Early Product Development Research Articles

Research and Development of a Large-Scale Axial-Flux Generator for Hydrokinetic Power System

The study demonstrates an application of actual technologies and tools for the development of an axial-flux electricity generator. The specifics of its application—a run-of-river sited power station—predefine some of the design parameters that are close to a wind turbine generator. An extensive study of available solutions is used as a starting point for further concept development. The study aims to provide a viable solution for a large-scale electrical machine. A step-based methodology is defined for concept parameters’ assessment and a feasibility study. It demonstrates the advantages of virtual prototyping when assessing various design parameters such as air gaps, coil thickness, and the number of rotor disks. Several simulations over different virtual prototypes provide sufficient information to elaborate an improved design concept. The major result is a ready-for-detailed design concept, with defined major parameters and studied work behavior for a specific, large structure of an electrical machine. Another important result is the presentation of the application of virtual prototyping in the assessment of large structures, for which physical prototyping is an expensive and time-consuming approach. The application of virtual prototyping at a very early product development stage is an effective way to undertake efficient solutions involving the concept of the product.

Rapid estimation of carbon footprints in agrochemical development: correlation of process mass intensity with CO2 emissions.

The agricultural sector faces a challenge in balancing increasing food demand while minimizing environmental impacts. Crop protection products are crucial for achieving high crop yields and ensuring food security. However, life cycle assessment (LCA), the standard framework for evaluating environmental impact, is time-consuming and costly, especially during early product development. To address this, a novel tool correlating process mass intensity (PMI) with greenhouse gas (GHG) emissions has been developed as a streamlined alternative. A strong linear correlation (R2 = 0.95) was identified between PMI and product GHG emissions, enabling rapid carbon footprint estimation using simplified PMI data. The model was validated using 13 small molecule active ingredients (AIs), showing a mean absolute error (MAE) of 55 g CO₂/kg AI and a root mean square error (RMSE) of 64 kg CO₂/kg AI. Residual analysis demonstrated random distribution, suggesting reliable predictions. The PMI-based tool provides rapid, accurate estimates of product carbon footprint (PCF), supporting early-stage decision-making in research and development for agrochemical processes. Its simplicity makes it applicable across various chemical sectors and valuable for sustainability efforts. © 2024 Society of Chemical Industry.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of ‘inhalation biopharmaceutics’ i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using ‘simple’ Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

Comparative Analysis of Transmission Housings to Evaluate Whining Noise Performance

A quite cabin is always a preferred choice of the customer. Powertrain acts as a source for many noise and vibration problems in a passenger car. Transmission plays a major role in modulating the power from engine to the drive train and is exposed to a high vibration and noise environments. Hence design of transmission for low vibration & noise is need of the hour. This paper attempts to perform a comparative study of 6 housings of different design of a two-wheel drive passenger car to evaluate the vibration performance and Noise radiation characteristics by using FEM (Finite Element Method) & BEM (Boundary Element Method) & finite element analysis techniques. The authors also try to put forward a layout comparison study for the housings and conclude what design is best suited for better NVH whine performance in view of vibrations & sound radiation. These indicative results from this paper can be referred by the design & analysis engineers during early product development of the transmission.
 Keywords: Transmission, Housings, Whining Noise, Bionic Design, NVH Analysis, Durability Analysis, Study of Housings, Housings NVH Analysis

Eco-performance evaluation of product designs – an integrated fuzzy complex proportional assessment with life cycle assessment

ABSTRACT The growing public awareness has driven enterprises to develop environmentally friendly designs to fulfill customer satisfaction. Some eco-design tools have been introduced to designers to support greener product design and development qualitatively. However, most require qualitative judgement during the evaluation process. Although life cycle assessment (LCA) helps quantify a product system’s environmental loads, it requires much time and resources for data collection. Design selections are not preferred during the early product development stage, especially when the product development schedule is rather tight nowadays. This paper proposes a practical approach integrating a fast-track LCA, fuzzy-set, with COmplex PRoportional ASsessment (COPRAS). This paper proposes an approach by incorporating the fuzzy-set, COPRAS, and LCA for decision-makers to evaluate design alternatives at the early product development stage. The originality of the paper is to provide an efficient approach to evaluating various design alternatives by quantifying their corresponding environmental burdens using LCA and fuzzy-set. Three distinct features can be found in the proposed generic approach. This study brings two contributions to the related field. For the area related to environmental impact assessment, this study illustrates the applicability of LCA in conjunction with COPRAS and fuzzy-set for the design alternative selection. Decision-makers can apply the proposed method that in-depth knowledge of environmental impact assessment is not essential, and the qualitative input required is minimal compared to a comprehensive LCA study.

Alternative methods go green! Green toxicology as a sustainable approach for assessing chemical safety and designing safer chemicals

Green toxicology is marching chemistry into the 21st century. This emerging framework will transform how chemical safety is evaluated by incorporating evaluation of the hazards, exposures, and risks associated with chemicals into early product development in a way that minimizes adverse impacts on human and environmental health. The goal is to minimize toxic threats across entire supply chains through smarter designs and policies. Traditional animal testing methods are replaced by faster, cutting-edge innovations like organs-on-chips and artificial intelligence predictive models that are also more cost-effective. Core principles of green toxicology include utilizing alternative test methods, applying the precautionary principle, considering lifetime impacts, and emphasizing risk prevention over reaction. This paper provides an overview of these foundational concepts and describes current initiatives and future opportunities to advance the adoption of green toxicology approaches. Chal-lenges and limitations are also discussed. Green shoots are emerging with governments offering carrots like the European Green Deal to nudge industry. Noteworthy, animal rights and environ-mental groups have different ideas about the needs for testing and their consequences for animal use. Green toxicology represents the way forward to support both these societal needs with sufficient throughput and human relevance for hazard information and minimal animal suffering. Green toxi-cology thus sets the stage to synergize human health and ecological values. Overall, the integration of green chemistry and toxicology has potential to profoundly shift how chemical risks are evaluated and managed to achieve safety goals in a more ethical, ecologically-conscious manner.

The role of economic evaluations in advancing HIV multipurpose prevention technologies in early-stage development.

Product development is a high-risk undertaking, especially so when investments are prioritized for low- and middle-income countries (LMICs) where markets may be smaller, fragile, and resource-constrained. New HIV prevention technologies, such as the dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA), are being introduced to these markets with one indication, meeting different needs of groups such as adolescent girls and young women (AGYW) and female sex workers (FSWs) in settings with high HIV burden. However, limited supply and demand have made their uptake a challenge. Economic evaluations conducted before Phase III trials can help optimize the potential public health value proposition of products in early-stage research and development (R&D), targeting investments in the development pathway that result in products likely to be available and taken up. Public investors in the HIV prevention pipeline, in particular those focused on innovative presentations such as multipurpose prevention technologies (MPTs), can leverage early economic evaluations to understand the intrinsic uncertainty in market characterization. In this perspective piece, we reflect on the role of economic evaluations in early product development and on methodological considerations that are central to these analyses. We also discuss methods, in quantitative and qualitative research that can be deployed in early economic evaluations to address uncertainty, with examples applied to the development of future technologies for HIV prevention and MPTs.

Supporting Sustainable Product Design with Engineering Data Management Capabilities

Today, innovations are no longer defined just by technical progress but also, in particular, by environmental aspects (such as carbon gas emissions). The issue of reuse is also becoming increasingly central to purchasing decisions and is forcing manufacturing companies to deal transparently with environmental impacts. This is also receiving a lot of political attention and is underlined by increasingly far-reaching regulations on sustainability, such as CSRD, Product Declarations, Transparent Supply Chains, Substance Compliance, etc. Since 80% of the environmental impact is already determined in the early product development phases, there is a high potential for improvement. This is where engineering data management approaches (such as PLM) come into play as a systematic approach to data, document, and information management. Many KPIs for determining the environmental impact are often already available in PLM. Still, it is necessary to bring them into context in a targeted way to support early qualitative and quantitative evaluations in the engineering phases regarding the current environmental impact of the design. The paper, therefore, presents a concept based on PLM-available data along the product engineering process for assessing ecological impact. This includes the product life cycle (and the supply chain) as well as the prototypical provision of environmental information and is demonstrated using platform technology by CONTACT Software.

Higher or Lower? - The Resolution of Analytical Pipelines for the Evaluation of Lipid Nanoparticle Critical Quality Attributes

Dynamic light scattering (DLS) is a routinely used analytical technique to measure the size distribution of a colloidal sample. Nanoparticle tracking analysis (NTA) has more recently emerged as an orthogonal technique to determine particle size and estimated concentration, although widespread use of NTA for lipid nanoparticle (LNP) analysis is not reported. Here, we use DLS and NTA to screen the stability of oligonucleotide drug loaded lipid nanoparticles (oligo-LNPs) at ultra low storage temperatures (-80 °C) in the presence and absence of a cryoprotectant (20 % sucrose, w/v) as a case study to highlight differences in technique resolution. NTA was able to detect additional LNP subpopulations samples for all measured samples, whereas DLS was unable to detect these subpopulations. Our study conveys that the use of orthogonal sizing techniques can support early stage product development, where a more in-depth analysis of formulation and process parameters on LNP stability would support comprehensive understanding of variable defining product stability.

A Colourful Way to Unravel the Important Fluidization-Related Granule Size Effect on Semi-Continuous Drying.

Continuous twin screw wet granulation (TSWG) systems are possible pathways for oral solid dosage manufacturing in the pharmaceutical industry. TSWG requires a drying step after granulation before the tableting process. Typically, semi-continuous fluidized bed dryers (FBDs) are used for this purpose. At the same time, the pharmaceutical sector is interested in mathematical prediction models to save resources during the early drug product development (DPD) stage or to control manufacturing. Several authors have already developed prediction models for semi-continuous drying processes. However, these model structures reported systematic prediction offsets, which could be related to the incomplete implementation of fluidization and granule segregation phenomena. This study evaluates the complex fluidization behavior of wet granules in industrially relevant semi-continuous FBDs. A transparent perspex version of the dryer was used for the analysis of bed height, pressure drop, porosity, segregation, and spatial heating patterns at varying process settings. The investigated behaviors of the fluidizing bed will be helpful to derive phenomenological (sub)models for the detailed description of segregation in the semi-continuous fluidized bed system. In this study, it was found that semi-continuous FBDs are characterized by a change in fluidization regime from plug flow to a bubbling bed at the moment that the granule bed slumps. Secondly, the presence of size-based vertical segregation phenomena as well as spatial temperature differences were proven. The experimental results suggest that larger granules are dried under more intense drying conditions than smaller granules.

In-house CHO HCPs platform: A promising approach for HCPs ELISA monitoring

A key aspect that must be supervised during the development of recombinant therapeutic products is the potential presence of impurities.Residual host cell proteins (HCPs) are a major class of process-related impurities derived from the host organism that even in trace amount have the potential to affect product quality, safety, and efficacy. Therefore, the product purification processes must be optimized to consistently remove as many HCPs as feasible, with the goal of making the product as pure as possible. The workhorse of HCP monitoring and quantitation during bioprocessing manufacturing is sandwich ELISA (enzyme‐linked immunosorbent assay), which employs polyclonal anti-HCP antibodies for both capture and detection. Commercial ELISA kits developed from Chinese Hamster Ovary (CHO) cell lines are widely applied in early drug development stages (preclinical, phase I, and phase II), but are not specifically designed for a given manufacturer's proprietary cell line, and users do not have control over reagent availability and lot-to-lot consistency. For later development stages, the upstream process-specific method is preferred to guarantee an improved sensitivity and coverage. In agreement with the USP General Chapter 〈1132〉, a platform assay can be used in place of the commercial one through all stages of product development, if already available when product development starts.This proof-of-concept study was carried out to demonstrate the feasibility and the advantages of the development of a proprietary CHO HCPs platform ELISA. Different proprietary mock materials have been characterized and compared by orthogonal bidimensional electrophoresis techniques (SDS-PAGE coupled to SS/WB and 2D DIGE) with the scope of selecting the best antigen-antibody couple for setting up the in-house ELISA. A preliminary evaluation of the in-house method performance has been done in comparison with the commercial assay, demonstrating that the platform method is promising for an accurate and precise CHO HCPs quantification during the early phase product and process development.

A Novel Approach to Predict the Structural Dynamics of E-Bike Drive Units by Innovative Integration of Elastic Multi-Body-Dynamics

This paper presents a novel approach to address noise, vibration, and harshness (NVH) issues in electrically assisted bicycles (e-bikes) caused by the drive unit. By investigating and optimising the structural dynamics during early product development, NVH can decisively be improved and valuable resources can be saved, emphasising its significance for enhancing riding performance. The paper offers a comprehensive analysis of the e-bike drive unit’s mechanical interactions among relevant components, culminating—to the best of our knowledge—in the development of the first high-fidelity model of an entire e-bike drive unit. The proposed model uses the principles of elastic multi body dynamics (eMBD) to elucidate the structural dynamics in dynamic-transient calculations. Comparing power spectra between measured and simulated motion variables validates the chosen model assumptions. The measurements of physical samples utilise accelerometers, contactless laser Doppler vibrometry (LDV) and various test arrangements, which are replicated in simulations and provide accessibility to measure vibrations onto rotating shafts and stationary structures. In summary, this integrated system-level approach can serve as a viable starting point for comprehending and managing the NVH behaviour of e-bikes.

Life Cycle Assessment Research Trends and Implications: A Bibliometric Analysis

Acknowledging the importance of sustainability and implementing measures to achieve the UN’s 17 Sustainable Development Goals (SDGs) by 2030 represent a holistic approach to promoting peace and prosperity for the planet and its inhabitants. LCA is a valuable tool for organisations to enhance sustainability and reduce environmental impact. There has been a notable increase in LCA research subjects, indicating a recognition of its significance in promoting sustainability. The field has experienced a significant expansion in the past decade, with a 30% annual percent growth rate in LCA publications since 2010. In the most recent 4 years alone, 47% of all LCA publications since 1991 were produced. This paper presents a comprehensive review of LCA research from 1991 to 2022, with a specific focus on the period from 2019 to 2022. The study identifies research avenues and trends in LCA research using diverse bibliometric analysis techniques alongside content examination and the SciVal topic clusters prominence indicator. This comprehensive approach reveals evolving trends, such as an increased emphasis on practical applications for global sustainability goals, LCA’s expansion into bio-based materials due to plastic pollution concerns, and quantification of circular economy benefits in solid waste management. Moreover, deeper exploration of energy-related sustainability aspects and the integration of LCA into early product development for eco-conscious design are observed. These trends signify widespread LCA adoption across industries to address energy and design-related sustainability challenges. The study acknowledges interdisciplinary collaboration among researchers, industry, and governments, shaping a robust LCA research landscape. China’s heightened contributions as a leading contributor to the field have reshaped the global LCA landscape mirrored in the evolving prominence of journals, institutes, and funding organisations.

EXPANDING USER NEED FINDING THROUGH ABDUCTIVE REASONING

AbstractPrior research has shown the importance of latent user needs for enabling innovation in early product development phases. The success of a product is largely dependent on to what extent the product satisfies customer needs, and latent user needs play a significant role in impacting the way the product or service unexpectedly delights the user. Complications arise because traditional need finding methods are not able to account for the nuances of latent user needs. A user's need is multidimensional while traditional methods are built on deductive reasoning. The traditional method isolates parts of the user's needs, only pointing to what is deducible within its search space. To address this, we introduce abduction as a way to broaden traditional need finding methods. From a logic based argument it is shown that abduction accounts for the dimensionality of user needs by integrating various traditional need finding theories using design knowledge to isolate the latent need. This theoretical development shows that latent need finding must go beyond a deductive focus, to developing methods that are able to conjecture with the deduced facts in order to abduce the latent user need.

NEW OPPORTUNITIES AND BENEFITS IN THE PRODUCT DEVELOPMENT PROCESS USING THE MACHINE LEARNING BASED DIRECT INVERSE METHOD FOR MATERIAL PARAMETER IDENTIFICATION

AbstractFinite element (FE) simulations can be used both in the early product development phase to evaluate the performance of developed components as well as in later stages to verify the reliability of functions and components that would otherwise require a large number of physical prototype tests. This requires calibrated material cards that are capable of realistically representing the specific material behavior. The necessary material parameter identification process is usually time-consuming and resource-intensive, which is why the direct inverse method based on machine learning has recently become increasingly popular. Within the neural network (NN) the generated domain knowledge can be stored and retrieved within milliseconds, which is why this method is time and resource-efficient. This research paper describes advantages and potentials of the direct inverse method in the context of the product development process (PDP). Additionally, arising transformation opportunities of the PDP are discussed and an application scenario of the method is presented followed by possible linkage potentials with existing development methods such as shape optimization.

Prototyping in smart product design: Investigating prototyping tools to support communication in the early stage smart product development

ABSTRACT Smart product design (SPD) is more complex than traditional product design (TPD), requiring intense interdisciplinary collaboration. It is well understood that prototypes are an effective means to facilitate communicating design concepts. However, there is limited research concerning prototyping preferences of design disciplines involved in SPD. The research explores the use of prototyping in smart product development. Specifically, it aims to understand the preferences and dimensions of fidelity of different prototyping tools that can support communication in the SPD process for various stakeholders. This paper presents two surveys. The first investigates the use of prototyping tools by different disciplines involved in SPD versus TPD. The second compares elements of key prototyping tools used across disciplines within SPD. Results show that the interactivity and environment dimensions of fidelity of prototyping tools motivate differences in preference between SPD and TPD. Moreover, user depiction and contextual information are key elements of prototyping that support designers in communicating interactive and environmental qualities of SPD concepts.

Challenges in Geometry Assurance of Megacasting in the Automotive Industry

Abstract Megacasting is a new concept in the automotive industry. A large number of sheet metal parts will be replaced with one large aluminum casting, i.e., a megacasting. This helps to reduce weight, opens up for larger design flexibility, allows for a more circular production, and takes away a large number of assembly steps in the production process. However, there are also challenges related to the use of megacastings. This position paper outlines challenges associated with the geometrical quality of the final product. It covers robust design and tolerancing in early product development phases as well as inspection preparation during pre-production and digital twin setup during full production to ensure the geometrical quality of a product containing a megacasting. Simulations of both part-level and assembly-level deviation and variation are discussed. The paper outlines a geometry assurance process for products containing megacastings in the automotive industry, and what research challenges that are the most important ones to address in this area. It is concluded that computer-aided tolerancing tools must be able to predict the dimensional effects from joining methods such as flow-drill fasteners or self-pierced riveting, to use casting simulation as input, and to handle combinations of solid and surface meshes. Furthermore, there might be a need for adjustments to the joining process based on digital twins to achieve proper quality at a reasonable price. Experiences in using megacastings in the body-in-white are lacking and a fast learning curve is required.

Developing Picture Storybook in English with Wetlands Theme for Young Learners

Stories encourage young learners to understand concepts and vocabulary while expanding their background knowledge about their surroundings. Therefore, providing young learners with a variety of storybooks to develop their understanding of their environment is important to be done by considering their interests and the content of the books. Based on this view, this research aimed to design a picture storybook written in English and with a wetlands environment. Simultaneously this research and development (R&D) referred to development procedures by Borg and Gall (2007) that simplified the process to only seven procedures: prelim approach methods data collection, research planning, early product development, expert validation, revision, field testing, and the last is disseminating and implementing the final product. The instruments used to collect data were a questionnaire, an interview with 15 kindergarten teachers on the need analysis stage and field testing stage, and two validation sheets validating the content and design stage. The results from data analysis showed that it is important to name some animals and plants that live specifically in South Kalimantan wetlands as the main characters of the storybook, such as timpakul, haruan, papuyu, bekantan, mangrove trees, and kasturi. Next, the developed picture storybook was feasible to be used as media for introducing English and wetlands since it was proven to be valid, practical, and effective.

Potency Assay Development: A Keystone for Clinical Use.

Potency can be described as the quantitative measure of biological activity, that is, the ability of an Advanced Therapy Medicinal Product (ATMP) to elicit the intended effect necessary for clinical efficacy. Potency testing is part of the quality control strategy necessary for batch release and is required for market approval application of an ATMP. Thus, it is crucial to develop a reliable and accurate potency assay. As a prerequisite for potency assay development, it is essential to define the mode of action of the product and thereby also the relevant biological activity that should be measured. The establishment of a potency assay should be initiated already during early product development followed by its progressive implementation into an ATMP's manufacturing, quality control and release process. Potency testing is indispensable for clinical use with a wide range of applications. A potency assay is a valuable tool to determine the product's stability, detect the impact of changes in the manufacturing process on the product, demonstrate quality and manufacturing consistency from batch to batch, estimate clinical efficacy and define the effective dose. This chapter describes the requirements and challenges to be considered for potency assay development and the importance of a well-established potency assay for clinical use.

Impedance–based haptenation of skin sensitizers with self–assembled monolayer of gold nanoparticles and cysteine modified screen printed carbon electrode

Haptenation of skin sensitizer is indicated because of the covalent attachment of a skin sensitizer to a skin protein. The idea of this research is to explore the haptenation of skin sensitizer with a modified screen printed carbon electrode (SPCE) and a self–assembled monolayer of gold nanoparticles (AuNPs) and cysteine (designated as ACC modified SPCE) using the impedance technique. The ACC modified SPCE was characterized using Fourier–Transform infrared spectroscopy–attenuated total reflectance (FTIR–ATR), atomic force microscopy (AFM), and Energy Dispersive X–Ray Spectroscopy (EDX). The presence of AuNPs and cysteine on the working electrode of the ACC modified electrode was detected by FTIR–ATR and EDX. AuNPs, possessing a homogeneous dot shape, and cysteine was randomly distributed on the carbon surface of SPCE shown by FESEM images. The AFM images indicated the possibility of a monolayer of adsorption of skin sensitizer onto ACC modified SPCE. The ACC modified SPCE has good reproducibility and stability with an RSD of 8.43 %. In addition, the interaction of extreme/strong skin sensitizer with the ACC modified SPCE was discovered with a high value of changes of charge transfer resistance of skin sensitizer (ΔRCTskinsensitizer) when compared to moderate and weak/non skin sensitizers. A total of 9 min was reported to be the optimum contact time of the skin sensitizer onto ACC modified SPCE. The adsorption isotherm studies of skin sensitizers with ACC modified SPCE showed Langmuir isotherm adsorption and spontaneous mechanism. Maleic anhydride (as a model of extreme/strong skin sensitizers) showed a fast–binding rate (18.2149 M−1) with the addition of a slow dissociation rate of 0.0549 M, while glycerol (as a model of weak/non skin sensitizer) showed a slow binding rate of 4.5977 M−1 as a result of a rapid dissociation rate of 0.2175 M. The change in Gibbs free energy (ΔG°) was calculated for ACC modified SPCE with glycerol and maleic anhydride to be at –3.78 × 10+03 kJ/mol and –7.19 × 10+03 kJ/mol, respectively. This study proved that the ACC modified SPCE could be used for routine screening during the early product development stage in qualitative skin sensitization measurements.