Application of the Quality by Design Concept (QbD) in the Development of Hydrogel-Based Drug Delivery Systems.

Hydrogel-based drug delivery systems are of interest to researchers for many reasons, such as biocompatibility, high diversity, and the possibility of administration from different routes. Despite these advantages, there are challenges, such as controlling the drug release rate and their mechanical properties during the manufacturing of these systems. For this reason, there is a need for the production and development of such drug delivery systems with a scientific strategy. For this reason, the quality by design (QbD) approach is used for the development of drug delivery systems. This approach, by identifying the most effective factors in the manufacturing of pharmaceutical products and controlling them, results in a product with the desired quality with the least number of errors. In this review article, an attempt is made to discuss the application and method of applying this approach in the development of hydrogel-based drug delivery systems. So that for the development and production of these systems, according to the type of drug delivery system, what target characteristics should be considered (QTPP) and what factors, such as material properties (CMA) or process parameters (CPP), should be taken into account to reach the critical quality attributes of the product (CQA).

Satisfying QTPP of Erythropoietin Biosimilar by QbD through DoE-Derived Downstream Process Engineering.

Well-characterized and scalable downstream processes for the purification of biologics are extremely demanding for delivering quality therapeutics to patients at a reasonable price. Erythropoietin (EPO) is a blockbuster biologic with diverse clinical applications, but its application is limited to financially well-off societies due to its high price. The high price of EPO is associated with the technical difficulties related to the purification challenge to obtain qualified products with a cost-effective defined process. Though there are reports for the purification of EPO there is no report of a well-characterized downstream process with critical process parameters (CPPs) that can deliver EPO consistently satisfying the quality target product profile (QTPP), which is a critical regulatory requirement. To advance the field, we applied the quality by design (QbD) principle and design of experiment (DoE) protocol to establish an effective process, which is scalable up to 100× batch size satisfying QTPP. We have successfully transformed the process from static mode to dynamic mode and validated it. Insignificant variation (p > 0.05) within and between 1×, 10×, and 100× batches showed that the process is reproducible and seamlessly scalable. The biochemical analysis along with the biofunctionality data ensures that the products from different scale batches were indifferent and comparable to a reference product. Our study thereby established a robust and scalable downstream process of EPO biosimilar satisfying QTPP. The technological scheme presented here can speed up the production of not only EPO but also many other life-saving biologics and make them available to the mass population at a reduced cost.

A Novel Approach for Determining the Critical Quality Attributes of Mesenchymal Stem Cells by Specifying Cell Population With Replication Potential.

We introduce a novel approach to determine the critical quality attributes (CQAs) of mesenchymal stem cells (MSCs) expected to exert immunosuppressive effects. MSCs retained homeostatic replication potentials, such as sustainable growth and consistent cell morphology as a population, in early passages, but lost them in late passages. Characteristic surface markers of MSCs (ie, CD73, CD90, and CD105) were no longer expressed at 2 weeks after subcutaneous transplantation into NOG mice when MSCs from late passages were transplanted, but not when MSCs from early passages were transplanted, suggesting that the biological effects of the MSCs differed according to the timing of cell harvesting and highlighting the importance of specifying MSCs that retained homeostatic features to define the CQAs. The homeostatic features of MSCs related to the balance of the redox system, nutrient requirements, and mitochondrial function were also observed until a certain passage. Therefore, we could define the CQAs of MSCs related to manufacturing by selecting process parameters (PPs) underlying the homeostatic features of MSCs and measuring these PPs quantitatively to specify the cell population with homeostatic features by limiting the passage number. The validity of the PPs stipulated in our pilot study was verified using an SKG murine arthritis model, and critical PPs (CPPs) were then selected among the PPs. Thus, CQAs related to manufacturing in the developmental phase could be defined by the CPPs in this manner, and the concept of CQAs could be refined continuously toward commercial manufacturing.

A simulating method for dripping process of Ginkgo biloba leaf dripping pills based on computational fluid dynamics technology / 药学学报

A simulating method for dripping process of Ginkgo biloba leaf dripping pills based on computational fluid dynamics was constructed. Ginkgo biloba leaf dripping pills was explored as the experimental subject to simulate the dripping process based on FLOW-3D software. The dripping process was simulated through the derivation of the governing equations, the selection of the models, and simulation parameters. Firstly, the droplet morphologies and drop speeds under different liquid viscosity were simulated. It was found that with the increase of the liquid viscosity, the drop speed decreased and the difficulty of droplet preparation gradually increased. The simulation results were consistent with the experiment results. Secondly, the droplet morphologies at different drop speeds were investigated and verified by experiments. It was found that the simulation results had a good correlation with the experiment results. The results shown that the viscosity of the liquid was the critical material attribute, and the drop speed was the critical process parameter, according to the droplet morphology. The establishment of the simulation method can deepen the understanding of the dripping process and provide a reference for the selection of raw materials and process parameters.

An Improved Impact Ratio for Identifying Critical Process Parameters in Pharmaceutical Manufacturing Processes.

The identification of critical process parameters in biologics and small molecule process development is a key element of quality by design. The objectivity and consistency of procedures to identify critical process parameters can be improved with the use of impact ratios. Impact ratios quantify a process parameter's practical effect on a critical quality attribute relative to the critical quality attribute's acceptance limits. If the impact ratio is large, i.e., exceeds a predefined impact ratio threshold, the recommendation is to classify the process parameter as a critical process parameter. This article introduces an improved and mathematically well-defined impact ratio. Benefits of this impact ratio are a consistent interpretation for many scenarios commonly encountered in practice, high suitability to automation, and the possibility of standardizing on a single impact ratio definition for pharmaceutical manufacturing.

[Study on extraction kinetics of Salviae Miltiorrhizae Radix et Rhizoma: model establishment and investigation of critical process parameters].

In this study, Fick's first law and partition equilibrium were used to represent the internal and external mass transfer processes of Salviae Miltiorrhizae Radix et Rhizoma at the macroscopic level, and a mass transfer model was established. The specific surface area was integrated into the mass transfer resistance, which effectively avoided the irregular shape of medicinal materials and expanded the application scope of the model. Meanwhile, the mass transfer model was further combined with the kinetic model of salvia-nolic acid degradation to establish the extraction kinetic models of salvianolic acid B, lithospermic acid and Danshensu. The model was applied to study the extraction process of Salviae Miltiorrhizae Radix et Rhizoma. According to the sensitivity analysis results, the relative error of the model prediction was within 5% near the maximum extraction rate(320 min), and the prediction performance of the model was good. According to the investigation results of different process parameters, stirring could significantly accelerate the mass transfer rate of salvianolic acid B, while the mass transfer resistance and degradation rate constant were not affected by solvent-to-solid ratio. The linear relationship between the reciprocal of temperature and the logarithm of mass transfer resistance was good(R~2=0.996), indicating that the temperature and mass transfer resistance conformed to Arrhenius formula. In addition, we also found that the concentration changes of lithospermic acid and Danshensu were weakly affected by mass transferwhen the extraction temperature was higher than 358 K. This study has provided the basis for the process optimization and quality control of traditional Chinese medicine extraction.

Study on extraction kinetics of Salviae Miltiorrhizae Radix et Rhizoma: model establishment and investigation of critical process parameters / 中国中药杂志

In this study, Fick's first law and partition equilibrium were used to represent the internal and external mass transfer processes of Salviae Miltiorrhizae Radix et Rhizoma at the macroscopic level, and a mass transfer model was established. The specific surface area was integrated into the mass transfer resistance, which effectively avoided the irregular shape of medicinal materials and expanded the application scope of the model. Meanwhile, the mass transfer model was further combined with the kinetic model of salvia-nolic acid degradation to establish the extraction kinetic models of salvianolic acid B, lithospermic acid and Danshensu. The model was applied to study the extraction process of Salviae Miltiorrhizae Radix et Rhizoma. According to the sensitivity analysis results, the relative error of the model prediction was within 5% near the maximum extraction rate(320 min), and the prediction performance of the model was good. According to the investigation results of different process parameters, stirring could significantly accelerate the mass transfer rate of salvianolic acid B, while the mass transfer resistance and degradation rate constant were not affected by solvent-to-solid ratio. The linear relationship between the reciprocal of temperature and the logarithm of mass transfer resistance was good(R~2=0.996), indicating that the temperature and mass transfer resistance conformed to Arrhenius formula. In addition, we also found that the concentration changes of lithospermic acid and Danshensu were weakly affected by mass transferwhen the extraction temperature was higher than 358 K. This study has provided the basis for the process optimization and quality control of traditional Chinese medicine extraction.

Process Characterization by Definitive Screening Design Approach on DNA Vaccine Production.

Plasmid DNA is a vital biological tool for molecular cloning and transgene expression of recombinant proteins; however, decades ago, it has become an exceptionally appealing as a potential biopharmaceutical product as genetic immunization for animal and human use. The demand for large-quantity production of DNA vaccines also increases. Thus, we, herein, presented a systematic approach for process characterization of fed-batch Escherichia coli DH5α fermentation producing a porcine DNA vaccine. Design of Experiments (DoE) was employed to determine process parameters that have impacts on a critical quality attribute of the product, which is the active form of plasmid DNA referred as supercoiled plasmid DNA content, as well as the performance attributes, which are volumetric yield and specific yield from fermentation. The parameters of interest were temperature, pH, dissolved oxygen, cultivation time, and feed rate. Using the definitive-screening design, there were 16 runs, including 3 additional center points to create the predictive model, which then was used to simulate the operational ranges for capability analysis.

A cross-industry forum on benchmarking critical quality attribute identification and linkage to process characterization studies.

Identification of Critical Quality Attributes (CQAs) and subsequent characterization in process development studies are the key elements of quality by design (QbD) for biopharmaceutical products. Since the inception of ICH Q8R2, several articles have been published on approaches to conducting CQA risk assessments as well as the application to process understanding. A survey was conducted by multiple companies participating in an International Consortium working group on the best practices for identifying CQAs with linkages to process characterization (PC) studies. The results indicate that the companies surveyed are using similar approaches/timing to identify CQAs during process development. Consensus was also observed among the companies surveyed with approaches to linkage of CQAs to process characterization studies leading to impact to control strategies and lifecycle management.

[Identification of critical process parameters of Jinqing alcohol precipitation of Reduning Injection by big data].

Lonicerae Japonicae Flos and Artemisiae Annuae Herba(LA or Jinqing) alcohol precipitation has various process parameters and complex process mechanism, and is one of the key units for manufacturing Reduning Injection. In order to identify the critical process parameters(CPPs) affecting the weight of the extract produced from the alcohol precipitation process, 259 batches of historical production data from 2017 to 2018 were collected, with a total of 829 318 data points. These data showed characteristics of large data, such as a large data volume, a low value density, and diverse sources. The data cleaning and feature extraction were first performed, and 48 feature variables were selected. The original data points were reduced to 9 936. Then, a combination of Pearson correlation analysis and grey correlation analysis were used to screen out 15 potential critical process parameters(pCPPs). After that, the partial least squares(PLS) was used in prediction of the weight of the extract, proving that the performance of predictive model based on 15 pCMAs is equivalent to that of predictive model based on 48 feature variables. The variable importance in projection(VIP) index was used to identify 9 CPPs, including 2 alcohol precipitation supernatant volume parameters, 4 initial extract weight parameters and 3 added alcohol volume parameters. As a result, the number of data points was 1 863, accounting for 0.28% of the original data. The big data analysis approach from a holistic point of view can effectively increase the value density of the original data. The critical process parameters obtained can help to accurately describe the quality transfer mechanism of the Jinqing alcohol precipitation process.

Quality control of ethanol extraction process of Corydalis Rhizoma based on quality by design (QbD) / 中草药

Objective: To improve the quality control level of ethanol extraction process of Corydalis Rhizoma (CR) by using quality by design (QbD), so as to meet the extraction requirements of Kedaling Tablets. Methods: The critical process parameters were solvent multiple, extraction time and soaking time, and the critical quality attributes were dry extract rate, content and transfer rate of dehydrocorydaline. The response surface methodology was used to establish the mathematical model between the critical process parameters and the critical quality attributes. The overlapping design space of multiple index design spaces was established to select the optimal operation space, where the process verification was carried out. Results: The operating space parameters of ethanol extraction of CR was 14-24 h of the immersion time, 3.0-4.0 times of the first time solvent multiple, 1.5-2.0 times of the second and third time solvent multiple, and 1.5-2.5 h of the extraction time. Under this operating space, the extraction yield of CR was ranged from 6%-8%, the content of dehydrocorydaline was more than 2.8%, and the transfer rate was not less than 85%. Conclusion: The concept of QbD is helpful to improve the ethanol extraction process of CR, and to obtain a reliable and suitable extraction operation space for the production of Kedaling Tablets.

Quantitative CPP Evaluation from Risk Assessment Using Integrated Process Modeling.

Risk assessments (RAs) are frequently conducted to assess the potential effect of process parameters (PPs) on product quality attributes (e.g., a critical quality attribute (CQA)). To evaluate the PPs criticality the risk priority number (RPN) for each PP is often calculated. This number is generated by the multiplication of three factors: severity, occurrence, and detectability. This mathematical operation may result in some potential errors due to the multiplication of ordinal scaled values and the assumption that the factors contribute equally to the PPs criticality. To avoid these misinterpretations and to assess the out of specification (OOS) probability of the drug substance, we present a novel and straightforward mathematical algorithm. This algorithm quantitatively describes the PPs effect on each CQA assessed within the RA. The transcription of severity and occurrence to model effect sizes and parameters distribution are the key elements of the herein developed approach. This approach can be applied to any conventional RA within the biopharmaceutical industry. We demonstrate that severity and occurrence contribute differently to the PP criticality and compare these results with the RPN number. Detectability is used in a final step to precisely sort the contribution of each factor. To illustrate, we show the misinterpretation risk of the PP critically by using the conventional RPN approach.

Scale-Up Strategy in Quality by Design Approach for Pharmaceutical Blending Process with Discrete Element Method Simulation.

An approach combining quality by design (QbD) and the discrete element method (DEM) is proposed to establish an effective scale-up strategy for the blending process of an amlodipine formulation prepared by the direct compression method. Critical process parameters (CPPs) for intermediate critical quality attributes (IQAs) were identified using risk assessment (RA) in the QbD approach. A Box-Behnken design was applied to obtain the operating space for a laboratory-scale. A DEM model was developed by the input parameters for the amlodipine formulation; blending was simulated on a laboratory-scale V-blender (3 L) at optimal settings. The efficacy and reliability of the DEM model was validated through a comparison of simulation and experimental results. Change of operating space was evaluated using the validated DEM model when scaled-up to pilot-scale (10 L). Pilot-scale blending was simulated on a V-blender and double-cone blender at the optimal settings derived from the laboratory-scale operating space. Both pilot-scale simulation results suggest that blending time should be lower than the laboratory-scale optimized blending time to meet target values. These results confirm the change of operating space during the scale-up process. Therefore, this study suggests that a QbD-integrated DEM simulation can be a desirable approach for an effective scale-up strategy.

Defining Processing Times for Accelerator Produced 225Ac and Other Isotopes from Proton Irradiated Thorium.

During the purification of radioisotopes, decay periods or time dependent purification steps may be required to achieve a certain level of radiopurity in the final product. Actinum-225 (Ac-225), Silver-111 (Ag-111), Astatine-211 (At-211), Ruthenium-105 (Ru-105), and Rhodium-105 (Rh-105) are produced in a high energy proton irradiated thorium target. Experimentally measured cross sections, along with MCNP6-generated cross sections, were used to determine the quantities of Ac-225, Ag-111, At-211, Ru-105, Rh-105, and other co-produced radioactive impurities produced in a proton irradiated thorium target at Brookhaven Linac Isotope Producer (BLIP). Ac-225 and Ag-111 can be produced with high radiopurity by the proton irradiation of a thorium target at BLIP.

Aplicación del Análisis de Componentes Principales en el proceso de fermentación de un anticuerpo monoclonal / Application of Principal Components Analysis in the fermentation process of a monoclonal antibody

En el Centro de Inmunología Molecular (La Habana, Cuba) se produce un anticuerpo monoclonal terapéutico que ha encontrado una efectiva aplicación en el tratamiento de pacientes aquejados de cáncer de cabeza y cuello. Dada la gran variabilidad que ha tenido la concentración de este anticuerpo en la etapa de fermentación industrial de la planta donde es producido, se hizo necesaria la aplicación de una técnica de análisis multivariante como el Análisis de Componentes Principales, con el fin de reducir la dimensionalidad de los datos y de explicar las principales fuentes de variabilidad del proceso. Para llevar a cabo el Análisis de Componentes Principales mediante el programa THE UNSCRAMBLER se partió de la determinación de los parámetros críticos de la etapa de fermentación a través de un modelo de riesgo basado en matriz de entradas y salidas empleando los datos de la campaña realizada en el año 2014. Como resultado se obtuvo que dos componentes principales logran explicar más del 99 por ciento de la varianza total, y se logró definir cuáles son los parámetros críticos que mayor aporte tienen a la variabilidad del proceso de fermentación. Dichos resultados corroboraron experiencias prácticas de especialistas de la planta y permitieron dar recomendaciones a considerar en el Plan de Verificación Continuada del Proceso, como proponer la inclusión en la estrategia de control del proceso a la temperatura, la velocidad de agitación, el oxígeno disuelto y el tiempo de duración del cultivo(AU)

In the Center of Molecular Immunology (Havana, Cuba) an effective therapeutic monoclonal antibody against head and neck cancer is produced. Given the great variability of the concentration of this antibody in the industrial fermentation stage of the plant, it became necessary to apply a multivariate analysis technique such as the Principal Component Analysis, in order to reduce data dimensionality and to explain the main sources of variability of the process. In order to carry out the Principal Component Analysis through the software THE UNSCRAMBLER, the determination of the critical parameters of the fermentation stage through a risk model based on input and output matrix using data from the campaign of the year 2014 was carried out. As a result, two main components were able to explain more than 99 percent of the total variance, and it was possible to define the critical parameters that have the greatest contribution to the variability of the fermentation process. These results corroborated the practical experiences of specialists of the plant and allowed to give recommendations to consider in the Plan of Continuous Verification of the Process as proposing the inclusion in the strategy of control of the process the variables temperature, the speed of agitation, dissolved oxygen and the culture duration(AU)

[Application of quality by design in granulation process for Ginkgo leaf tablet (⠢)： process control strategy based on design space].

In this paper, under the guidance of quality by design (QbD) concept, the control strategy of the high shear wet granulation process of the ginkgo leaf tablet based on the design space was established to improve the process controllability and product quality consistency. The median granule size (D50) and bulk density (Da) of granules were identified as critical quality attributes (CQAs) and potential critical process parameters (pCPPs) were determined by the failure modes and effect analysis (FMEA). The Plackeet-Burmann experimental design was used to screen pCPPs and the results demonstrated that the binder amount, the wet massing time and the wet mixing impeller speed were critical process parameters (CPPs). The design space of the high shear wet granulation process was developed within pCPPs range based on the Box-Behnken design and quadratic polynomial regression models. ANOVA analysis showed that the P-values of model were less than 0.05 and the values of lack of fit test were more than 0.1, indicating that the relationship between CQAs and CPPs could be well described by the mathematical models. D50 could be controlled within 170 to 500 µm, and the bulk density could be controlled within 0.30 to 0.44 g•cm⁻³ by using any CPPs combination within the scope of design space. Besides, granules produced by process parameters within the design space region could also meet the requirement of tensile strength of the ginkgo leaf tablet..

Application of quality by design in granulation process for Ginkgo leaf tablet (Ⅲ)： process control strategy based on design space / 中国中药杂志

In this paper, under the guidance of quality by design (QbD) concept, the control strategy of the high shear wet granulation process of the ginkgo leaf tablet based on the design space was established to improve the process controllability and product quality consistency. The median granule size (D50) and bulk density (Da) of granules were identified as critical quality attributes (CQAs) and potential critical process parameters (pCPPs) were determined by the failure modes and effect analysis (FMEA). The Plackeet-Burmann experimental design was used to screen pCPPs and the results demonstrated that the binder amount, the wet massing time and the wet mixing impeller speed were critical process parameters (CPPs). The design space of the high shear wet granulation process was developed within pCPPs range based on the Box-Behnken design and quadratic polynomial regression models. ANOVA analysis showed that the P-values of model were less than 0.05 and the values of lack of fit test were more than 0.1, indicating that the relationship between CQAs and CPPs could be well described by the mathematical models. D₅₀ could be controlled within 170 to 500 μm, and the bulk density could be controlled within 0.30 to 0.44 g•cm⁻³ by using any CPPs combination within the scope of design space. Besides, granules produced by process parameters within the design space region could also meet the requirement of tensile strength of the ginkgo leaf tablet..

A design space exploration for control of Critical Quality Attributes of mAb.

A unique "design space (DSp) exploration strategy," defined as a function of four key scenarios, was successfully integrated and validated to enhance the DSp building exercise, by increasing the accuracy of analyses and interpretation of processed data. The four key scenarios, defining the strategy, were based on cumulative analyses of individual models developed for the Critical Quality Attributes (23 Glycan Profiles) considered for the study. The analyses of the CQA estimates and model performances were interpreted as (1) Inside Specification/Significant Model (2) Inside Specification/Non-significant Model (3) Outside Specification/Significant Model (4) Outside Specification/Non-significant Model. Each scenario was defined and illustrated through individual models of CQA aligning the description. The R(2), Q(2), Model Validity and Model Reproducibility estimates of G2, G2FaGbGN, G0 and G2FaG2, respectively, signified the four scenarios stated above. Through further optimizations, including the estimation of Edge of Failure and Set Point Analysis, wider and accurate DSps were created for each scenario, establishing critical functional relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). A DSp provides the optimal region for systematic evaluation, mechanistic understanding and refining of a QbD approach. DSp exploration strategy will aid the critical process of consistently and reproducibly achieving predefined quality of a product throughout its lifecycle.

Characterization of a Saccharomyces cerevisiae fermentation process for production of a therapeutic recombinant protein using a multivariate Bayesian approach.

The principle of quality by design (QbD) has been widely applied to biopharmaceutical manufacturing processes. Process characterization is an essential step to implement the QbD concept to establish the design space and to define the proven acceptable ranges (PAR) for critical process parameters (CPPs). In this study, we present characterization of a Saccharomyces cerevisiae fermentation process using risk assessment analysis, statistical design of experiments (DoE), and the multivariate Bayesian predictive approach. The critical quality attributes (CQAs) and CPPs were identified with a risk assessment. The statistical model for each attribute was established using the results from the DoE study with consideration given to interactions between CPPs. Both the conventional overlapping contour plot and the multivariate Bayesian predictive approaches were used to establish the region of process operating conditions where all attributes met their specifications simultaneously. The quantitative Bayesian predictive approach was chosen to define the PARs for the CPPs, which apply to the manufacturing control strategy. Experience from the 10,000 L manufacturing scale process validation, including 64 continued process verification batches, indicates that the CPPs remain under a state of control and within the established PARs. The end product quality attributes were within their drug substance specifications. The probability generated with the Bayesian approach was also used as a tool to assess CPP deviations. This approach can be extended to develop other production process characterization and quantify a reliable operating region. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:799-812, 2016.

Comparison on three methods for identification of critical process parameters / 中草药

Objective: To investigate the characteristics of multiple linear regression method, stepwise regression method, and standardized partial regression coefficient method for the identification of critical process parameters. Methods: The acid precipitation and alkaline dissolution process of Scutellariae Radix (SR) water extract was investigated as an example. Results: Similar results were obtained using three different methods. The concentration of SR water extract, pH value of acid precipitation, pH value of alkali dissolution, and refrigeration temperature were considered as critical process parameters. Conclusion: The selection of threshold values of the three methods all are subjective. Multiple linear regression method is simple, but is not as sensitive as stepwise regression method. The effects of a parameter on several process indices can be considered simultaneously and easily weighted using standardized partial regression coefficient method.