ABSTRACT
Safety is the core of the quality of Chinese materia medica products， and microbial pollution caused by medicinal materials， decoction pieces， intermediate products and others can bring certain impact on the quality and safety of Chinese materia medica products. The reasons for this are not only the problems of medicinal materials themselves， but also the exogenous pollution introduced in the production process. How to effectively use microbial detection technology and establish an appropriate microbial quality control strategy in the whole process of Chinese materia medica production is of great significance to improve the quality of Chinese materia medica products. Therefore， the authors put forward a microbial quality control strategy in the whole process of Chinese materia medica production based on the guidance of quality by design （QbD） concept， emphasizing the scientific linkage between the internal and external microbial quality control systems to jointly ensure the quality of products in all aspects. Among them， the internal microbial quality control system includes the control of the whole chain of Chinese materia medica-decoction pieces-intermediate products-excipitents-packaging materials-final products， which should be carried out by stages and characteristics， while the external microbial quality control system includes the control of personnel-equipment and facilities-pharmaceutical water-environment， emphasizing the principle of quality risk management and the development of monitoring programs， aiming to closely integrate microbial quality risk management with the production process of Chinese materia medica products， and to classify and develop microbial control strategies in order to minimize the impact of contaminating microorganisms and effectively guarantee the quality of Chinese materia medica products.
ABSTRACT
@#[Objective] To explore the application of Quality by Design (QbD) tools in assessing geographical variations of Phyllanthus emblica (P. emblica) from five distinct Indian states. [Methods] In the current experiment, the Box-Behnken design with a reduced quartic model and 105 runs was employed with the use of the Design Expert software for randomized response surface mapping. Three different extraction methods (Soxhlet, maceration, and sonication) along with three solventst [distilled water, methanol, and water-methanol mixture (50 : 50 v/v)] were considered in the present study. The anti-oxidant activities, total flavonoid content (TFC), and total phenolic content (TPC) in the P. emblica were determined and analysed by gas chromatography-mass spectrometry (GC-MS) to identify the major components. [Results] The QbD overlay plot showed that the extractive value of the P. emblica was no less than 30% w/w, 2,2-diphenyl-1-picrylhydrazyl (DPPH) no less than 60% mcg/mL (micrograms per millilitre), TFC no less than 75 mg QE/g (milligrams of quercetin equivalents per gram), and TPC no less than 80 mg GAE/g (milligrams of gallic acid equivalents per gram). Moreover, the GC-MS data confirmed the presence of variation in the bioactives of P. emblica extracts. [Conclusion] The model was significant in describing the variation in extractive value, DPPH, TFC, and TPC. The QbD approach may tend to prioritize thoroughness in the extraction process, ultimately resulting in improved quality in the extracted products.
ABSTRACT
After more than 100 years of development， spray drying technology has become more mature and widely used， and it is of great importance in the field of traditional Chinese medicine （TCM）. TCM powders prepared by spray drying is the raw material of dispensing granules， and the powder properties have an important influence on subsequent molding process and product quality. As a new form of TCM， dispensing granules have been included in the management category of TCM decoction pieces， indicating a broader application market， and a consensus has also been reached on the importance of TCM powder research. Based on this， the author summarized the application progress of spray drying in the study of TCM powders， including the factors affecting spray drying process， such as liquid properties， process parameters and equipment factors， as well as the application of computational fluid dynamics （CFD） and thermodynamic model in spray drying process simulation. Moreover， some commonly used pharmaceutical excipients for the modification of TCM powders were also introduced such as maltodextrin， microcrystalline cellulose and povidone. In addition， spray drying technology can also be used as a preparation technology for new drug delivery systems such as microcapsules and solid dispersions. Through the summary of this paper， the author suggests that the future research direction of spray drying of TCM can be carried out from the aspects of application rule of the coprocessing auxiliary materials based on the "unification of medicines and excipients"， the "structure-property" relationship of spray-dried powders and the application of computer simulation and design， so as to further enrich the application of spray drying in the field of TCM powders.
ABSTRACT
As intelligent production of traditional Chinese medicine （TCM） has been inevitable， informatization and automation of the production process have become the precondition for realizing intelligent manufacturing of TCM， of which the accumulation of critical material attribute and the critical quality attribute are the basis. The study of material properties is of great significance to achieve the quality control of the final product in the process， but there is a lack of systematic induction and summary of the research on the attribute of TCM pills. Therefore， the authors analyzed and summarized the attributes of raw materials， excipients and intermediates in the pill unit process according to the classification of powder properties， rheological properties and texture properties. What’s more， the impact of material attributes on the quality of the final product was summarized. Besides， this review summarized the attribute characterization techniques involved in the pill process and provided some suggestions for the characterization of product quality attributes. Finally， based on the concept of quality by design （QbD）， the authors proposed that the study of material attribute should be combined with process analytical technology （PAT）， and the focus of drug quality control should be moved forward to guide equipment upgrading， so as to realize intelligent continuous manufacturing of TCM pills.
ABSTRACT
ObjectiveA feedforward control model for dry granulation of polysaccharide components was established to guide the adjustment and optimization of critical process parameters （CPPs） in the design space， so as to reduce the impact of fluctuations in raw materials properties on the quality of medicines. MethodTaking Astragali Radix extract powder as the model drug， the design space of dry granulation CPPs was determined by Box-Behnken design. Astragali Radix mixed powder with different powder properties were prepared by mixture design， the variance inflation factor （VIF） was used to diagnose the multicollinearity of the powder properties， and principal component analysis （PCA） was used to extract the characteristic data of the model. Radial basis function neural network （RBFNN） was used to establish a feedforward control model for reflecting the relationship between the powder properties of polysaccharide components， dry granulation CPPs and one-time molding rate. ResultThe design space for dry granulation CPPs of polysaccharide components was 16-35 Hz for feeding speed， 10-23 Hz for roller speed， and 10-46 kg·cm-2 for roller pressure. The established RBFNN feedforward control model had a good predictive effect on the one-time molding rate of dry granulation of polysaccharide components， which could be used to guide the adjustment and optimization of CPPs in the design space， the relative error was 0.38%-6.73%， and the average relative error was 3.42%. ConclusionThe established feedforward control model can well reflect the relationship between the powder properties of the polysaccharide components， the dry granulation CPPs and the one-time molding rate of the granules， which can be used to guide the adjustment and optimization of CPPs in the design space， reduce the impact of material property fluctuation on product quality， and provide ideas for promoting the quality of traditional Chinese medicine from passive control to active control.
ABSTRACT
The mixing process is one of the key operation units for solid preparation of traditional Chinese medicine. The physical properties such as particle size, density and viscosity of the mixture are key factors that need to be controlled, which will directly affect the performance of the preparation molding process and product quality. Subsequent dripping process performance and appearance qua-lity of dripping pills will be affected by dynamic viscosity of materials in the mixing process. Based on this, with mixing process of compound Danshen dripping pills as the object, a feedforward control method for the dripping pill mixing process was established based on the concept of quality by design(QbD). Firstly, critical quality attribute(CQA)-dynamic viscosity, critical material attributes(CMAs)-the moisture content of compound Danshen extract, average molecular weight of polyethylene glycol 6000 and critical process parameter(CPP)-mixing temperature were identified through the analysis of properties for multiple batches of the raw materials and excipients as well as technological mechanism. Then the Box-Behnken experimental design was used to establish the regression model among CMA, CPP and CMA(R■=0.972 0, RMSE =16.24) to obtain the design space. Finally, through the verification of three batches within the design space, the mixing process temperature was adjusted according to the properties of the raw materials and exci-pients to achieve accurate control of the dynamic viscosity attribute. The relative deviation between the actual dynamic viscosity value and the target value was less than 3.0 %. The feedforward control of the mixing process of compound Danshen dripping pills was rea-lized in this study, which can contribute to improving quality consistency of the mixing process intermediates, simultaneously provide a reference for the research on the process quality control of other Chinese medicine dripping pills.
Subject(s)
Drugs, Chinese Herbal , Medicine, Chinese Traditional , Quality Control , Research DesignABSTRACT
From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for population pharmaceutical quality evaluation.A descriptive analysis method based on QbD concept was first established to characterize the process by critical evaluation attributes(CEAs).Then quantitative analysis method based on an improved statistical process control(SPC)method was established to investigate the process indicators(PIs)in the process population,such as mean distri-bution,batch-to-batch difference and abnormal quality probability.After that rules for risk assessment were established based on the SPC limitations and parameters.Both the SPC parameters of the CEAs and the risk of PIs were visualized according to the interaction test results to obtain a better understanding of the population pharmaceutical quality.Finally,an assessment strategy was built and applied to generic drug consistency assessment,process risk assessment and quality trend tracking.The strategy demon-strated in this study could help reveal quality consistency from the perspective of process control and process risk,and further show the recent development status of domestic pharmaceutical production processes.In addition,a process risk assessment and population quality trend tracking provide data-based information for approval.Not only can this information serve as a further basis for decision-making by the regulatory authority regarding early warnings,but it can also reduce some avoidable adverse reactions.With continuous addition of data,dynamic population pharmaceutical quality is meaningful for emergencies and decision-making regarding drug regulation.
ABSTRACT
The development of Chinese materia medica (CMM) has risen to the level of national strategy. Under the new situation that the pharmaceutical industry implements the "Made in China 2025" strategy, quality control of the production process of CMM is one of the key areas in which the CMM industry needs to accelerate its breakthrough. The key common issues in process design, analysis and detection, process modeling, and manufacturing equipment and other aspects in the field of quality control of CMM production processes was analyzed in the paper. The progress in the three aspects of process understanding, real-time analysis method development and process control strategy establishment in the quality control system of CMM production process was reviewed. Combined with the author's corporate research practices, this paper introduces the application progress of key technologies such as quality by design (QbD), process analytical technology (PAT), experimental design (DOE), and multivariate statistical analysis in the above three research directions, and analyzes the difficulties problems in practical industrial application. The application prospect is prospected. The purpose of this article is to provide reference for CMM enterprises to apply and improve the quality control technology in the production process.
ABSTRACT
Objective: To optimize andrographolide pellet by using a quality by design (QbD) approach. Methods: Usingthe cumulative in vitro release as evaluation index, the single-factor investigation and hazard analysis were used to study the core and coating process of andrographolide colon-targeting pellets, and the central composite design-response surface method was used to optimize and predict the three key factors of plasticizer dosage, aging time, and coating weight gain. Results: The optimum coating process parameters were as following: plasticizer dosage of 3 g, coating weight gain of 20%, and aging time of 1 h. The process had been verified that the optimal formulation process had a cumulative in vitro release of 6.9% in the acid phase (0.1 mol/L HCl)-buffered salt phase (pH 6.0) and a cumulative in vitro release of more than 90% in the pH 7.2 buffered salt phase. Conclusion: It is feasible to apply the QbD concept optimization in the study of andrographolide colon-targeting pellets.
ABSTRACT
Chinese materia medica (CMM) compound is the main form and method of clinical drug in traditional Chinese medicine. On the basis of guaranteeing the safety, efficiency, stability, and controllability of CMM compound preparations, it is particularly important to rationally design process routes, production equipment, and quality control methods, and to establish a processing research model which conforms to the characteristics of CMM compound preparations. According to the status of policy, process, and equipment of CMM compound preparations, we analyze the technological mode of CMM compound preparations using holistic view, dynamic view, and dialectical view, break through the difficulties of this study, and propose research strategies for the development of CMM compound preparations, hoping to provide references for the preparation of CMM compound formulations.
ABSTRACT
According to Quality by Design (QbD) concept, quality should be built into product/method during pharmaceutical/analytical development. Usually, there are many input factors that may affect quality of product and methods. Recently, Design of Experiments (DoE) have been widely used to understand the effects of multidimensional and interactions of input factors on the output responses of pharmaceutical products and analytical methods. This paper provides theoretical and practical considerations for implementation of Design of Experiments (DoE) in pharmaceutical and/or analytical Quality by Design (QbD). This review illustrates the principles and applications of the most common screening designs, such as two-level full factorial, fractionate factorial, and Plackett-Burman designs; and optimization designs, such as three-level full factorial, central composite designs (CCD), and Box-Behnken designs. In addition, the main aspects related to multiple regression model adjustment were discussed, including the analysis of variance (ANOVA), regression significance, residuals analysis, determination coefficients (R2, R2-adj, and R2-pred), and lack-of-fit of regression model. Therefore, DoE was presented in detail since it is the main component of pharmaceutical and analytical QbD.
Subject(s)
Research Design/trends , Pharmaceutical Preparations/analysis , Pharmaceutical Preparations/standards , Total Quality ManagementABSTRACT
Objective To optimize the process of vildagliptin based on the principle of quality by design(QBD),so as to con?trol the safety and quality of the product. Methods Process route was confirmed through investigating literature and the advantages or disadvantages of each route were discussed. The key process parameters were determined according to the single factor experiments , which were designed by understanding of product process and process controls. Meanwhile,impurities of intermediates were studied and the safety and quality of the product could be guaranteed. Results and Conclusion Industrial process of vildagliptin was devel?oped by the principle of QBD,which can promise the safety and quality of vildagliptin,improve product quality and meet the registra?tion requirements of State Food and Drug Administration(SFDA).
ABSTRACT
Objective To optimize the process of vildagliptin based on the principle of quality by design(QBD),so as to control the safety and quality of the product. Methods Process route was confirmed through investigating literature and the advantages or disadvantages of each route were discussed. The key process parameters were determined according to the single factor experiments, which were designed by understanding of product process and process controls. Meanwhile, impurities of intermediates were studied and the safety and quality of the product could be guaranteed. Results and Conclusion Industrial process of vildagliptin was developed by the principle of QBD, which can promise the safety and quality of vildagliptin, improve product quality and meet the registration requirements of State Food and Drug Administration(SFDA).
ABSTRACT
The pharmaceutical quality was built by design, formed in the manufacturing process and improved during the product's lifecycle. Based on the comprehensive literature review of pharmaceutical quality by design (QbD), the essential ideas and implementation strategies of pharmaceutical QbD were interpreted. Considering the complex nature of Chinese medicine, the "4H" model was innovated and proposed for implementing QbD in pharmaceutical development and industrial manufacture of Chinese medicine product. "4H" corresponds to the acronym of holistic design, holistic information analysis, holistic quality control, and holistic process optimization, which is consistent with the holistic concept of Chinese medicine theory. The holistic design aims at constructing both the quality problem space from the patient requirement and the quality solution space from multidisciplinary knowledge. Holistic information analysis emphasizes understanding the quality pattern of Chinese medicine by integrating and mining multisource data and information at a relatively high level. The batch-to-batch quality consistence and manufacturing system reliability can be realized by comprehensive application of inspective quality control, statistical quality control, predictive quality control and intelligent quality control strategies. Holistic process optimization is to improve the product quality and process capability during the product lifecycle management. The implementation of QbD is useful to eliminate the ecosystem contradictions lying in the pharmaceutical development and manufacturing process of Chinese medicine product, and helps guarantee the cost effectiveness.
ABSTRACT
Coptis chinensis (Huanglian) is a commonly used traditional Chinese medicine (TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance liquid chromatography (RP-HPLC) method allowing the separation of six alkaloids in Huanglian was for the first time developed under the quality by design (QbD) principles. First, five chromatographic parameters were identified to construct a Plackett-Burman experimental design. The critical resolution, analysis time, and peak width were responses modeled by multivariate linear regression. The results showed that the percentage of acetonitrile, concentration of sodium dodecyl sulfate, and concentration of potassium phosphate monobasic were statistically significant parameters (P < 0.05). Then, the Box-Behnken experimental design was applied to further evaluate the interactions between the three parameters on selected responses. Full quadratic models were built and used to establish the analytical design space. Moreover, the reliability of design space was estimated by the Bayesian posterior predictive distribution. The optimal separation was predicted at 40% acetonitrile, 1.7 g·mL(-1) of sodium dodecyl sulfate and 0.03 mol·mL(-1) of potassium phosphate monobasic. Finally, the accuracy profile methodology was used to validate the established HPLC method. The results demonstrated that the QbD concept could be efficiently used to develop a robust RP-HPLC analytical method for Huanglian.
Subject(s)
Alkaloids , Bayes Theorem , Chromatography, High Pressure Liquid , Methods , Reference Standards , Chromatography, Reverse-Phase , Methods , Coptis , Chemistry , Drugs, Chinese HerbalABSTRACT
Objective: The aim of this investigation was to use a quality by design (QbD) approach to optimize andrographolide solid lipid nanoparticles (And-SLNs). Methods: The And-SLNs were prepared by melt-emulsion and followed by high pressure homogenization methods. The And-SLNs with ideal encapsulation efficiency (EE) and particle size distribution were used various experimental statistical design modules. Plackett-Burman design for independent variables was first conducted to prescreen various formulation and process variables during the development of SLNs. Selected primary variables were further optimized by Box-Behnken design. The particle size distribution, Zeta potential, morphology, and in vitro drug release behavior of And-SLNs were studied by Malvern Particle Size Analyzer and Transmission Electron Microscope (TEM), respectively. Results: The EE, particle size, and Zeta potential of And-SLNs were found to be (91.4 ± 3.7)%, (258.4 ± 42.1) nm, and (-36.1 ± 3.4) mV, respectively. The And-SLNs were found to be small and spherical with uniform particle size and smooth surface as seen in TEM. The in vitro accumulated release of And reached up to 52.4% within 48 h. Conclusion: This study demonstrates that the QbD approach could optimize the formulation and process variables to achieve favorable responses for And-SLNs.
ABSTRACT
The sample preparation of samples containing bovine serum albumin (BSA), e.g., as used in transdermal Franz diffusion cell (FDC) solutions, was evaluated using an analytical quality-by-design (QbD) approach. Traditional precipitation of BSA by adding an equal volume of organic solvent, often successfully used with conventional HPLC-PDA, was found insufficiently robust when novel fused-core HPLC and/or UPLC-MS methods were used. In this study, three factors (acetonitrile (%), formic acid (%) and boiling time (min)) were included in the experimental design to determine an optimal and more suitable sample treatment of BSA-containing FDC solutions. Using a QbD and Derringer desirability (D) approach, combining BSA loss, dilution factor and variability, we constructed an optimal working space with the edge of failure defined as Do0.9. The design space is modelled and is confirmed to have an ACN range of 8373%and FA content of 170.25%.
ABSTRACT
El presente trabajo ilustra la implementación de los principios de la calidad basada en el diseño (QbD) en la fabricación industrial de medicamentos. Como caso de estudio se eligió la elaboración de tabletas masticables, cuya formulación y proceso de manufactura se rediseñaron. Se tomó como punto de partida la definición del perfil de calidad para el producto, el que sirvió de base para identificar los atributos críticos de calidad. Posteriormente, se analizó el impacto y la criticidad de cada una de las operaciones de fabricación en la calidad del producto, y para cada una de las operaciones que resultaron críticas, se realizó el análisis de riesgos. De acuerdo con los resultados obtenidos, se diseñaron e implementaron las estrategias de mitigación, logrando una formulación acorde con las expectativas desde el punto de vista organoléptico y la reducción en un 25% de los tiempos de producción.
This research work illustrates the implementation of Quality by Design (QbD) principles into pharmaceutical industry. The manufacture of chewable tablets was chosen as case study. In this way, product formulation and preparation procedure were reformulated. The starting point was the definition of the product quality profile from which the critical quality attributes were identified. Also, the impact and the criticality of each stage of manufacture for the product were examined regarding to their influence in achieving the critical quality attributes. Risk assessment was made for critical manufacture stages and considering the results, mitigation strategies were proposed and implemented. This leads to a formulation satisfying the requirements for the organoleptic properties like the 25% reduction in the production time.
ABSTRACT
Lacidipine (LCDP) is a dihydropyridine derivative categorized as an Anti-hypertensive Ca+2 channel blocker belonging to BCS class IV drug with low solubility and low permeability which presents a challenge to the formulation scientists. The development of a solid dispersion by solvent evaporation is a practically viable method to enhance dissolution of LCDP from oral dosage form. Solvent evaporation by Fluidized Bed Process (FBP) was the method of choice for SD as it improves wettability with simultaneous increase in porosity of granules resulting enhanced surface area producing higher dissolution rate and bioavailability of poorly water-soluble drug. Thus, the main object of the present invention is to provide stable pharmaceutical dosage form of LCDP with desired dissolution rate i.e. at least 80% drug release within 45 minutes, without use of disintegrant(s) and/or surfactant(s) or without micronization of the active ingredient per se. One more object of this invention is to provide a sophisticated robust process for the preparation of said pharmaceutical dosage form by Quality by Design (QbD) concept focusing on thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing by IRMA & FMEA study of the product with process and how best to mitigate those risks by developing design space with DoE & MVDA with outlined control strategy.