agencies, making the need for a more integrated and collaborative digital approach evident.

BioPharm International® Quality and Regulatory Sourcebook

is scientific leader, QbD and digital platforms, medicines development and supply at GSK Upper Providence, Collegeville, PA, USA.


is scientific leader, QbD and digital platforms, medicines development and supply at GSK Upper Merion, King of Prussia, PA, USA.


is head vaccines projects CMC statistics technical R&D, Projects, and Digital Sciences at GSK, Rixensart, Belgium.


phil.j.borman@gsk.com, is director and senior fellow, QbD and digital platforms, medicines development and supply at GSK, Stevenage, UK.


*To whom all correspondence should be addressed.

When referring to this article, please cite it as Borman, P. Digitalization of QbD Risk Assessments. 

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Quality

The digital transformation of quality-by-design assessment workflows can improve efficiency, reduce human errors, and facilitate integration within a much broader digital ecosystem.

Digitalization of QbD Risk Assessments

The adoption of single-use technologies (SUTs) in biopharmaceutical manufacturing reduces manufacturing costs, increases the manufacturing line flexibility, and improves the speed and efficacy of the line changeovers or the batch turnaround times. The closed manufacturing systems also facilitate production of a safe and regulatory-compliant product. SUTs are used throughout the biopharma manufacturing process flow, the single-use filter capsules, tubing, and connectors being the most widely used in the final fill/finish applications of the injectable preparations. The single-use bioreactor bags and buffer storage bags are used for upstream applications. This paper reviews the drivers for adoption of SUTs and how the risks from the use of these technologies can be overcome in a planned, proactive, and compliant manner. 

The adoption of single-use components emerged from the mid-1980s. Initially, blood bags replaced glass bottles and soon became available with a plastic tube or two as well as connectors, valves, and vials for taking biological samples. The polyvinyl chloride blood bags used for blood donations were more than just bags. Evolving from these examples are the current single-uses systems (SUS) that are gaining wider use in the biopharmaceuticals industry, especially for the production of specialized and/or small-batch biopharmaceutical drugs. These SUS are the alternatives to the systems made of relatively inflexible stainless-steel vessels and reactors, hard piping, valves, and so on. Such fixed systems must be cleaned and sterilized between batches, a relatively labor and energy-intensive operation. The adoption of aseptic connectors, tubing, mixers, storage bags, and sampling bags and usage of capsule filters in a wide range of applications in the late 1990s lead to the “plastic factory” concept in the 2000s. The technology was further expanded to the upstream and downstream unit operations in the biopharma industry, such as the bioreactors, chromatography, virus removal filtration, concentration, and purification steps. This expansion has evolved over time to the current-day concept of closed continuous processing technology, which is almost completely based on SUTs and assemblies (1,2).

Single-use or disposable bioprocessing equipment is now used for ≥85% of pre-commercial scale (i.e., preclinical and clinical) biopharma manufacturing and is increasingly being adopted for commercial product manufacturing, according to an industry survey (3). The leading reasons cited in the survey as being “very important” for the adoption of SUS include a decrease in the risk of cross-product contamination, cited by 46.2% survey respondents; eliminating cleaning requirements, cited by 41.2% of respondents; reducing time to get facility up and running, cited by 44.1% of respondents; and reduction in capital investment in facility and equipment, cited by 40.4% of respondents.

A study found that SUTs, when adopted, required 87% less water (primarily by reducing steaming in place [SIP], cleaning, and changeover between batches), 21% less labor (primarily by reducing cleaning in place [CIP] activities), 38% less space, and 29% less energy (4). According to industry sources (5), SUS lower operating costs by offering 46% water and energy reductions, a 35% more favorable carbon dioxide footprint due to lower facility emissions, and a 40% lower initial investment cost. The technology allows biopharma manufacturers to push products to market faster by increasing throughput and making scalability easier (5). The availability of this technology has made new biopharma companies adopt SUS, as it requires less upfront capital investment and enables quick advancement of development efforts towards new products (6).

1. Rathore, A. S.; Agarwal, H.; Sharma, A. K.; Pathak, M.; Muthukumar, S. Continuous Processing for Production of Biopharmaceuticals. 

 (8), 836–849. DOI: 10.1080/10826068.2014.985834.
2. Klutz, S.; Magnus, J.; Lobedann, M.; et al. Developing the Biofacility of the Future Based on Continuous Processing and SUT. 

, 120–130. DOI: 10.1016/j.jbiotec.2015.06.388
3. Langer, E. S.; Rader, R. A. Biopharmaceutical Manufacturing is Shifting to SUS. Are the Dinosaurs, the Large Stainless-Steel Facilities, Becoming Extinct? 

 online, Oct. 23, 2018.
4. Lim, J.; Cox, S.; Leveen, L.; Monge, M.; Sinclairm A. The Environmental Impact of Disposable Technologies. 

.
5. Single Use Support. Pioneering Biopharma. 

 (accessed Jan. 21, 2024).
6. Das, S. The Appeal of Single-use Tech. 

Ramesh Raju Mavuleti*, rrajum@gmail.com, is head of operations, Validation Services India; Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC; and Tathagata Ray, is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd.; K. Vasantakumar Pai, PhD , is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University; K. Sreedhara Ranganath Pai, PhD, is professor, epartment of Pharmacology, Manipal Academy of Higher Education; and Somasundaram Gopalakrishnan, is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

When referring to this article, please cite it as Mavuleti, R. R.; Pai, K. V.; Pai, K. S. R.; et al. Review of SUT Adoption in Biopharma Manufacturing. 

Manufacturing

The evolution of therapeutic modalities drives the adoption of single-use technologies.

Review of SUT Adoption in Biopharma Manufacturing

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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.”

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

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. 

The authors discuss subjectivity in the ICH Q9 (R1) guidance document.

Subjectivity in Quality Risk Management

Cell and gene therapies (CGTs) offer the potential to revolutionize healthcare by addressing unmet medical needs. However, the science is advancing at a pace faster than regulatory authorities can issue relevant laws, regulations, and guidance documents. Therefore, it is imperative that the industry apply appropriate compliance controls in the manufacturing of CGT products. These products pose unique manufacturing and compliance challenges due to their inherent nature (i.e., originating from living organisms, being used in the treatment of only one or a limited number of persons, extremely small batch sizes, and challenging contamination control). There is limited manufacturing and regulatory experience with CGTs, as only few products have yet obtained marketing authorization; 31 CGTs were approved by FDA (1) by mid-2023 and 25 by the European Medicines Agency (EMA) (2). CGTs are termed advanced therapy medicinal products (ATMP) in Europe. Yet, the pipeline is still growing, with more than 2000 CGTs/ATMPs in clinical pipelines (3). These products are at the forefront of research and, as a consequence, many companies involved in their discovery are small and medium-sized enterprises, often with staff who are inexperienced or unfamiliar with regulatory expectations and/or spin-offs from academic research centers.

The importance of applying the appropriate level of compliance in the respective phases of the product’s lifecycle cannot be over-emphasized. The chemistry, manufacturing, and controls (CMC) for these products will be scrutinized by the approving regulatory authorities, such as FDA and EMA. Any delay to the approval of clinical trials or license to market the CGT will not only be costly, but it will also delay essential therapies, often without any alternative, for patients. For instance, some sponsors have experienced delays with FDA at key trial milestones for reasons including failure to agree on the required potency assays to fully define a specific therapy. These types of setbacks illustrate that proactive planning for CMC compliance is a significant contributor to ultimate success of a product. Where compliance may be an afterthought, there are often regulatory delays, which are exacerbated by the growing pipeline of therapies and under-resourced regulatory agencies. Therefore, going to the back of the queue at later stages because of preventable compliance mistakes is costly and can jeopardize a highly valuable first-to-market position.

Good manufacturing practices (GMPs) apply from clinical Phase I onwards (4) (see Figure 1). This implies that, at this point, a pharmaceutical quality system (PQS) in accordance with International Council for Harmonisation (ICH) Q12 (5) must be in place. Knowledge about the product increases along the lifecycle (i.e., knowledge about the quality target product profile [QTPP], the process, material, and environmental properties impacting the QTPP, and the necessary controls to achieve the desired product quality, safety, and efficacy).

The recommended and anticipated regulatory expected level of GMP is illustrated using the example of chimeric antigen receptor T-cell (CAR-T) productscell products, which are cell therapy drugs. There are generally two components for manufacturing CAR-T drug products: a vector carrying well-characterize genes, and T cells from the patient or a donor. The T cells are genetically modified ex vivo with a vector to enable recognition of a desired target antigen on the surface of tumor cells. The modified T cells are then introduced back to the patient for therapeutic purpose.

Zhongren Wu, PhD, is principal consultant at Parexel; Siegfried Schmitt, PhD, is vice president, Technical, at Parexel; and Lynne Ensor, PhD, is senior director, Pharma Biotech and Dietary Supplements Consulting at NSF.

When referring to this article, please cite it as, Zhongren, W.; Schmitt, S.; Ensor, L. Phase-appropriate Compliance for Cell and Gene Therapies. 

BioPharm International Quality and Regulatory Sourcebook

Gene and Cell Therapies

Understanding how to apply phase-appropriate GMPs is crucial for achieving successful regulatory approval.

Quality and Regulatory Sourcebook, March 2024 eBook

Digitalization of QbD Risk Assessments

Review of SUT Adoption in Biopharma Manufacturing

Subjectivity in Quality Risk Management

Phase-appropriate Compliance for Cell and Gene Therapies