Four critical engineering and technical problems in manufacturing measurement of traditional Chinese medicine / 中国中药杂志

Focusing on the development and quality improvement strategy of the traditional Chinese medicine(TCM) industry, the scientific and technological innovation of the new engineering of TCM should be paid attention to solve the "stuck neck" dilemma. Under the background of the ecological and industrial revolution of the scientific and technological innovation system, the super-scale information interaction and multi-dimensional integration will inevitably lead to profound changes in the manufacturing mode of TCM. Manufacturing measurement of TCM is formed on the basis of the reliability engineering theory of process control of TCM production. It is the development extension of system theory and system science ideas and a cross-fertilization discipline that combines theory with practice and adheres to the "four-oriented" re-epistemology improvement of the TCM discipline. In response to the problems of complex raw material sources, coarse process technology, unclear material basis, and poor applicability of equipment and technology in the manufacture of TCM, the transformation research mode of "aiming at the integration of pharmaceutical industry-developing intelligent production line-enabling industrial transformation" has been developed. This paper proposed the four key engineering technical problems, i.e., the identification of critical quality attributes(CQA) in the manufacture of TCM, the quality by design(QbD) and product development of the manufacturing process of TCM, the quality transfer principle and multivariate process capability index of TCM manufacturing, and the development of measurement technology and equipment of the manufacturing measurement of TCM, to achieve the systematization of quality control indicators, real-time process control, digitalization of manufacturing process, transparency of quality transfer, and intelligent whole-process control. In this paper, the new concepts, new theories, and new technologies provide a reference for the industrialization of TCM.

Analysis on Quality Attribute of Substance Benchmarks of Shentong Zhuyutang Based on Supramolecular "Imprinting Template" Theory / 中国实验方剂学杂志

ObjectiveBased on the supramolecular "imprinting template" theory， the autonomous action law of the component groups of Shentong Zhuyutang in the preparation process of medicinal materials-decoction pieces-formulas was studied to clarify the quantitative transfer law of its quality attributes. MethodUltra performance liquid chromatography（UPLC） fingerprint of Shentong Zhuyutang was established with mobile phase of 0.4% phosphoric acid aqueous solution（A）-acetonitrile（B） for gradient elution（0-2.5 min， 100%A； 2.5-6 min， 100%-96%A； 6-15 min， 96%-92%A； 15-25 min， 92%-88%A； 25-35 min， 88%-75%A； 35-50 min， 75%-65%A； 50-60 min， 65%-50%A； 60-65 min， 50%-30%A； 65-70 min， 100%A） and detection wavelength of 235 nm， and the total statistical moments， information entropy and primary feeding amount of fingerprint of medicinal materials， decoction pieces and benchmark samples were calculated. Dry extract rate of the benchmark samples， the transfer rates and the addition parameters of medicinal materials-decoction pieces-formulas were calculated. ResultSimilarities of the total statistical moments of UPLC fingerprint of 15 batches of medicinal materials and decoction pieces were>0.89， the relative standard deviations（RSDs） of information entropy of UPLC fingerprint of 12 medicinal materials and decoction pieces were<10%. RSDs of total first-order moment（MCRTT） and information entropy of Shentong Zhuyutang（medicinal materials） were 5.5% and 2.3%， while the RSDs of MCRTT and information entropy of Shentong Zhuyutang（decoction pieces） were 4.8% and 2.6%， respectively. The dry extract rate of 45 batches of Shentong Zhuyutang was 17.2%-20.2%. The transfer rate of medicinal materials to decoction pieces was within the range of data fluctuation， which was 70%-130% of the average value. The overall transfer rates of medicinal materials to decoction pieces and decoction pieces to benchmark samples were 101.8% and 83.0%， respectively. ConclusionThe quality properties of Shentong Zhuyutang benchmark samples can be studied by total statistical moment analysis and primary feeding amount analysis， which can confirm the supramolecular "imprinting template" theory to a certain extent.

Optimization of ethanol precipitation process of Nauclea officinalis extract based on concept of quality by design(QbD) / 中国中药杂志

The ethanol precipitation process of Nauclea officinalis extract was optimized based on the concept of quality by design(QbD). Single factor tests were carried out to determine the levels of test factors. The ethanol volume fraction, pre-ethanol precipitation drug concentration, and ethanol precipitation time were taken as critical process parameters(CPPs). With the comprehensive scores of strictosamide transfer rate and solid removal rate as the critical quality attributes(CQAs), Box-Behnken design was employed to establish the mathematical models and space design between CPPs and CQAs, and the obtained optimal operating space was validated. The optimal operating space included ethanol volume fraction of 65%-70%, pre-ethanol precipitation drug concentration of 22-27 mg·mL~(-1), and ethanol precipitation time of 12 h. Based on the concept of QbD, this study adopted the design space to optimize the ethanol precipitation process of N. officinalis extract, which provided a reliable theoretical basis for the quality control in the production process of N. officinalis preparations. Moroever, this study provided a reference value for guiding the research and industrial production of traditional Chinese medicines.

Desarrollo de un inyectable liofilizado de ácido zoledrónico 5 mg. Estudio de estabilidad / Development of a lyophilized injectable of zoledronic acid 5 mg. Stability study / Desenvolvimento de um injetável liofilizado de ácido zoledrónico de 5 mg. Estudo de estabilidade

RESUMEN Introducción: El ácido zoledrónico es un inhibidor de la resorción ósea que se utiliza en el tratamiento de la enfermedad de Paget, la prevención de la osteoporosis inducida por glucocorticoides y la osteoporosis en mujeres posmenopáusicas y hombres. Objetivo: Evaluar la estabilidad de un nuevo inyectable liofilizado de ácido zoledrónico 5 mg a través de los parámetros de calidad. Métodos: Se validó un método de HPLC con detector UV para determinar la estabilidad química de la formulación a través de la presencia de productos de degradación y la concentración del ácido zoledrónico en el producto terminado. También se midieron las características organolépticas, pH, esterilidad y endotoxinas bacterianas, partículas en inyectables y totalidad y transparencia de soluciones de este. Resultados: El método cromatográfico resultó satisfactorio para su empleo en la evaluación del producto terminado. Se elaboraron 3 lotes del inyectable de ácido zoledrónico 5 mg liofilizado, los cuales cumplieron con los límites de calidad establecidos durante los 6 meses (estabilidad acelerada) y hasta los 24 meses (vida útil).

SUMMARY Introduction: Zoledronic acid is an inhibitor of bone resorption used in the treatment of Paget's disease, the prevention of glucocorticoid-induced osteoporosis, osteoporosis in postmenopausal women and in men. Aim: To evaluate the stability of a new lyophilized injection of zoledronic acid 5 mg through the quality parameters. Methods: An HPLC method with UV detector was validated for the finished product and the chemical stability of the formulation was determined through the presence of degradation products and the concentration of zoledronic acid in the finished product. In addition, the organoleptic characteristics, pH, sterility and bacterial endotoxins, particles in injectables and totality and transparency of solutions were measured. Results: The chromatographic method was satisfactory for its use in the evaluation of the finished product. 3 batches of the lyophilized 5 mg zoledronic acid injection were made which met the quality limits established during 6 months (accelerated stability) and up to 24 months (shelf life).

RESUMO Introdução: O ácido zoledrónico é um inibidor da reabsorção óssea utilizado no tratamento da doença de Paget, na prevenção da osteoporose induzida por glico-corticóides e na osteoporose em mulheres e homens na pós-menopausa. Objetivo: Avaliar a estabilidade de um novo injetável liofilizado de ácido zoledrónico 5 mg por meio de parâmetros de qualidade. Métodos: Um método de HPLC com detector UV foi validado para determinar a estabilidade química da formulação através da presença de produtos de degradação e da concentração de ácido zoledrónico no produto acabado. Também foram medidas as características organolépticas, pH, esterilidade e endotoxinas bacterianas, partículas em injetáveis e totalidade e transparência de suas soluções. Resultados: O método cromatográfico foi satisfatório para sua utilização na avaliação do produto acabado. Foram produzidos três lotes de injeção de ácido zoledrónico liofilizado de 5 mg, que atenderam aos limites de qualidade estabelecidos para 6 meses (estabilidade acelerada) e até 24 meses (prazo de validade).

Progress in the design and quality control of placeboes for clinical trials of traditional Chinese medicine / 中西医结合学报

In recent years, new preparations of traditional Chinese medicines (TCMs) have been developed, increasing the need for their clinical trials. Using placeboes rather than control drugs is increasingly popular in clinical trials of TCMs, as the therapeutic effects of the tested TCMs can be more properly judged. The basic attributes of TCM placeboes include similarity, safety, applicability and controllability. In particular, it is necessary to have similarities in appearance, color, smell and taste between the tested TCMs and placeboes. This is quite difficult for some TCMs due to their distinctive smell and taste. On the other hand, according to the TCM theory on homology of medicine and food, many foods also have certain bioactivities, potentially further complicating the selection of materials for TCM placeboes. In this review, firstly, studies on the special smell and taste of TCMs were introduced. Then, the preparation quality evaluation processes for TCM placeboes were summarized and discussed, based on the relevant literature published in recent years and the research results from our own lab. This review will facilitate the further research and development of TCM placeboes.

Study on critical quality attributes of Qingjin Huatan Decoction based on serum pharmacochemistry / 中国中药杂志

Qingjin Huatan Decoction is a classic prescription with the effects of clearing heat, moistening lung, resolving phlegm, and relieving cough. In order to explore the critical quality attributes of Qingjin Huatan Decoction, we identified the blood components of Qingjin Huatan Decoction by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS) under the following conditions, chromatographic column: Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm); mobile phase: 0.1% formic acid acetonitrile(A)-0.1% formic acid in water(B); gradient elution; flow rate: 0.2 mL·min~(-1); column temperature: 30 ℃; injection volume: 5 μL. The electrospray ionization(ESI) source was used to collect data in both positive and negative ion modes under the following conditions, capillary voltage: 3 kV for the positive ion mode and 2 kV for the negative ion mode; ion source temperature: 110 ℃; cone voltage: 30 V; cone gas flow rate: 50 L·h~(-1); nitrogen degassing temperature: 350 ℃; degassing volume flow rate: 800 L·h~(-1); scanning range: m/z 50-2 000. In this experiment, a total of 66 related components of Qingjin Huatan Decoction were identified, including 22 prototype components and 44 metabolites. The results of this study preliminarily revealed the pharmacodynamic material basis of Qingjin Huatan Decoction in vivo, which has provided an experimental basis for the determination of quality markers of Qingjin Huatan Decoction and the development of new drugs.

QbD enabled Process Variable Study to Develop Sustained Release Chitosan-Alginate Embedded Delivery System for Improved Patient Compliance

Abstract The current investigation entail systematic Quality by Design (QbD)-enabled approach for the development of Sustained released embedded drug delivery systems of L-Arginine employing ionic gelation technique to attain improved patient compliance. Hence, in this QbD enabled systematic approach; quality target product profile (QTTP) was defined and critical quality attributes (CQAs) were identified. Further the risk assessment studies were undertaken through Ishikawa fish bone diagram to locate the critical material attributes (CMAs) and/or critical process parameters (CPPs) for the formulation of beads that may affect CQAs of drug product. A face centered central composite design (CCD) for two factors at three levels each with α =1 was employed for the optimization process to checkout the impact of concentration of sodium alginate and concentration of chitosan as CMAs which wereprior identified from risk assessment study and further evaluated for CQAs viz. bead size, swelling index and percent drug entrapment. The optimum formulation was embarked upon by using mathematical model being developed yielding desired CQAs. Thereby chitosan coated calcium-alginate delivery system was successfully developed by strategically employing QbD approach.In a nutshell, the presentinvestigation reports the successful development of optimized chitosan coated alginate beads employing QbD approach which can serve as a platform for other drugs too.

Critical quality attribute assessment of big brand traditional Chinese medicine: quality control of Tongren Niuhuang Qingxin Pills in texture and sensory attributes / 中国中药杂志

Texture sensory attributes are the key items in quality control of Chinese medicinal honeyed pills. The purpose of this study is to develop a quality control method for assessing the texture sensory attributes of Chinese medicinal honeyed pills based on real-world Tongren Niuhuang Qingxin pilular masses and finished products. First, parameters of texture profile analysis(TPA) were optimized through single factor and central composite design(CCD) experiments to establish a detection method for texture sensory attri-butes of Tongren Niuhuang Qingxin Pills. The results showed that the established detection method was stable and reliable, with the optimal parameters set up as follows: deformation percentage of 70%, detection speed at 30 mm·min~(-1), and interval time of 15 s. Furthermore, 540 data points yielded form six texture sensory attributes of pills from 30 batches were subjected to multivariate statistical process control(MSPC) with Hotelling T~2 and squared prediction error(SPE) control charts to establish the quality control method of Tongren Niuhuang Qingxin Pills. This study is expected to provide a reference for improving the quality control system of Chinese medicinal honeyed pills.

Detection and quantitation of host cell proteins in monoclonal antibody drug products using automated sample preparation and data-independent acquisition LC-MS/MS / 药物分析学报

Ensuring the removal of host cell proteins (HCPs) during downstream processing of recombinant pro-teins such as monoclonal antibodies (mAbs) remains a challenge.Since residual HCPs might affect product stability or safety,constant monitoring is required to demonstrate their removal to be below the regulatory accepted level of 100 ng/mg.The current standard analytical approach for this procedure is based on ELISA;however,this approach only measures the overall HCP content.Therefore,the use of orthogonal methods,such as liquid chromatography-mass spectrometry (LC-MS),has been established,as it facilitates the quantitation of total HCPs as well as the identification and quantitation of the indi-vidual HCPs present.In the present study,a workflow for HCP detection and quantitation using an automated magnetic bead-based sample preparation,in combination with a data-independent acquisi-tion (DIA) LC-MS analysis,was established.Employing the same instrumental setup commonly used for peptide mapping analysis of mAbs allows for its quick and easy implementation into pre-existing workflows,avoiding the need for dedicated instrumentation or personnel.Thereby,quantitation of HCPs over a broad dynamic range was enabled to allow monitoring of problematic HCPs or to track changes upon altered bioprocessing conditions.

Use of subcutaneous tocilizumab to prepare intravenous solutions for COVID-19 emergency shortage: Comparative analytical study of physicochemical quality attributes / 药物分析学报

COVID-19, a disease caused by the novel coronavirus SARS-CoV-2, has produced a serious emergency for global public health, placing enormous stress on national health systems in many countries. Several studies suggest that cytokine storms (interleukins) may play an important role in severe cases of COVID-19. Neutralizing key inflammatory factors in cytokine release syndrome (CRS) could therefore be of great value in reducing the mortality rate. Tocilizumab (TCZ) in its intravenous (IV) form of administration-RoActemra? 20 mg/mL (Roche)-is indicated for treatment of severe CRS patients. Preliminary in-vestigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe, with several ongoing clinical trials. This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals, which has resulted in drug shortages. Here, we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion, at 6 mg/mL and 4 mg/mL, prepared from RoActemra? 20 mg/mL (IV form) and from RoActemra? 162 mg (0.9 mL solution pre-filled syringe, subcutaneous(SC) form), to evaluate the use of the latter for preparing clinical solutions required for IV administration, so that in a situation of shortage of the IV medicine, the SC form could be used to prepare the solutions for IV delivery of TCZ. It is important to remember that during the current pandemic all the medicines are used off-label, since none of them has yet been approved for the treatment of COVID-19.

Design and Optimization of the Formulation and Technology of Theophylline Gel Matrix Sustained-release Tablets Based on QbD Concept / 中国药房

OBJECTIVE： To design and optimize the formulation and technology of Theophylline hydrophilic gel matrix sustained-release tablets （self-made sustained-release tablets for short） based on the concept of “Quality by Design” （QbD）. METHODS： Diluent type， tablet diameter， the property of adhesive （ratio of different adhesive types）， the amount of adhesive were regarded as critical process parameters （CPPs）. Similarity factor of dissolution curves of self-made Theophylline sustained-release tablets and reference preparation and its accumulative release rate at different time points were regarded as critical quality attributes （CQAs）. L18（34） orthogonal tablet was adopted for design and trial， and secondary polynomial regression model was established. By using Modde 12.0 software， the design space and its acceptable range （PAR） were calculated through the optimal model. The optimal formulation and technology of Theophylline sustained-release tablets was determined， and validation test and Monte Carlo simulation verification were conducted. RESULTS： The optimal model with good coincidence， accuracy， validity and reproducibility was obtained， which could better fit the relationship between CQAs and CPPs. The design space and PAR value were obtained by further calculation （The optimum value of diluent was lactose； tablet diameter was 9.07-9.33 mm， and the optimal value was 9.20 mm； ratio of HPMC K4M to HPMC was 0.50-0.83， and the optimal value was 0.80； total amount of HPMC was 0.036 0-0.041 3 g per tablet， and the optimal value was 0.038 g per tablet）. The optimal formulation and technology included that ratio of theophylline， HPMC K4M and HPMC K100M were 50％， 15.48％ and 3.87％， respectively； the rest was filled with lactose and the diameter of the tablet was 9.20 mm. The results of validation confirmed that self-made Theophylline sustained-release tablets had similar in vitro release behavior compared with reference preparation. CONCLUSIONS： Based on the concept of QbD， the formulation and technology of Theophylline sustained-release tablets can meet the requirements of design， and the CPPs can be adjusted within the PAR range to meet the requirements of CQAs. This shows that the QbD concept is scientific and effective in the design and optimization of the formulation and technology of sustained and controlled release preparations.

Consideration on critical quality attributes determination of Chinese materia medica preparations / 中草药

In this paper, through the analysis of the key issues in the confirmation of the critical quality attributes (CQAs) of traditional Chinese medicine preparations, it is proposed that the determination of the CQAs should fully consider factors such as the efficacy, safety, nature of the drug substance, requirements of formulation and overall requirements of drug quality control. Complete quality control items that can characterize the properties of drugs should be extracted to provide a basis for the establishment of process control and drug quality standards.

Spray drying technology of Shenpu Penyan Granule based on quality by design concept / 中草药

Design space approach was applied to optimize the spray drying process of Shenpu Penyan Granule (SPG) based on the concept of quality by design (QbD). The yield, moisture content, the content of paeoniflorin, chlorogenic acid, polydatin and salvianolic acid B were defined as the process critical quality attributes (CQAs). Based on the Plackett-Burman design, three critical process parameters (CPPs) including inlet temperature, specific gravity, and feeding speed were identified by using the weighted standardized partial regression coefficient method. And stepwise regression method was then used to establish the mathematical model between CQAs and CPPs in the Box-Behnken design. The variance analysis results showed that the P values of the five models were less than 0.05 and the mismatch values were all greater than 0.05, indicating that the model could describe the relationship between CQAs and CPPs. Probability based design space was obtained and verified using Monte-Carlo simulation method. According to the verification results, the robustness of first ethanol precipitation process of SPG can be guaranteed by operating within the design space parameters, which helps to improve the quality uniformity between batches of phenol extracts and provides data support for industrialization production.

Research on extraction process of Digeda-4 flavored decoction based on QbD concept / 中国中药杂志

To establish and validate the design space of the Digeda-4 flavored decoction( DGD-4D) extraction process by using the quality by design( Qb D) concept. With DGD-4D decoction pieces as a model drug,with the transfer rate of aesculin,picroside I,picroside Ⅱ,geniposide and the yield of extract as critical quality attributes( CQAs),the single factor experiment design was used to determine the level of each factor; the Plackett-Burman experiment design was used to select the critical process parameters( CPPs);and the Box-Behnken experiment design was used to optimize the extraction process. The design space of the DGD-4D extraction process was established,and finally,four experimental points were selected to verify the established model. The single factor experiment determined the levels of each factor,including soaking time 60 min and 30 min,water adding volume 12 times and 8 times,extraction time 90 min and 30 min,number of extraction times 3 times and 1 time,as well as extraction temperature 100 ℃ and 90 ℃.By Plackett-Burman experimental design,the DGD-4D water addition,extraction time and number of extraction times were determined to be CPPs. The Box-Behnken experimental variance analysis showed that P of the regression model was less than 0. 01 and the misstated value was more than 0. 01,indicating that the model had good predictive ability,and the operation space of CPPs in the DGD-4D extraction process was determined as follows: the amount of water addition was 10-12 times; extraction time 50-80 min; and number of extraction times was 3 times. The design space of DGD-4D extraction process based on the concept of Qb D is conducive to improving the stability of product quality and laying a foundation for the future development of DGD-4D.

Film coating process of Xianqu Tablets based on concept of quality by design / 中草药

Objective To investigate the film coating process of Xianqu Tablets based on the concept of quality by design (QbD), and improve the coating efficiency and stability. Methods Using the QbD as an experimental guidance and the Design-Expert software as a tool, the critical quality attributes affecting Xianqu film coating targets were first determined as the response values, and the process parameters of influencing critical quality attributes were selected as the key factors. Then the Box- Behnken design was used to optimize the process parameters and establish a control space. Finally, the design space were verified by measuring the hygroscopicity of Xianqu Tablets. Results The results showed that the design space was optimized to reduce the actual error by 95% confidence interval, the best range of process parameters were obtained as follow: bed temperature 37-43 ℃, coating solution concentration 9%-11%, coating weight gain 4%-5%. After the Xianqu Tablets were coated under the given conditions, the hygroscopicity of Xianqu Tablets, which had a smooth surface and uniform color, was significantly reduced. Conclusion The desired effects by using a reasonable experimental design concept of QbD were efficiently achieved, it provides a predictive model for the film coating process of Xianqu Tablets through constructing reasonable design space, which not only enhances the flexibility and applicability of the coating process, but also ensures the stable product quality.

Comparison Study on the Critical Quality Attributes between Similar Biological Medicine (YD057) and Dulaglutide / 中国药学杂志

OBJECTIVE: To investigate whether there is significant difference between the GLP-1-Fc fusion protein(YD057) that is expressed by gene recombination and the marketed drug dulaglutide(Lilly). METHODS: SDS-PAGE, SEC, CE-SDS and CIEF were used to analyze the differences in molecular weight, purity and charge heterogeneity. The amino acid sequence, biological activity and receptor binding analysis were measured to assess whether the cytological function and molecular binding capacity were consistent. Oligosaccharide distribution was measured to assess whether N-linked glycosylation modification ratio was consistent. RESULTS: There was no significant difference in physicochemical properties, amino acid primary sequence, N-linked glycosylation modification ratio, cell biology function and receptor binding capacity between the biological similar drugs(YD057) and dulaglutide. CONCLUSION: Their critical quality attributes are basically the same.

Efecto de la fuerza de compresión sobre los atributos críticos de calidad en tabletas de liberación inmediata de furosemida / Effect of compression force on critical quality attributes of immediate release tablets of furosemide

RESUMEN La furosemida es un fármaco poco soluble en agua (0,01825 mg/mL). Debido a su baja solubilidad y baja permeabilidad, se ubica en la clase IV del Sistema de Clasificación Biofarmacéutica (BCS, por sus siglas en inglés). Se absorbe rápida pero incompletamente en el tracto gastrointestinal (GI). Actualmente, este fármaco se comercializa en tabletas, las que para su obtención deben ser sometidas a un proceso de compresión. La fuerza aplicada en dicha compresión puede influenciar algunas de las características de calidad del producto; por ello, la presente investigación estudia el efecto de la fuerza de compresión sobre los atributos críticos de calidad en el proceso de fabricación (dureza, friabilidad y desintegración) y en el producto terminado (uniformidad de dosificación y disolución) de comprimidos de furosemida. El efecto sobre la disolución se determinó por los factores de diferencia (f 1) y de similitud (f 2) de los perfiles de disolución y los parámetros de eficiencia de la disolución (ED) y tiempo medio de disolución (TMD), los cuales se calcularon con el software académico kinetDS®. Los resultados obtenidos permitieron definir el rango de la fuerza de compresión para el cual se obtuvo una ED superior al 85% y un TMD inferior a 7,5 min.

SUMMARY Furosemide is poorly water soluble drug (0.01825 mg/mL). Due to its low solubility and low permeability, it is labeled in class IV of the Biopharmaceutical Classification System (BCS). It is rapidly but incompletely absorbed from the gastrointestinal (GI) tract. Currently, this drug is marketed as tablets, which should be subjected to a compression process. The force applied in this compression can influence some of the quality characteristics of the product. Therefore, this investigation was carried out to determine the effect of compression force on the critical quality attributes of the product in process (hardness, friability and disintegration) and of the finished product (uniformity of dosage and dissolution). The effect on the dissolution was determined by the difference factor (f 1) and similarity factor f 2 ) of the dissolution profiles, the dissolution efficiency (ED) and mean dissolution time (TMD) parameters, which were calculated by kinetDS® academic software. The results obtained allowed to define the range of compression force for which the ED was higher than 85% and the TMD lower than 7.5 min.

Pre-harvest application of calcium chloride and chitosan on fruit quality and storability of 'Early Swelling' peach during cold storage / Efeito da aplicação pré-colheita de cloreto de cálcio e quitosano na qualidade e no armazenamento de frutos de pessegueiro da variedade 'Early Swelling' durante o armazenamento a frio

ABSTRACT Studies related with the storage of peach fruits have received great relevance in Egypt. In this study, the effect of pre-harvest sprays of calcium chloride and chitosan, separately and in combination, on quality attributes and storability of peach fruits stored at 0±1 °C was studied. 'Early Swelling' peach trees were sprayed twice with 1% or 2% calcium chloride. The first spraying was at pea stage, while the second one was performed at 10 days before harvesting. Chitosan sprays were performed at 0.5 or 1%, alone or in combination with 1 and 2% calcium chloride, at 10 days before harvesting. Untreated trees served as control. Fruits were harvested at maturity stage, then packaged and stored at 0±1 °C and 85-90% of relative humidity. Fruit physical and chemical properties were evaluated at 7-day intervals. Results showed that pre-harvest application with 2% CaCl2+1% chitosan was most effective in minimizing weight loss (%) and decay (%), as well as in maintaining maximum firmness and lengthening shelf life. Fruit color was not affected by any of the treatments, while untreated fruits and calcium chloride treatment alone, at both applied concentrations, maintained higher total soluble solids (TSS, %), total phenolic content, and lower titratable acidity percentage.

RESUMO Estudos relacionados ao armazenamento de pêssego tem sido considerado de grande relevância no Egito. Neste estudo, o efeito da pulverização pré-colheita com cloereto de calico e quitosano, isoladamente ou em conjunto, na qualidade e na capacidade de armazenamento de frutos de pessegueiro armazenados a 0±1 °C foi avaliada. Frutos da variedade 'Early Swelling' foram tratados com 1,0 ou 2,0% de cloreto de cálcio. O primeiro tratamento foi aplicado num estado precoce de formação do fruto enquanto o segundo foi aplicado 10 dias antes da colheita. Quitosano foi aplicado nas concentrações de 0,5 ou 1,0%, isoladamente ou em combinação com 1,0% ou 2,0% de cloreto de cálcio também 10 dias antes da colheita. Árvores não tratadas serviram como controle. Os frutos foram colhidos quando maduros, empacotados e mantidos a 0±1 °C e sob condições de humidade relativa de 85-90%. Propriedades físicas e químicas dos frutos foram avaliadas em intervalos de 7 dias. Os resultados mostraram que a aplicação de 2% CaCl2 + 1% quitosano foi a mais eficaz em minimizar a perda de peso (%) e a senescência (%), bem como na manutenção da rigidez e aumento do período de vida em prateleira. A cor dos frutos não foi afectada por nenhum dos tratamentos enquanto frutos não tratados e cloreto de cálcio isoladamente, em ambas as concentrações, mantiveram um elevado teor de sólidos solúveis totais (TSS, %), elevado teor de fenóis e reduzida percentagem de acidez de titulação.

Studying on purification technology of Resina Draconis phenol extracts based on design space method / 中国中药杂志

The "design space" method was used to optimize the purification process of Resina Draconis phenol extracts by using the concept of "quality derived from design" (QbD). The content and transfer rate of laurin B and 7,4'-dihydroxyflavone and yield of extract were selected as the critical quality attributes (CQA). Plackett-Burman design showed that the critical process parameters (CPP) were concentration of alkali, the amount of alkali and the temperature of alkali dissolution. Then the Box-Behnken design was used to establish the mathematical model between CQA and CPP. The variance analysis results showed that the P values of the five models were less than 0.05 and the mismatch values were all greater than 0.05, indicating that the model could well describe the relationship between CQA and CPP. Finally, the control limits of the above 5 indicators (content and transfer rate of laurine B and 7,4'-dihydroxyflavone, as well as the extract yield) were set, and then the probability-based design space was calculated by Monte Carlo simulation and verified. The results of the design space validation showed that the optimized purification method can ensure the stability of the Resina Draconis phenol extracts refining process, which would help to improve the quality uniformity between batches of phenol extracts and provide data support for production automation control.

Characterization and comparability of biosimilars: a filgrastim case of study and regulatory perspectives for Latin America

Background: Developing countries have an estimate of ten times more approved biosimilars than developed countries. This disparity demands the need of an objective regulation that incorporates health policies according to the technological and economical capabilities of each country. One of the challenges lies on the establishment of comparability principles based on a physicochemical and biological characterization that should determine the extent of additional non-clinical and clinical studies. This is particularly relevant for licensed biosimilars in developing countries, which have an extensive clinical experience since their approval as generics' in some cases more than a decade. To exemplify the current status of biosimilars in Mexico' a characterization exercise was conducted on licensed filgrastim biosimilars using pharmacopeial and extended characterization methodologies. Results: Most of the evaluated products complied with the pharmacopeial criteria and showed comparability in their Critical Quality Attributes (CQAs) towards the reference product. These results were expected in accordance with their equivalent performance during their licensing as generics. Accordingly' a rational approval and registration renewal scheme for biosimilars is proposed, that considers the proper identification of CQAs and its thoroughly evaluation using selected techniques. Conclusions: This approach provides support to diminish uncertainty of exhibiting different pharmacological profiles and narrows or even avoids the necessity of comparative clinical studies. Ultimately, this proposal is intended to improve the accessibility to high quality biosimilars in Latin America and other developing countries.