Rapid Scale-up Research Articles

Exploring the critical factors in pharmaceutical supply chains revealed during COVID-19 and addressing missing links

The COVID-19 pandemic revealed profound weaknesses in global pharmaceutical supply chains, resulting in widespread shortages of critical medical supplies, delayed drug manufacturing, and disruptions in vaccine distribution. These supply chain vulnerabilities were exacerbated by several key factors, including an overreliance on a limited number of countries for active pharmaceutical ingredients (APIs), insufficient local manufacturing capacity, and logistical constraints in transportation and distribution networks. The pandemic also exposed inefficiencies in regulatory frameworks, leading to delays in approvals and limited agility in responding to rapidly changing demands. Furthermore, the lack of transparency and real-time monitoring across global supply chains hindered effective decision-making and coordination, aggravating the crisis. This paper provides an in-depth analysis of the critical factors that contributed to pharmaceutical supply chain disruptions during COVID-19, identifying missing links such as the need for diversification of supply sources, enhanced flexibility in manufacturing processes, and the integration of advanced technologies like artificial intelligence (AI), blockchain, and automation for supply chain optimization. The analysis highlights how supply chain visibility, digital innovation, and risk management strategies could improve resilience in the face of future global health crises. In addition to identifying these challenges, the paper proposes solutions to address the missing links in pharmaceutical supply chains, including the decentralization of production, the development of regional manufacturing hubs, and the creation of public-private partnerships to bolster local production. The role of government policies in facilitating faster regulatory approvals, fostering international cooperation, and incentivizing innovation is also explored. Case studies on successful post-COVID-19 adaptations, such as the rapid scale-up of vaccine production and the reconfiguration of personal protective equipment (PPE) supply chains, offer insights into effective strategies for building more resilient systems. Ultimately, this paper underscores the importance of a collaborative, multi-stakeholder approach to ensuring the stability and security of pharmaceutical supply chains. It calls for proactive measures to strengthen global supply chain infrastructures, improve regulatory agility, and embrace emerging technologies that can predict and respond to disruptions. These steps are crucial to safeguarding the continuous delivery of essential pharmaceuticals during future pandemics or other large-scale disruptions, ensuring global health security in an increasingly interconnected world.

Handling client financial insolvency in maternity services: An occurrence, experience and policy gap qualitative analysis among healthcare stakeholders in North-Central Nigeria.

To assess the occurrence of client financial insolvency, experiences of key healthcare stakeholders, and policy gaps on handling the situation during maternity services. A qualitative study was conducted in North-Central Nigeria. Participants were key healthcare stakeholders including healthcare workers from private, primary, secondary, and tertiary facilities, healthcare administrators/facility-heads, program managers and policy makers at local and state government levels through In-depth and Key Informant interviews. Identified themes were occurrence, experiences of stakeholders, and prevention of client financial insolvency. Data were analyzed with the Nvivo statistical package. Participants confirmed the occurrence of client financial insolvency. Clients' inability to pay hospital bills was due to being indigent, awaiting support from relations, or clients who were uncommitted to the payment. Health facilities lack guiding policy documents; potential cases are referred from private to public or from primary to secondary/tertiary facilities. Methods of handling financial insolvency included healthcare worker-related (staff scavenging for needed consumables, fund-raising among facility staff), facility-related (revolving fund, medical social welfare, welfare committee, discharge with re-payment plan, fee-waiver), community-related (ward development committee, religious organizations/philanthropists) interventions, or hospital detention of insolvent clients. Although clients' bills did not increase during detention, many clients did not honor post-discharge re-payment agreements. Participants suggested a client-friendly billing system, early initiation of birth preparedness, partner involvement, and a rapid scale-up of health insurance for pregnant women to curb financial insolvency. Tackling client financial insolvency requires policy documents, support to private facilities, effective debt-recovery mechanisms, and scale up of health insurance for pregnant women.

Carbon capture via electrochemically mediated alkaline absorption: Lab-scale continuous operation

Energy-efficient capture technologies need to be deployed by 2050 to abate global warming caused by excessive carbon dioxide (CO2) emissions. CO2 capture using alkaline solutions and absorbent regeneration mediated through bipolar membrane electrodialysis (BMED) have been tested previously as a standalone technology. However, the continuous operation of an integrated system remains largely unclear. Here, a bench-scale study was conducted using an integrated prototype to analyze the performance of CO2 capture and electrochemical regeneration using potassium hydroxide (KOH) aqueous solution. A wide range of current densities from 150 to 1000 A/m2 was applied to demonstrate the continuous operation of the CO2 capture system emphasizing the stability in attainable high rich carbon loading and CO2 desorption. The electrochemical regeneration module achieved CO2 desorption efficiency of 70% and absorbent recovery up to 89% under industrial relevant current densities of 500–1000 A/m2. The absorbent recovery has been identified to be a result of the combined effect of load ratio and rich carbon loading. The observed inefficient CO2 separation indicates significant potential to enhance energy efficiency. These results represent a pivotal step forward in electrochemically mediated CO2 capture technology, with promising potential for rapid industrial scale-up in the near future.

Adherence of healthcare providers to Enhanced Adherence Counseling (EAC) intervention protocol in West Amhara Public Health Facilities, Northwest Ethiopia, 2023: mixed method evaluation

BackgroundIn Ethiopia, there were an estimated 670,906 people living with the Human Immune Virus (HIV). Implementing an HIV test and treat strategy and rapid scale-up of anti-retroviral treatment (ART) provided health facilities increased the number of the number of people living with HIV/AIDS. In the same way, the expansion of viral load monitoring in these health facilities and poor adherence to ART increase the number of high-viral load (HVL) patients. To alleviate this problem, the World Health Organization (WHO) recommended EAC intervention for HVL patients. Therefore, the aim of this research was to determine the level of healthcare providers’ adherence to the EAC intervention protocol and explore barriers and facilitators of the intervention in West Amhara, Northwest Ethiopia.MethodDescriptive cross-sectional study design with concurrent mixed-method evaluation was employed. The adherence dimension, with its sub-dimensions of content, coverage, frequency, and duration of the EAC intervention, was used with sixteen indicators. A total of 20 high-case-load public health facilities and 173 HVL patients were included in our study. Quantitative data was entered into Epi Info and exported to SPSS version 25 for analysis. Descriptive statistics are analyzed in terms of frequencies, percentages, variances, and means and presented as narrations, frequency tables, graphs, and charts. Qualitative data were transcribed, translated, coded, and analyzed thematically using Open Code version 4.0 software. The qualitative findings were used to triangulate the quantitative findings.ResultThe average adherence level of health care providers (HCPs) to the EAC intervention protocol was 55.3%, from which content, coverage, frequency, and duration of the intervention contributed 70.3%, 86.3%, 36.9%, and 27.7%, respectively. Most of the intervention contents were delivered during the session, but none of the providers developed a patient adherence plan at the end of the session. All HVL patients were linked and enrolled in the EAC intervention. But only 6% of them were tested for repeat VL.ConclusionThe average adherence level of HCPs to the EAC intervention protocol was very inadequate. The main gap identified was difficulties in completing the EAC intervention sessions based on schedules. Implementing adherence improvement strategies, assigning an adequate number of EAC providers in ART and Prevention of Mother-to-Child Transmission (PMTCT) clinics, and allowing sufficient time during EAC sessions are important.

(Invited) Looking Beyond the Stack: A Systems Engineering Approach to Optimize Stack and System Design of Electrolysers

In the coming decade green hydrogen production is expected to grow at an unparalleled rate. Much of the international focus is currently on the Gigawatt scale plants, with regular announcement of new projects. From a European perspective, the rapid scale-up is necessary to reduce the reliance on fossil fuels and achieve CO₂ reduction targets. Importing green hydrogen or derivatives such as ammonia from regions where renewable electricity cost are low, is key driver for investments for the energy intensive industry, especially in the North Western part of Europe. This will require hydrogen production on a very large-scale. In contrast to the differentiation on application level, a one-size fits all approach for stack manufacturing appears to be attractive, with a high degree of standardisation and volume of production.However, as the case for the Netherlands illustrates, there are more drivers for green hydrogen production, such as addressing (regional) grid congestion, improving the business case for offshore wind farm developments, and providing green energy to small and medium enterprises. For all these use cases the requirements for the electrolyser system differ. Aspects such as the variability of the energy supply, capacity factors, logistics for operation and maintenance, available footprint, are application specific. Therefore, electrolyser system designs may need to be optimized for different markets and applications.At TNO we focus on the development, integration and validation of novel materials and innovative cell components for the different generations of electrolyser technology, both for low temperature (liquid alkaline, PEM, AEM) and high temperature electrolysers. To understand and assess the requirements for future generations of electrolyser technology, a systems engineering approach is developed together with the industrial partners. This allows to translate the requirements from the application, to the system and stack design, down to the requirements on a cell and component level.Results will be presented from several studies carried out by TNO and industrial partners in the field of low temperature electrolyser systems to understand: How to optimize a stack design for a specific application. Should an electrolyser be designed to maximize flexible operation and achieve a broad operating range? Or will a high efficiency be the most important target? And how application specific is such an optimisation.How to bring down the cost of the total system. What impact do the design choices for the electrolyser stack have on the complexity of the system around the electrolyser, the balance-of-plant? What can we learn from this for the future stack requirements?How different operating strategies impact a certain design. Which stack requirements change in large multi-stack systems powered by renewable electricity supply? Can different strategies improve overall system performance and bring down the overall cost of hydrogen production?How can the desired safety level be achieved against the lowest cost by optimizing component and stack design? As both the electrolyser technology and the value chains become more mature, a systems engineering approach will be indispensable, bringing together the requirements of the different levels: from application, electrolyser system and stack design, down to the performance of individual components.

Impacts of large-scale deployment of vertical bifacial photovoltaics on European electricity market dynamics

Self-sufficiency, climate change and increasing geopolitical risks have driven energy policies to make renewable energy sources dominant in the power production portfolios. The initial boom in the mid-2000s of global photovoltaic installations demonstrated the feasibility of the ambitious renewable energy targets. However, this rapid scale-up has introduced challenges, including price volatility and system integration issues. This communication calls the attention to these emerging challenges and offers quantitative insights on how rapid adoption of a more diversified photovoltaics deployment strategies can mitigate price volatilities, reduce fossil fuel dependence and steer Europe towards a forward-thinking sustainable energy pathway. The analysis reveals that as innovative bifacial photovoltaic systems are incorporated on a large-scale disruptive scenario, four main patterns emerge: economic value of solar production increases, base-load electricity price decreases, sun-rich countries expand their solar contributions, whereas nations with ample grid interconnections enhance their energy imports from neighbouring countries. It also underscores the importance of maintaining photovoltaics an attractive option for energy investors and traders in the future. Establishing this groundwork is critical since a successful integration of large-scale solar systems contributing to decrease price volatilities in Europe and US will carry significant repercussions for global energy policy formulation.

Reforming Climate and Development Finance for Clean Cooking

A transition to clean fuels and technology for cooking is increasingly recognised as a cornerstone of sustainable development. However, sufficient, appropriate, affordable finance to support the transition is lacking. Grounded in primary data collection via expert interviews, this study’s research objective was to critically assess development finance institutions’ (DFIs) delivery of climate and development finance to address cooking poverty. Interview findings underscore DFIs’ important role in the transition, including to create the ecosystem conditions conducive to sustained investment. However, as a group they are not demonstrating the risk appetite and financial solutions that clean cooking markets need. Nor are they operating with the agility and flexibility required for rapid scale-up. Consequently, DFIs are not optimally fulfilling their mandates to create additionality and mobilise private capital in these markets. Interviewees call for DFIs to reconsider their approach, and we rely on these findings to posit a theory of change for clean cooking finance.

Rapid Scale-Up of Screening for Early Detection of Sudan Virus Disease (SVD) in Healthcare Facilities (HCFs) during the 2022 Outbreak in Uganda

Background: The Uganda Ministry of Health (MoH) and implementing partners instituted an infection prevention and control (IPC) response strategy during the Uganda SVD outbreak in 2022 that involved rapid enhancement of screening capacity at HCFs. Rapid scale-up of screening for infectious diseases, such as SVD, is critical for early identification and triage of suspected or confirmed cases in HCFs. We describe the rapid deployment of a multimodal IPC strategy implemented in response to the SVD outbreak and the resulting impact on screening measures at HCFs. Methods: We implemented a multimodal IPC strategy in HCFs from five high risk districts to improve screening practices from November 2022–January 2023. The strategy included training health workers (HCWs) identified as IPC mentors; establishing screening areas; and providing screening supplies and communication materials. The three-day training utilized an MoH standardized training package with didactic and practice sessions. The mentors then cascaded screening information and skills to other HCWs through onsite trainings and mentorships and established screening areas. Baseline and endline (3 months after baseline) cross-sectional assessments were conducted using the MoH IPC Assessment Tool adapted from the WHO Ebola IPC Scorecard. The five main screening parameters assessed included presence of ≥ 1 meter distance between screener and the person screened, availability of a functional handwashing facility and infrared thermometer, correct record of each person’s temperature, and appropriate referral process for those suspected of having SVD to holding areas. IPC capacity was measured through the summation of each of these parameter results and calculated as an overall percentage. IBM SPSS Statistics 20 software was used for data analysis and a paired t-test done to determine any significant findings between mean scores (percentage) at baseline and endpoint. Results: A total of 296 IPC mentors were trained, screening information was cascaded to 3,899 HCWs, and screening areas were established in 1,135 HCFs. Based on the screening results from the MoH IPC assessment tool, capacity improved from 44% (SD=37) at baseline to 67% (SD=34) at endpoint. Screening capacity improved from baseline to endpoint among level II and public HCFs from 33% (SD=35) to 60% (SD=35) (p < 0 .05) and from 54% (SD=38) to 76% (SD=31) (p < 0 .05), respectively. Conclusion: Rapid implementation of a multimodal IPC strategy was successful in enhancing screening capacity across Uganda’s HCFs during a SVD response, which is critical for early identification of infected patients to interrupt transmission. This multimodal approach should be recommended for future response actions.

A unified European hydrogen infrastructure planning to support the rapid scale-up of hydrogen production

Hydrogen will become a key player in transitioning toward a net-zero energy system. However, a clear pathway toward a unified European hydrogen infrastructure to support the rapid scale-up of hydrogen production is still under discussion. This study explores plausible pathways using a fully sector-coupled energy system model. Here, we assess the emergence of hydrogen infrastructure build-outs connecting neighboring European nations through hydrogen import and domestic production centers with Western and Central European demands via four distinct hydrogen corridors. We identify a potential lock-in effect of blue hydrogen in the medium term, highlighting the risk of long-term dependence on methane. In contrast, we show that a self-sufficient Europe relying on domestic green hydrogen by 2050 would increase yearly expenses by around 3% and require 518 gigawatts of electrolysis capacity. This study emphasizes the importance of rapidly scaling up electrolysis capacity, building hydrogen networks and storage facilities, deploying renewable electricity generation, and ensuring coherent coordination across European nations.

Intimate Partner Violence and HIV Outcomes Among Women Living with HIV in Durban, South Africa

We examined the impact of past-year intimate partner violence (IPV) on HIV outcomes among women living with HIV (WLHIV) in Durban, South Africa. We assessed past-year IPV using the WHO Violence Against Women Questionnaire. We conducted logistic regression to assess associations between demographic variables and IPV at baseline, and between IPV at baseline and longitudinal HIV outcomes. Among 235 WLHIV, 17% reported past-year emotional, physical, or sexual IPV. At baseline, HIV-disclosure to partner was associated with 4.35-fold odds of past-year IPV (95% CI 1.17–16.10) after controlling for children, education, and harmful alcohol use. In the prospective analysis, IPV was associated with not achieving the co-primary outcome of retention in care and viral suppression in univariate (OR = 2.32, 95% CI 1.04–5.18), but not in the multivariate model. In the context of rapid treatment scale-up, the high burden of IPV among WLHIV needs to be prioritized, with an emphasis on disclosure support.

Self-swabbing versus assisted swabbing for viral detection by qRT-PCR: the experience from SARS-CoV-2 based on a meta-analysis of six prospectively designed evaluations conducted in a UK setting

PurposeIn April 2020, the UK Government implemented NHS Test and Trace to provide SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing for the public, with nose-and-throat swabbing for samples performed by trained staff. Self-swabbing (SS) would allow rapid scale-up of testing capacity and access. Six studies were undertaken to determine whether SS was as effective for detecting SARS-CoV-2 as swabbing performed by trained staff.MethodsSix prospective studies were conducted between April–October 2020, using six swab/media combinations. Differences between assisted swabbing (AS) and SS were evaluated for concordance, positivity, sensitivity, cycle threshold (Ct) values and void rates. Statistical analysis was performed using 95% confidence intervals (CIs), paired t-tests and model-based methods.ResultsOverall, 3,253 individuals were recruited (median age 37 years, 49% female), with 2,933 having valid paired qRT-PCR results. Pooled concordance rate was 98% (95% CI: 96%, 99%). Positivity rate differences for SS (8.1%) and AS (8.4%) and differences in pooled sensitivities between SS (86%; 95% CI: 78%, 92%) and AS (91%; 95% CI: 78%, 96%) were nonsignificant. Both types of swabbing led to pooled void rates below 2% and strongly correlated Ct values. Age, sex and previous swabbing experience did not have a significant impact on concordance or sensitivity.ConclusionThe UK adopted a policy to promote self-testing for SARS-CoV-2 based on data demonstrating equivalence of SS versus AS. Positive outcomes with SS are likely generalisable to testing for other respiratory pathogens, and we consider self-sampling and self-testing essential for future pandemic preparedness.

Rapid purification and scale-up of tilianin using counter-current chromatography with rectangular horizontal tubing

In counter-current chromatography (CCC), linear scale-up is an ideal amplification strategy. However, when transferring from analytical to predictable preparative processes with high throughput, linear scale-up would be challenging due to limitations imposed by differences in instrument parameters, such as gravitational forces, tubing cross-section area, tubing length, column volume and flow rate. Some effective scale-up strategies have been studied for different instrument parameters, but so far, these scale-up works have only been tested on standard circular (SC) tubing.The previous research of our group found that rectangular horizontal (RH) tubing can double the separation efficiency compared with conventional SC tubing, and has industrial production potential. This paper used the separation of tilianin from Dracocephalum moldavica L. as an example to demonstrate how to scale up the optimized process from analytical SC tubing to preparative RH tubing. After systematic optimization of solvent systems, sample concentration and flow rate on the analytical CCC, the optimized parameters obtained were successfully transferred to the preparative CCC. The results showed that a crude sample of 2.07 g was successfully separated using a solvent system of n-hexane - ethyl acetate - ethanol - water (1:4:1:5, v/v/v/v) in reversed phase mode, and the three consecutive separations produced a total of 380 mg tilianin in 75 min with high purities of 98.3%, as analyzed by HPLC. The total throughput achieved from the analytical to semi-preparative scale was improved by 138 times (from 12 mg/h to 1.66 g/h), while the column volume was increased by only 46.5 times (from 15.5 mL to 720 mL). This is the successful application of CCC for the separation and purification of tilianin. Given that SC tubing is the traditional configuration for CCC columns, this study is a necessary step to prove the applicability of RH tubing columns for routine use and potential large-scale industrial applications.

The Challenge Initiative: Lessons on Rapid Scale-Up of Family Planning and Adolescent and Youth Sexual and Reproductive Health Services.

The Challenge Initiative: Lessons on Rapid Scale-Up of Family Planning and Adolescent and Youth Sexual and Reproductive Health Services.

Boron-Silicon Alloy Nanoparticles as a Promising New Material in Lithium-Ion Battery Anodes.

Silicon's potential as a lithium-ion battery (LIB) anode is hindered by the reactivity of the lithium silicide (Li x Si) interface. This study introduces an innovative approach by alloying silicon with boron, creating boron/silicon (BSi) nanoparticles synthesized via plasma-enhanced chemical vapor deposition. These nanoparticles exhibit altered electronic structures as evidenced by optical, structural, and chemical analysis. Integrated into LIB anodes, BSi demonstrates outstanding cycle stability, surpassing 1000 lithiation and delithiation cycles with minimal capacity fade or impedance growth. Detailed electrochemical and microscopic characterization reveal very little SEI growth through 1000 cycles, which suggests that electrolyte degradation is virtually nonexistent. This unconventional strategy offers a promising avenue for high-performance LIB anodes with the potential for rapid scale-up, marking a significant advancement in silicon anode technology.

Decarbonisation of high-temperature endothermic chemical reaction processes using a novel turbomachine: robustness of the concept to feed variability

This paper presents a revolutionary turbomachinery concept, referred to as the turbo-reactor, which has the potential to replace gas-fired radiant furnaces and decarbonise a wide range of hard-to-abate, high-temperature endothermic chemical reaction processes. Although previous studies by the authors have confirmed the feasibility of using a turbo-reactor for steam cracking reactions, the numerical investigation presented in this work broadens the scope of potential applications for the machine to a variety of energy-intensive chemical processes, including those used for hydrogen production. This step change in technology could be the catalyst needed to enable rapid scale-up of low-carbon hydrogen technology. The innovative design of the turbo-reactor is fundamentally based on converting all of the imparted mechanical energy into internal energy, rather than pressure. This enables temperatures of up to 1,700°C to be achieved within an axial length on the order of one metre, resulting in an increase in the power density of 50 to 1,000 times compared to a surface heat exchanger. This paper presents the first comprehensive analysis of the turbo-reactor’s robustness and controllability across a broad spectrum of feeds, chemical reaction stages, Mach number regimes, and operating points, conclusively demonstrating the feasibility of a universal stage design strategy for repeatedly imparting and dissipating energy for various endothermic reaction processes.

Characterizing Use of Supervised Consumption Services among Street-involved Youth and Young Adults in the Context of an Overdose Crisis.

In response to an increase in overdose deaths, there was a rapid scale-up of supervised consumption services (SCS), including federally sanctioned SCS and low-barrier SCS known as overdose prevention sites (OPS), in Vancouver, Canada, beginning in December 2016. However, little is known about the use of such services among adolescents and young adults (AYA) in this context. We therefore sought to characterize factors associated with the use of federally sanctioned SCS and OPS among street-involved AYA who inject drugs in Vancouver during an overdose crisis. From December 2016 to March 2020, data were collected from a prospective cohort of street-involved AYA aged 14 to 26 at baseline. Using multivariable generalized estimating equation analyses, we identified factors associated with recent use of federally sanctioned SCS and OPS, respectively. Among 298 AYA who inject drugs, 172 (57.8%) and 149 (50.0%) reported using federally sanctioned SCS and OPS during the study period, respectively. In multivariable analyses, public injecting, negative police interactions, and residing or spending time ≥ weekly in the Downtown Eastside neighborhood were all positively associated with the use of federally sanctioned SCS and OPS, respectively. Additionally, ≥ daily unregulated opioid use and residential eviction were positively associated with federally sanctioned SCS use, while requiring help injecting was inversely associated. Self-identified female or non-binary gender was also positively associated with OPS use (all p < 0.05). Both federally sanctioned SCS and OPS successfully engaged AYA at heightened risk of adverse health outcomes. However, the lack of accommodation of AYA who require manual assistance with injecting at federally sanctioned SCS may be inhibiting service engagement.

Hepatitis C Elimination in Rwanda: Progress, Feasibility, and Economic Evaluation

ObjectivesIn 2018, Rwanda launched a national program to eliminate the hepatitis C virus (HCV). We aim to assess the impact of the program to date and identify strategies to achieve the World Health Organization’s HCV elimination goals by 2030. MethodsWe developed a microsimulation model to simulate Rwanda’s HCV epidemic from 2015 through 2050 and evaluated temporal trends in HCV infection, prevalence, mortality, and the total cost of care for scenarios that could achieve HCV elimination by 2030. ResultsBetween 2018 and 2022, over 7 million people were screened for HCV, and 60 000 were treated. The study projected that Rwanda could achieve HCV elimination as early as 2027. A feasible strategy of an annual screening rate of 15% and a treatment rate of 100% would achieve all World Health Organization elimination goals by 2028, requiring screening an additional 4 million people and treating 23 900 patients by 2030. The elimination strategy costs $25 million for screening and diagnosis and $21 million for treatment from 2015 to 2050. The national program would avert 4900 hepatocellular carcinoma cases and 6700 HCV-related deaths and save the health system $25.33 million from 2015 to 2050. ConclusionsRwanda is poised to become one of the first countries in the world to eliminate HCV. Rwanda’s program serves as a blueprint for other countries in the African region. By rapid screening and treatment scale-up (eg, by leveraging HIV platforms) and by drug price negotiations, HCV elimination is not only feasible but can be cost-saving in low-income settings.

Toward Large-Scale Production of Solid-State Batteries: Manufacturing Process Analysis and Cost Assessment for the Composite Cathode

In 2022 the lithium-ion battery (LIB) price has increased for the first time since its commercialization while LIBs are approaching their physicochemical energy limits.1,2 Therefore, next-generation or post LIB concepts are being intensively researched, solid-state batteries (SSBs) being evaluated to be among the most promising.3 While companies are already announcing ambitious large-scale production plans for SSBs, academic SSB research is still mainly confined to the laboratory-scale.4 The number of studies regarding SSB material scale-up, large-scale manufacturing or cost calculations is very limited.This work aims to address some of the named research gaps and reduce the knowledge gap between academia and industry. Particularly, the scaled cathode production and its cost assessment for sulfidic and oxidic SSBs are regarded. Therefor, suitable materials and processing pathways for giga-scale production of the composite cathode were ascertained by aggregating the data from a literature review, a patent analysis and expert interviews. Further, the cathode production cost was calculated by adapting the cost model of Duffner et al. (2021).5 Regarding the processing of sulfide-based SSB cathodes a wet and a dry production route is being distinguished . The wet route contains the identical process steps, as already established in LIB production, hence a quick adoption and rapid scale-up is feasible, which is expressed in the technology readiness level (TRL) of 6, the highest of all observed processes. However, challenges regarding densification and solvent compatibility must be solved beforehand. The dry route omits solvent compatibility problems. Next to equivalent challenges with densification, the scale-up of the newly implemented steps ‘dry mixing’ and ‘dry coating’ is currently limiting the large-scale potential, which is reflected in a lower TRL of 4. The scale-up of the oxidic SSB cathode production is still in its infancy (TRL 4), associated with limited processing know-how. The overall process chain will be similar to LIB production, but with the addition of a final co-sintering step, which is also the biggest barrier toward scale-up. Sintering process innovations are evaluated as promising by experts and could potentially enable low-cost, high throughput processing, but are still far from industrial scale.Cost calculations revealed that in the basic scenario, assuming a giga-scale production with state-of-the-art materials (cathode active material: NMC811, catholyte: Li6PS5Cl/Li7La3Zr2O12) while considering ascertained challenges, both SSB electrodes show significantly higher production cost than the LIB equivalent. Particularly, oxide-based cathodes show about three times the production cost of LIB cathodes (Figure 1a). By overcoming material and process challenges significant cost reductions are possible as simulated in an optimized future scenario (Figure 1b). The cost difference of LIB and oxidic SSB cathodes reduces to 16% and the dry process for sulfide-based cathodes even results in cost parity (~ 44 $ kWh1), showing the potential for cost competitiveness. The biggest drivers towards cost reduction are the increase of the cathode active material share and decreased prices of the solid electrolyte. On the process-level especially optimized mixing and drying for the sulfide-based cathode and a reduction of the sintering temperature below 500 °C for the oxide-based cathode lead to significant cost reductions. References J. Liu, Z. Bao, Y. Cui, E. J. Dufek, J. B. Goodenough, P. Khalifah, Q. Li, B. Y. Liaw, P. Liu, A. Manthiram, Y. S. Meng, V. R. Subramanian, M. F. Toney, V. V. Viswanathan, M. S. Whittingham, J. Xiao, W. Xu, J. Yang, X.-Q. Yang and J.-G. Zhang, Nat Energy, 4(3), 180–186 (2019).BloombergNEF, Lithium-ion Battery Pack Prices Rise for First Time to an Average of $151/kWh | BloombergNEF, https://about.bnef.com/blog/lithium-ion-battery-pack-prices-rise-for-first-time-to-an-average-of-151-kwh/ (2022). J. Janek and W. G. Zeier, Nat Energy, 8(3), 230–240 (2023). T. Schmaltz, T. Wicke, L. Weymann, P. Voß, C. Neef and A. Thielmann (2022).F. Duffner, L. Mauler, M. Wentker, J. Leker and M. Winter, International Journal of Production Economics, 232, 107982 (2021). Figure 1

Microporous Transport Layers Facilitating Low Iridium Loadings in Polymer Electrolyte Water Electrolyzers

Minimizing iridium content in the anodic catalyst layer (CL) of polymer electrolyte water electrolyzers (PEWE) is essential for facilitating the needed rapid scale-up of hydrogen production capacity. However, reducing the iridium loading inevitably produces thinner CLs (if not changing the catalyst itself). This can have severe effects on performance and stability, mainly due to the losses in the connectivity of the 3D structure. Microporous layers (MPLs) have the potential to improve the performance and catalyst layer utilization of PEWE cells[1], especially at low Ir-loadings since they minimize the in-plane transport length of the required species (i.e. electric and fluidic transport).In this work, we characterized the 3D structure and transport properties of typical IrO2/TiO2 core-shell PEWE catalyst layers[2] by synchrotron-based ptychographic X-ray laminography (PyXL)[3]. Furthermore, we fabricated CLs at different Ir-loadings between 2.5 – 0.1 mgIr cm-2 depositing them either on the membrane i.e. catalyst-coated membranes (CCM) or on the MPL/PTL i.e. porous transport electrode (PTE). We tested the electrodes in PEWE cells using novel MPLs and standard commercial porous transport layers (PTLs) and compared their electrochemical performance and overpotentials. We observe that ultra-low iridium loadings (0.1 mgIr cm-2) with only relatively small setbacks in performance are possible when using Pt-coated MPLs. Moreover, we correlate the electrochemical results with the 3D structure of the CL by PyXL and the MPL/CL interface by lab-based X-ray tomographic microscopy (Figure 1). Finally, we will discuss the challenges of fabricating low-loaded anodic CLs in CCM and PTE configuration and the advantages of using an MPL in both scenarios.[1] T. Schuler, J. M. Ciccone, B. Krentscher, F. Marone, C. Peter, T. J. Schmidt, F. N. Büchi, Adv. Energy Mater. 2020, 10, 1903216.[2] S. De Angelis, T. Schuler, M. Sabharwal, M. Holler, M. Guizar-Sicairos, E. Müller, F. N. Büchi, Sci Rep 2023, 13, 4280.[3] M. Holler, M. Odstrcil, M. Guizar-Sicairos, M. Lebugle, E. Müller, S. Finizio, G. Tinti, C. David, J. Zusman, W. Unglaub, O. Bunk, J. Raabe, A. F. J. Levi, G. Aeppli, Nature Electronics 2019, 2, 464.Figure 1. Surface renderings from XTM/PyXL and SEM images of porous transport electrodes (PTE, left) and catalyst-coated membranes (CCM, right) of selected samples used in this work. Figure 1

Lipid Nanoparticle-Mediated Gene Editing of Human Primary T Cells and Off-Target Analysis of the CRISPR-Cas9 Indels

Background and Aims: The CRISPR/Cas9 system has emerged as a powerful tool for gene editing of primary cells. In our previous work, we demonstrated a novel lipid nanoparticle (LNP) reagent for the multi-step engineering of gene-edited CAR T cells. We showed high cell viabilities and potent CAR-T mediated killing, even after multiple genetic manipulations. Here, we extend this work by assessing potential off-target editing effects in both LNP-treated T cells and T-cells where the CRISPR reagents were delivered by electroporation. Further, we evaluated multiple Cas9 variants and guide RNA targets. Methods: LNPs encapsulating wild type or high fidelity S.p. Cas9 mRNA and various TRAC and CD52 targeted guide RNAs (sgRNAs) were produced using our scalable NanoAssemblrTM microfluidics platform. Concurrently, electroporation was performed to deliver equivalent cargoes. Purified primary T cells were cultured, activated, and expanded in serum-free media in plates, flasks, or small bioreactors. The LNPs were added to cells by direct addition for gene editing. Gene expression and cell viability were measured using flow cytometry or colorimetric assays. Multi-target performance of CRISPR-Cas9 editing was evaluated through rhAmpSeq-based targeted next-generation sequencing (NGS) and indels analyzed for with CRISPRAltRations. Results: TCR or CD52 targeted Cas9 mRNA-LNP addition or electroporation yielded high single and double knockout efficiencies. High-throughput NGS analysis showed strong agreeance to flow cytometry for on-target analysis. We tested a range of sgRNA targets, wild-type and high-fidelity Cas9 mRNAs, and determined off-target editing for all targets and variants investigated. Similar results were obtained when comparing different LNP batch sizes (micro to milligram RNA) and cell culture vessels (0.1 to 45 million cells), demonstrating scalability of both LNP production and cell treatment. Conclusions: The results from this study further support the utility RNA-LNPs for the genetic engineering of primary T cells. The simple and gentle nature of LNP cell treatment allows for multiple genetic engineering steps for simultaneous expression and deletion of proteins for the next cell therapies. These LNPs can be easily manufactured from small-scale screening of RNA libraries to rapid scale-up for clinical translation.