Retesting a Model of the Deming Management Method

Anderson et al. (1994) developed a model of the theory of quality management underlying the Deming management method; Anderson et al. (1995) tested that model using path analysis. They used data from an existing database collected from 41 manufacturing plants in the electronics, machinery, and transportation industries with 100 or more employees. In this study, which retests their model, data were gathered from over 100 manufacturing and service companies of all sizes across the US and Canada. The measures used in the original study were modified to apply to both service and manufacturing organizations. The data were analysed using similar statistical analysis procedures, and comparisons were made with the results of the Anderson et al. (1995) study. The results showed strong support for the model developed by Anderson et al. (1994) with the exception of one construct, Employee Fulfilment. The findings suggest that implementing a continuous improvement effort without first implementing Visionary Leadership, Cooperation, Learning, and Process Management is a recipe for failure

Cost Accounting : Traditions and Innovations

89

Improving Competitiveness through Non-value-added Activity Analysis

Approaches for increasing the extent to which operations are adding value for the customer, thereby improving viability and survivability in the marketplace are provided. the current literature on value-adding analysis and its use in industry is reviewed. a review is provided of the methods used to improve the elimination of NVAA, as well as a convenience study that illustrates that when executives are properly trained in value-adding analysis and the use of tools for eliminating NVAA, tremendous gains can be experienced. There can be little doubt that in the omnipresent demand to remain competitive, value-adding analysis and improvement remains a key tool available to executives. in highly competitive environments, such efforts can yield tremendous results, which are transferred financially directly to the bottom line, while improving customer satisfaction and competitiveness. Such win/win opportunities are rare in industry, and while it does represent a significant commitment in terms of effort, resources, and cultural change, value-adding analysis by all accounts holds promise for all executives seeking to position their companies for a viable future

Cost accounting: traditions and innovations, 3rd.ed./ Barfield

xxxiii, 1065 hal.; 28 cm

Systematic LC/MS/MS Investigations for the IND-Enabling Extended Characterization of Antibody–Drug Conjugate Modifications

We hypothesized that systematic liquid chromatography-tandem mass spectrometry investigations of an antibody⁻drug conjugate (ADC), its small and large molecular components, and surrogate small-molecule conjugates might comprise a simple and efficient approach for the extended characterization of ADCs. Furthermore, we envisioned that results from this work might allow us to assign specific composition changes in the ADC based on monoisotopic mass shifts of conjugatable modifications as detected in the surrogate small-molecule conjugates. We tested our hypothesis with a case study using an aldehyde-tag-based ADC conjugated to a noncleavable linker bearing a maytansine payload. Nearly quantitative bioconversion from cysteine to formylglycine was observed in the monoclonal antibody, and bioorthogonal conjugation was detected only on the formylglycine residues in the ADC. Using our method, both conjugatable and nonconjugatable modifications were discovered in the linker/payload; however, only conjugatable modifications were observed on the ADC. Based on these results, we anticipate that our approach to systematic mass spectrometric investigations can be successfully applied to other ADCs and therapeutic bioconjugates for investigational new drug (IND)-enabling extended characterization

Site-Specific Tandem Knoevenagel Condensation–Michael Addition To Generate Antibody–Drug Conjugates

Expanded ligation techniques are sorely needed to generate unique linkages for the growing field of functionally enhanced proteins. To address this need, we present a unique chemical ligation that involves the double addition of a pyrazolone moiety with an aldehyde-labeled protein. This ligation occurs via a tandem Knoevenagel condensation–Michael addition. A pyrazolone reacts with an aldehyde to generate an enone, which undergoes subsequent attack by a second pyrazolone to generate a bis-pyrazolone species. This rapid and facile ligation technique is performed under mild conditions in the absence of catalyst to generate new architectures that were previously inaccessible via conventional ligation reactions. Using this unique ligation, we generated three site-specifically labeled antibody–drug conjugates (ADCs) with an average of four drugs to one antibody. The in vitro and in vivo efficacies along with pharmacokinetic data of the site-specific ADCs are reported

Aldehyde Tag Coupled with HIPS Chemistry Enables the Production of ADCs Conjugated Site-Specifically to Different Antibody Regions with Distinct in Vivo Efficacy and PK Outcomes

It is becoming increasingly clear that site-specific conjugation offers significant advantages over conventional conjugation chemistries used to make antibody–drug conjugates (ADCs). Site-specific payload placement allows for control over both the drug-to-antibody ratio (DAR) and the conjugation site, both of which play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of the ADC. In addition to the DAR and site of conjugation, linker composition also plays an important role in the properties of an ADC. We have previously reported a novel site-specific conjugation platform comprising linker payloads designed to selectively react with site-specifically engineered aldehyde tags on an antibody backbone. This chemistry results in a stable C–C bond between the antibody and the cytotoxin payload, providing a uniquely stable connection with respect to the other linker chemistries used to generate ADCs. The flexibility and versatility of the aldehyde tag conjugation platform has enabled us to undertake a systematic evaluation of the impact of conjugation site and linker composition on ADC properties. Here, we describe the production and characterization of a panel of ADCs bearing the aldehyde tag at different locations on an IgG1 backbone conjugated using Hydrazino-<i>iso</i>-Pictet-Spengler (HIPS) chemistry. We demonstrate that in a panel of ADCs with aldehyde tags at different locations, the site of conjugation has a dramatic impact on in vivo efficacy and pharmacokinetic behavior in rodents; this advantage translates to an improved safety profile in rats as compared to a conventional lysine conjugate