Creating an Assessment Indicator of Quality Culture Development in the Generic Pharmaceutical Industry in Japan.

In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan, and there is a growing awareness of the importance of corporate compliance and pharmaceutical manufacturing and quality controls. One cause of illicit manufacturing is the inadequate development of quality culture. This study focuses on the degree of quality culture development in Japanese pharmaceutical companies manufacturing generic drugs. Because no evaluation index for Japan can visualize the degree of quality culture development in each company, this study sought to establish this index to utilize it as a tool for evaluating the degree of quality culture development that would enable each company to continuously monitor and improve its own. We conducted a questionnaire survey among Japan Generic Medicines Association members to evaluate the degree of their quality culture development. The questionnaire contained 28 questions in five evaluation categories. Potential indicators of quality culture development included "Employee growth and satisfaction"; "Management commitment"; "Improvement activities"; "Communication"; and "Environment, health, and safety." We obtained 294 responses from 37 Marketing Authorization Holder (MAH) and 61 manufacturing sites. Respondents were classified by roles of management, manager, and nonmanager. The results confirmed the current status of quality culture development efforts, showing that important messages such as the corporate philosophy as communicated by the management is well known, awareness of quality culture development level differs by role, and appropriate resources are not adequately allocated to employees or facilities. Based on the results, use of the index of quality culture development helped to make relative comparisons and visualize the areas to be addressed for quality culture development. This study established and visualized the index for the degree of quality culture development in domestic generic drug manufacturing companies and we hope this indicator becomes a useful tool for evaluating a company's quality culture development level.

Quality Culture and Knowledge Management in the Japanese Pharmaceutical Industry-A Cross-Sectional Study and Case Report.

In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan. Insufficient good manufacturing practice compliance and lack of quality culture in some pharmaceutical companies have been suggested as the underlying reasons for such cases. We aimed to focus on knowledge management and fostering of quality culture in pharmaceutical companies in Japan to understand their current situation and find a strategy for the availability of high-quality reliable pharmaceutical products. A wide-ranging questionnaire survey was conducted to understand the issues related to knowledge management and fostering of quality culture across pharmaceutical companies in Japan. A published investigation report on an illicit manufacturing case was closely examined by organizing the available facts using the diagram. Based on 395 responses to the questionnaire survey, we found that although pharmaceutical companies understand the importance of knowledge management and quality culture, issues exist in their operational methods. A total of 94% of the respondents agreed that they mentioned "knowledge management" as an enabler of the Pharmaceutical Quality System of ICH Q10, and 98% of the respondents accepted that insufficient fostering of quality culture leads to corporate risk. However, the survey revealed that many companies are struggling with this approach. Based on a report on an illicit manufacturing case, we analyzed the direct causes of misconduct and prepared a systematic summary that can be easily comprehended. Comparison of the illicit manufacturing case report with our questionnaire results suggests that many pharmaceutical companies do not regard the misconduct case as a situation that could occur in their company. With the revision of the Pharmaceuticals and Medical Devices Act and good manufacturing practice Ministerial Ordinance, we advocate the need for all employees of pharmaceutical companies to reconsider the priorities of their companies from the patient perspective.

Hydrogen Peroxide Treatment of Softwood-Derived Poly(Ethylene Glycol)-Modified Glycol Lignin at Room Temperature.

Recently, a large-scale production system of softwood-derived poly(ethylene glycol) (PEG)-modified glycol lignin (GL) was developed to produce high-quality lignin derivatives with substantially controlled chemical structures and attractive thermal properties. In this study, the further upgrading of GL properties with carboxy functionalization was demonstrated through the room-temperature hydrogen peroxide (H2O2) treatment with the mass ratio of H2O2 to GL, 1:1 and 1:3, for 7 d. The changes in the chemical structure, carboxy group content, molecular weight, and thermal properties of the insoluble portions of partially oxidized glycol lignins (OGLs) were then investigated. Nuclear magnetic resonance and thioacidolysis data revealed that the oxidative functionalization involved the cleavage of ß-O-4 linkages and the oxidative cleavage of guaiacyl aromatic rings into muconic acid-type structures. This was validated by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and potentiometric titration. Overall, the results suggested that the varying outcomes of carboxy group content (0.81-2.04 mmol/g OGL) after 7-d treatment depended on the type of the GL origin having varying amounts of the retained native lignin structure (e.g., ß-O-4 linkages), which were prepared from different source-wood-meal sizes and PEG molecular masses.

Effect of Heat Treatment on the Chemical Structure and Thermal Properties of Softwood-Derived Glycol Lignin.

A large-scale glycol lignin (GL) production process (50 kg wood meal per batch) based on acid-catalyzed polyethylene glycol (PEG) solvolysis of Japanese cedar (JC) was developed at the Forestry and Forest Products Research Institute (FFPRI), Tsukuba, Japan. JC wood meal with various particle size distributions (JC-S < JC-M < JC-L) (average meal size, JC-S (0.4 mm) < JC-M (0.8 mm) < JC-L (1.6 mm)) and liquid PEG with various molecular masses are used as starting materials to produce PEG-modified lignin derivatives, namely, GLs, with various physicochemical and thermal properties. Because GLs are considered a potential feedstock for industrial applications, the effect of heat treatment on GL properties is an important issue for GL-based material production. In this study, GLs obtained from PEG400 solvolysis of JC-S, JC-M, and JC-L were subjected to heating in a constant-temperature drying oven at temperatures ranging from 100 to 220 °C for 1 h. All heat-treated GL series were thermally stable, as determined from the Klason lignin content, TMA, and TGA analyses. SEC analysis suggests the possibility of condensation among lignin fragments during heat treatment. ATR-FTIR spectroscopy, thioacidolysis, and 2D HSQC NMR demonstrated that a structural rearrangement occurs in the heat-treated GL400 samples, in which the content of α-PEG-ß-O-4 linkages decreases along with the proportional enrichments of ß-5 and ß-ß linkages, particularly at treatment temperatures above 160 °C.

Prevalence and Characteristics of Salmonella and Campylobacter in Retail Poultry Meat in Japan.

This study was performed to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Salmonella enterica subsp. enterica and Campylobacter spp. in poultry meat, and to analyze the association of genetic types of these bacteria with their geographical distribution and antimicrobial resistance profiles. Salmonella and Campylobacter isolates have been detected, respectively, in 54 and 71 samples out of 100 samples tested. Nine Salmonella serotypes were found, including S. enterica subsp. enterica serovar Infantis (33%), Schwarzengrund (12%), Manhattan (9%), and others. Campylobacter jejuni and C. coli were detected in 64 (64%) and 14 (14%) samples, respectively. S. enterica subsp. enterica isolates were very frequently resistant to tetracycline (78.3%) and streptomycin (68.3%). Many C. jejuni and C. coli isolates were resistant to sulfamethoxazole/trimethoprim (90.5%), nalidixic acid (47.3%), ampicillin (45.9%), and ciprofloxacin (40.5%). Cluster analysis was performed for the Salmonella isolates using pulsed-field gel electrophoresis (PFGE) data. For Campylobacter isolates, the cluster analysis was based on both PFGE and comparative genomic fingerprinting. The molecular typing results were compared with the information about antimicrobial resistance and geographical locations in which the poultry meat was produced. This analysis revealed that C. jejuni strains with a particular genotype and antimicrobial resistance profile are spreading in specific areas of Japan.

Determination of enterohemorrhagic Escherichia coli serotype O165:HNM infection in a hemolytic uremic syndrome patient with adenovirus seroype 41.

A 4-year-old girl who was positive for adenovirus according to a rapid immunochromatographic test conducted at a hospital, progressed to hemorrhagic diarrhea and hemolytic uremic syndrome (HUS). The presence of adenovirus serotype 41 (AdV-41) was confirmed by TaqMan real-time PCR and sequence analysis. However, most enteric viral infections cause mild to moderate diarrhea. In the present case, enterohemorrhagic Escherichia coli (EHEC) O165:HNM was isolated concomitantly with AdV-41. In addition, O165 antibody was specifically detected in patient sera. The EHEC isolate was positive for the virulence genes stx1, stx2a, eae type ε, ehxA, and norV. Therefore, we concluded that EHEC O165:HNM was the precise pathogen leading to HUS in this patient.

Isolation and identification of Escherichia albertii from a patient in an outbreak of gastroenteritis.

A microbial strain harboring the eae gene, which is known as the virulence gene of enteropathogenic Escherichia coli (EPEC) and most enterohemorrhagic E. coli, was isolated from a patient in a gastroenteritis outbreak that occurred in 22 patients in Akita Prefecture, Japan, in November 2011. The biochemical characteristics of the isolate were more similar to those of a novel Escherichia sp., E. albertii than E. coli. Partial 16S rRNA gene sequences of the isolate were identical to those of a certain E. albertii strain, but also showed a high degree of similarity to those of E. coli strains. Finally, we identified this isolate as E. albertii by performing PCR analysis that targeted the uidA, lysP, mdh, and cdtB genes in addition to stx and eae genes to differentiate between the EPEC and E. albertii strains.