Lean strategy for data mining and continuous improvement of Chinese pharmaceutical process: a case study of sporoderm-removal Ganoderma lucidum spore powder / 中国中药杂志

In the digital transformation of Chinese pharmaceutical industry, how to efficiently govern and analyze industrial data and excavate the valuable information contained therein to guide the production of drug products has always been a research hotspot and application difficulty. Generally, the Chinese pharmaceutical technique is relatively extensive, and the consistency of drug quality needs to be improved. To address this problem, we proposed an optimization method combining advanced calculation tools(e.g., Bayesian network, convolutional neural network, and Pareto multi-objective optimization algorithm) with lean six sigma tools(e.g., Shewhart control chart and process performance index) to dig deeply into historical industrial data and guide the continuous improvement of pharmaceutical processes. Further, we employed this strategy to optimize the manufacturing process of sporoderm-removal Ganoderma lucidum spore powder. After optimization, we preliminarily obtained the possible interval combination of critical parameters to ensure the P_(pk) values of the critical quality properties including moisture, fineness, crude polysaccharide, and total triterpenes of the sporoderm-removal G. lucidum spore powder to be no less than 1.33. The results indicate that the proposed strategy has an industrial application value.

Interventions in the diagnosis and adoption of pacemaker therapy in sinus node dysfunction patients: Results from the IMPROVE Brady study

Aims: IMPROVE Brady assessed whether a process improvement intervention could increase adoption of guideline-based therapy in sinus node dysfunction (SND) patients. Methods: /Results: IMPROVE Brady was a sequential, prospective, quality improvement initiative conducted in India and Bangladesh. Patients with symptomatic bradycardia were enrolled. In Phase I, physicians assessed and treated patients per standard care. Phase II began after implementing educational materials for physicians and patients. Primary objectives were to evaluate the impact of the intervention on SND diagnosis and pacemaker (PPM) implant. SF-12 quality of life (QoL) and Zarit burden surveys were collected pre- and post-PPM implant. A total of 978 patients were enrolled (57.7 ± 14.8 years, 75% male), 508 in Phase I and 470 in Phase II. The diagnosis of SND and implantation of PPM increased significantly from Phase I to Phase II (72% vs. 87%, P < 0.001 and 17% vs. 32%, P < 0.001, respectively). Pacemaker implantation was not feasible in 41% of patients due to insurance/cost barriers which was unaltered by the intervention. Both patient QoL and caregiver burden improved at 6-months post-PPM implant (P < 0.001). Conclusions: A process improvement initiative conducted at centers across India and Bangladesh significantly increased the diagnosis of SND and subsequent treatment with PPM therapy despite the socio-economic constraints.

Improvement of synthetic route of brivudine / 中国药科大学学报

@#This article summarizes and analyzes the reported synthetic routes of brivudine in patent and literature.2′-Deoxyuridine was employed as starting material, affording brivudine through iodization, heck coupling, hydrolysis, decarboxylation, bromination and recrystallization.After optimization of reaction conditions of each step, a synthetic route suitable for industrial production was achieved with simple synthetic process, high yield and excellent purity.

Improvement of synthesis process of mirabegron / 中国药科大学学报

@#Overactive bladder is a syndrome characterized by urgent urination, often accompanied by frequent urination and nocturia. The incidence of the disease is high all over the world, and it has a great impact on the lives of patients, which has been paid more and more attention by scholars at home and abroad. It is currently estimated that 50 million to 100 million people worldwide suffer from the disease. Mirabegron is an agonist of human β-3 adrenergic receptor used to treat symptoms of overactive bladder. In this study, the synthesis process of mirabegron was improved based on literatures. Using p-nitrophenethylamine hydrochloride, R-(-)-mandelicacid and 2-aminothiazole-4-acetic acid as starting materials, the target product with high purity was obtained through four steps of amide condensation, carbonyl reduction, nitro reduction and amide condensation, and one-step purification, with a total yield of 39%. In this study, the hydrogen source of nitro reduction in step 3 was changed from hydrogen to ammonium formate, which increased the feasibility of industrialization, and mirabegron was refined to improve the purity of the product. The improved process has the advantages of simplified operation and mild reaction conditions, which provides a new method for the preparation and purification of mirabegron.

Process improvement on the synthesis of atomoxetine / 中国药科大学学报

@#Atomoxetine is a highly selective norepinephrine reuptake inhibitor. Based on the analysis of the literature methods, the synthesis process of atomoxetine was improved. Using 3-chloropropiophenone-1 as the raw material, optically pure target product was obtained by asymmetric reduction, Mitsunobu reaction and condensation reaction in three steps, with a total yield of 26%. The third-step methylation sealing operation was changed to the reaction under normal pressure, which increased the feasibility of industrialization. The improved process operation was simplified and the reaction conditions were mild, which would provide a new method for the preparation of atomoxetine.

Synthetic process improvement of raltegravir / 国际药学研究杂志

Objective To improve the synthetic procedure of the HIV integrase inhibitor raltegravir. Methods With 2-ami-no-2-methyl-propionitrile hydrochloride as starting material,the target compound raltegravir was synthesized through amino protection by benzyl chloroformate ,amidoxime formation,cyclization induced by michael addition&Claisen rearrangement,N-methylation,N-acylation,hydroxyl protection by trimethylacetyl chloride,hydrogenolysis by the system of Pd/C and formic acid,amidation with the 5-methyl-1,3,4-oxadiazol-formyl chloride,and immediate hydrolysis without more purification. Results The chemical structure of raltegravir and the intermediates were characterized by 1H NMR,13C NMR and MS. The overall yield was about 19.45%. Conclusion Compared with the preceding process,the developed route is easy to operate,safe and suitable for industrialized production in accor-dance with the quality standard of active pharmaceutical ingredient(API).

Synthesis of (+)-ambrisentan / 中国药科大学学报

A five-step synthetic method of ambrisentan starting from benzophenone was developed.The reaction methods of resolution and substitution were optimized.A stable,facilitating method of detection and efficient resolution reagent,L-phenylglycinamide,was used and helped to obtain highly optical pure intermediates.In the substitution reaction,NaOH was chosen as the base,which is safe and suitable for the industry.This method was mild,easily operated with a total yield up to 31.0％,and may have a good application prospect.

A new synthetic process of dapagliflozin / 中国药科大学学报

This paper describes a practical process for a SGLT2 inhibitor dapagliflozin. The target product was synthesized from 1-chloro-2-( 4-ethoxybenzyl)-4-iodobenzene and 2, 3, 4, 6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide by iodine-magnesium exchange, and coupling and acetyl removing reactions with the total yield of 50%. This practical process highlights fewer reaction steps, less waste and mild reaction conditions.

Improved synthesis of dipyridyl thioselenosemicarbazones / 国际药学研究杂志

Objective To improve the synthesis process of N- allyl- 2-(di(pyridin- 2- yl)methylene)hydrazinecarboselenoamide(4)and2-(di(pyridin-2-yl)methylene)-N,N-dimethylhydrazinecarboselenoamide(8). Methods 4-allyl-3-thiosemicarbazide (1)was the starting material,which reacted with methyl iodide,sodium hydrogen selenide to obtain intermediate 4-allyl-3-selenosemicarbazide(3). Compound(3)reacted with di-2-pyridyl ketone to obtain the target compound 4. 4,4-Dimethyl-3-thiosemicarbazide was the starting materials,which reacted with di-2-pyridyl ketone to obtain intermediate dipyridyl thiosemicarbazone(6). Compound 6 reacted with methyl iodide,sodium hydrogen selenide to obtain the target compound 8. We optimized the reaction conditions of each step. Results We synthesized the target compound 4 and 8 according to the respective synthetic route,the structure of the target compounds and the intermediates were confirmed by 1H NMR and MS. Conclusion The improved processes are easy to operate,cost-saving and suitable for large scale preparation.

Optimization of synthesis process of photosensitizer chlorin f / 药学实践杂志

Objective To improve the synthesis process of chlorine f (1).Methods A "one-pot"method was applied to prepare Photosensitizer component (1),using pheophorbide a (3) as raw material by oxidating and cracking of the E-ring of (3) with bubbling oxygen in alcoholic solution of potassium hydroxide at 0 ℃ followed by refluxing in nitrogen atmosphere.In order to obtain the optimal synthetic procedure,the orthogonal experimental design of L9 (34 ) was adopted to investigate three different levels of four main factors i.e.ring opening reaction time,alcoholic variety,alkali concentration and refluxing reaction time.Results The target compound (1) was optimizedly synthesized through treatment of raw material (3) with bubbling oxy-gen in 25% ethanol solution of potassium hydroxide at 0℃ for 30 min,followed by refluxing in nitrogen atmosphere for 20 min in yield of 40.8%.Conclusion The procedure developed has some advantages of simple and safty operation,and high synthetic yield.

An improvement for synthesis of ceftriaxone sodium / 中国药科大学学报

@#To develop new synthetic process of ceftriaxone sodium, 7-amino-3-［(2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazin-3-yl)thiomethyl］-3-cephem-4-carboxylic acid(7-ACT)was synthesized from 7-aminocephalosporanicacid(7-ACA)by reaction with 2, 5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1, 2, 4-triazine(TTZ)under the catalysis of BF3/C2H3N. Ceftriaxone was prepared from 7-ACT by condensation with 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic thiobenzothiazole ester(AE)using triethylamine as catalyst. After removing the by-product 2-mercaptobenzothiazole(M)through filtration, the filtrate was treated with sodium acetate to give ceftriaxone sodium. This improved process eliminates the working procedure for separating compound M from the mother liquor, and has the advantages of less solvent consumption and convenient operation, and has been successfully used in commercial production.

Improved synthesis of dipyridyl thioselenosemicarbazones / 国际药学研究杂志

Objective To improve the synthesis process of N-allyl-2-(di(pyridin-2-yl)methylene)hydrazinecarboseleno?amide(4)and 2-(di(pyridin-2-yl)methylene)-N,N-dimethylhydrazinecarboselenoamide(8). Methods 4-allyl-3-thiosemicarbazide (1)was the starting material,which reacted with methyl iodide,sodium hydrogen selenide to obtain intermediate 4-allyl-3-selenosemi?carbazide(3). Compound(3)reacted with di-2-pyridyl ketone to obtain the target compound 4. 4,4-Dimethyl-3-thiosemicarbazide was the starting materials,which reacted with di-2-pyridyl ketone to obtain intermediate dipyridyl thiosemicarbazone(6). Compound 6 re?acted with methyl iodide,sodium hydrogen selenide to obtain the target compound 8. We optimized the reaction conditions of each step. Results We synthesized the target compound 4 and 8 according to the respective synthetic route,the structure of the target com?pounds and the intermediates were confirmed by 1H NMR and MS. Conclusion The improved processes are easy to operate,cost-saving and suitable for large scale preparation.

Implantação e avaliação das Boas Práticas de Fabricação – BPF: estudo de caso / Establishing and evaluating the Good Manufacturing Practices - GMP: a case study

O programa de Boas Práticas de Fabricação (BPF) é uma importante ferramenta, largamente utilizada para garantir o padrão de qualidade exigido pelo mercado consumidor. Este trabalho aborda os procedimentos empregados para realizar a implantação e monitoramento do BPF para uma planta de produção de farinhas e óleos de aves. Para a execução do trabalho, apresentou-se o programa à direção da empresa e formou-se uma equipe multidisciplinar. Na sequência, caracterizou-se o processo in loco para obter informações a respeito da elaboração do manual.Uma das etapas fundamentais do processo foi a aplicação de treinamentos ministrados pela gestora da qualidade. A última etapa do trabalho constituiu-se no monitoramento do programa por meio de auditorias internas. Observou-se que as auditorias influenciaram significativamente na melhoria de todas as etapas de implantação. A implantação das BPF resultou na aplicação de medidas corretivas com o envolvimento de toda equipe organizacional.

The Good Manufacturing Practices (GMP) Program is an important tool widely used to ensure the standard of quality required by the market. This paper discusses the procedures for implementing and monitoring the GMP for a plant of production of flour and oils obtained from birds. For performing this work, the program was presented to the company management and a multidisciplinary team was constituted. In sequence, the in loco process was characterized in order to get information regarding to the manual preparation. One of the key steps of the process was the implementation of training given by the quality manager, aiming at substantiating them on the awareness of employees requirements to convey the necessary knowledge to meet the GMP program. The last stage of the work was consisted of monitoring the program through the internal audits. It was observed that the audits significantly influenced for improving the all of the phases of implementation. The GMP implementation resulted in the improvement of corrective measures with the involvement of all organizational staff.

Formação de biofilmes de escherichia coli produtora de toxina Shiga sorotipos O153: H25, O113:H21 e O111: H8 em superfície de aço inoxidável e eficácia de sanitizante / Biofilm formation of shiga toxin-producing escherichia coli O153: H25, O113:H21 and O111: H8 on the stainless steel surface and the effectiveness of sanitizer

Neste estudo as cepas de Escherichia coli produtora de toxina Shiga (STEC) O153:H25, O113:H21 e O111:H8, isoladas de rebanhos do país, foram avaliadas quanto à capacidade de formar biofilmes em superfície de aço inoxidável utilizada na indústria de alimentos, bem como a eficácia de diferentes concentrações de hipoclorito de sódio na inativação desses biofilmes. A capacidade de formação de biofilme foi detectada em todas as cepas de E. coli produtoras de toxina Shiga. Na avaliação da eficáciado sanitizante hipoclorito de sódio, nas concentrações de 100 mg.L-1 e 200 mg.L-1, observou-se a redução a <1 log UFC/cm2 em todas as cepas e nos tempos avaliados. Estes dados reforçam aimportância do correto procedimento de higienização, uma vez que biofilmes podem tornar-se importantes fontes de contaminação no ambiente de produção de alimentos.

This study aimed at evaluating the biofilm formation of Shiga toxin-producing Escherichia coli O153:H25, O113:H21 and O111:H8 (STEC non-O157), isolated from Brazilian cattle, on the stainless steel surface, and also the efficacy of different s concentrations of sodium hypochlorite for inactivating these biofilms. The ability to form biofilm was demonstrated in all of Shiga toxin-producing E. coli strains. In assessing the effectiveness of sodium hypochlorite sanitizer, a reduction to <1 log CFU/cm2 was observed in all of the evaluated strains and times. These data strengthen the relevance of the correct cleaning procedure, considering that biofilms formations might be an important source of food contamination.

Optimization of synthesis of photosensitizer chlorin e6-C15 monomethyl ester by the orthogonal design / 药学实践杂志

Objective To optimize the synthesis of photosensitizer chlorine e6‐C15 monomethyl ester (1) .Methods Tar‐get compound 1 was synthesized through E ring cracking of pheophorbide a (3) in methanol solution of potassium hydroxide followed by adding H2 O for ester hydrolysis with“one‐pot” process .Four main factors that influencing the synthetic yield of target compound 1 are ring cleavage reaction time (A) ,reflux hydrolysis reaction time (B) ,alkali concentration (C) and weight ratio of material 3 to alkali (D) .Each of the four factors was chosen at three levels and evaluated by the orthogonal ex‐perimentaldesignofL9(34).Results Theoptimizationtermsofthesynthesisoftargetcompound1wereB1C2A2D1 .Theyield of compound 1 was raised from 43 .0% to 56 .5% .Conclusion The developed process has the advantages of simple operation , good safety and high reaction yield ,and is suitable for industrial production .

An improved preparing process for rivastigmine / 中国药科大学学报

@#An improved manufacturing process for rivastigmine(1)was developed by performing the condensation reaction of m-hydroxyacetophenone(4)with N-ethyl-N-methyl carbamoyl chloride, then Corey-Bakshi-Shibata(CBS)chiral reduction to(R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate(2)and then mesylation with methanesulfonyl chloride and nucleophilic substitution with dimethylamine, respectively. To be successful, a crucial reductive process in the conversion of ketone(3)to chiralalcohol(2)had to be correctly understood and optimized via orthogonal experiment. The whole improved process was convenient for operation and purification, with completion of the synthesis of rivastigmine and an overall yield of 88%.

An automated dispensing system for improving medication timing in the emergency department / 世界急诊医学杂志（英文）

BACKGROUND: Numerous medical conditions require timely medication administration in the emergency department (ED). Automated dispensing systems (ADSs) store premixed common doses at the point-of-care to minimize time to administration, but the use of such automation to improved time to medication administration has not been studied. Since vancomycin is a commonly used empiric antimicrobial, we sought to quantify the effect of using an ADS on time to drug delivery in patients presenting to the ED. The study aimed to determine the efficacy of utilizing an ADS to improve time to administration of vancomycin and determine any negative effects on dosing appropriateness.METHODS: The institional review board approved the retrospective quality improvement study took place in a single, urban academic tertiary care ED with an annual census of 80000. Study subjects were all patients receiving vancomycin for the management of sepsis between March 1 to September 30, 2008 and the same time period in 2009. The primary outcome was the proportion of patients who received vancomycin within one hour of bed placement and the secondary outcome was dosing appropriateness.RESULTS: Sixty-three patients had weight and dosing information available (29 before and 34 after intervention) and were included in the study. Before intervention, no patient received vancomycin in less than 60 minutes, while after intervention 14.7％ of the patients received it in less than 60 minutes (difference in proportions 14.7％, 95％ CI 0.39％-30.0％, P=0.04). A similar proportion of the patients received correct dosing before and after intervention (44.8％ vs. 41.2％, difference in proportions 3.7％, 95％ CI -20.0％-26.7％, P=0.770).CONCLUSION: The use of an ADS may improve the timing of medication administration in patients presenting to the ED without affecting dosing appropriateness.

Análise crítica de experiência com redesenho de processos em um laboratório clínico / Critical analysis of processes redesign experience in a clinical laboratory

INTRODUÇÃO: Para competir no mercado atual de medicina laboratorial, há a necessidade de processos com elevado nível de agregação de valor aos clientes e alta flexibilidade para atender às modificações constantes nos requisitos de clientes e legais, bem como capacidade de se adaptar às modificações no ambiente competitivo. Esses desafios exigem uma adaptação global do laboratório para uma visão baseada em processos. OBJETIVO: Avaliar criticamente uma iniciativa de mapeamento e redesenho de processos desenvolvida em um laboratório clínico de grande porte. Nessa análise crítica, serão apresentados e avaliados os resultados de um projeto de redesenho realizado na área técnica da empresa, incluindo processos técnicos e de apoio. MATERIAIS E MÉTODOS: Foram mapeados 37 processos técnicos, utilizando metodologia adaptada e identificando as principais desconexões e oportunidades de melhoria. Cada processo foi sequencialmente analisado e redesenhado e um plano de ação foi gerado para a implementação de cada novo processo. Resultados: Após a implementação dos novos processos redesenhados, a produtividade de pessoal técnico aumentou em mais de 30 por cento. Outro resultado importante foi obtido em termos de flexibilidade dos processos, principalmente em razão da nova estrutura de subáreas na área técnica. DISCUSSÃO: Os principais pontos críticos do projeto estiveram relacionados com a disponibilidade de recursos de tecnologia da informação (TI) e a não priorização de medições nos processos no momento inicial do projeto. CONCLUSÃO: A iniciativa de redesenho de processos, se implementada com um roteiro planejado, orientada a resultados e alinhada à estratégia da organização, pode proporcionar resultados significativos para os laboratórios clínicos.

INTRODUCTION: In order to ensure market competitiveness in laboratory medicine, there is a current demand for processes with high customer added value, high flexibility to attend fluctuating customer and legal requirements, as well as ability to adapt to changes. These challenges require global adaptation to a processbased view. OBJECTIVE: To evaluate critically an initiative of process mapping and redesigning developed in a major clinical laboratory. In this analysis, the results of the redesign project developed in the technical area are presented and evaluated, including technical and support processes METHODS: Thirty-seven technical processes were mapped by use of customized methodology, and key disconnections and improvement opportunities were identified. Each process was sequentially reviewed and redesigned. Furthermore, an action plan was outlined for the implementation of each new process. Results: After implementing new redesigned processes, staff productivity rose by over 30 percent. Another important result was obtained in terms of process flexibility, mainly due to the new subarea structure in the technical area. DISCUSSION: The main crucial points of the project were related to information technology (IT) resource availability and no prioritization of process assessment at the beginning of the project. CONCLUSION: Clinical laboratories may attain significant results with process redesign initiatives as long as these are result-oriented, aligned with the organization strategies and implemented with a planned approach.