AQbD-novel strategy for analytical methods

Using an innovative combination of quality-by-design and green analytical chemistry approaches for the development of a stability indicating UHPLC method in pharmaceutical products

This study described a successful application of the Quality by Design (QbD) approach to pseudorabies virus (PRV) production process development in a fixed-bed bioreactor using the serum-free medium (SFM). The innovated tube-fixed-bed bioreactor was used as a scale-down model of the fixed-bed bioreactor for process development. Risk analysis was performed using Ishikawa diagram combined with failure mode effects analysis (FMEA). The comparative experiment was performed to screen proper medium for adherent African green monkey kidney (Vero) cells from three commercially available SFMs (VP-SFM, ProVERO-1 and Vero-A). The Vero-A medium showed as an outstanding one for further study. The PRV titer in harvest medium was consider as Critical Quality Attribute (CQA) and the Critical Process Parameters (CPPs) [time of infection (TOI), multiplicity of infection (MOI) and initial inoculation cell density] ranked high with risk priority number (RPN) were taken into design of experiment (DoE) methodology. Then prediction model of PRV production process was established and a robust PRV production process was explored. Under the robust setpoint conditions, the Xcell 1L laboratory-scale fixed-bed bioreactor yielded PRV titer up to 7.87 log10 TCID50/mL at 3dpi, which was comparable with that in the tube-fixed-bed bioreactor. Combination of the tube-fixed-bed bioreactor and QbD approach could further accelerate the development of a robust virus production process.

The aim of our research work was to develop dermally applicable, semisolid film-forming systems (FFSs) containing silicones, which form a film on the skin in situ, with suitable mechanical properties for skin application. FFSs were developed and investigated by means of the Quality by Design (QbD) methodology. With this QbD approach, the initial risk assessment defines the critical quality attributes (CQAs), the critical material attributes (CMAs) and the critical process parameters (CPPs) to ensure the required quality. Different semisolid systems were formed with or without silicones. During the initial risk assessment, three CQAs, namely skin adhesion, film flexibility and burst strength, were found to be critical attributes, while film appearance, film integrity and the drying time of the semisolid system, were found to be medium attributes. These parameters were investigated. The initial risk assessment also showed that there are three high CMAs: the type of silicones, film-forming excipients, drying excipients, and that there was one medium CMA: viscosity-enhancing excipients. Based on our results, the silicone content had a great effect on the film-forming systems. Different silicones affected the mechanical properties of the films in varying ways, decreased the drying time and showed promising results regarding the drying mechanism.

Quality by design (QbD) is an essential part of the modern advance to pharmaceutical quality. QbD is best key to build a quality in all pharmaceutical products. Under this concepts of be throughout design and growth of product, it is important to identify desire product performance report [Target product profile (TPP), Quality Target product profile (QTPP)] and identify critical quality attributes (CQA). To recognize the impact of raw material [critical material attributes (CAM)], critical process parameters (CPP) on the CQAs and identification and control sources of changeability. The plan of pharmaceutical development is to design a quality products and its manufacturing process always deliver the future performance of the product. The base of Quality by design is ICH Guidelines Q8 for Pharmaceutical for development, Q9 quality risk management, Q10 for pharmaceutical quality systems.

Microcrystalline cellulose (MCC) is an excellent excipient for the production of pellets by extrusion spheronization. However, it causes slow release rate of poorly water soluble drugs from pellets. Co-processed excipient prepared by spray drying (US4744987; US5686107; WO2003051338) and coprecipitation technique (WO9517831) are patented. The objective of present study was to develop co-processed MCC pellets (MOMLETS) by extrusion-spheronization technique using the principle of Quality by Design (QbD). Co-processed excipient core pellets (MOMLETS) were developed by extrusion spheronization technique using Quality by Design (QbD) approach. BCS class II drug (telmisartan) was layered onto it in a fluidized bed processor. Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) for pellets were identified. Risk assessment was reported using Ishikawa diagram. Plackett Burman design was used to check the effect of seven independent variables; superdisintegrant, extruder speed, ethanol: water, spheronizer speed, extruder screen, pore former and MCC: lactose; on percentage drug release at 30 min. Pareto chart and normal probability plot was constructed to identify the significant factors. Box-Behnken design (BBD) using three most significant factors (Extruder screen size, type of superdisintegrant and type of pore former) was used as an optimization design. The control space was identified in which desired quality of the pellets can be obtained. Co-processed excipient core pellets (MOMLETS) were successfully developed by QbD approach. Versatility, Industrial scalability and simplicity are the main features of the proposed research.

Objective: To develop a validated Liquid Chromatography-Mass Spectrometry (LC-MS) method through Quality by Design (QbD) approach for the determination of tenofovir disoproxil fumarate (tenofovir DF) in bulk, pharmaceutical formulation and stress conditions.
 Methods: The analytical target profile (ATP) was to develop a simple, accurate, precise, specific, and robust method with the Critical Quality Attribute (CQA) being retention time, theoretical plate and peak tailing. Derived from the risk assessment studies, four high-risk factors were screened using resolution V irregular fraction design. Organic modifier strength, flow rate and injection volume were further optimized using Box-Behnken design (BBD). The optimized method condition was validated and applied for the determination of the analyte in pharmaceutical formulation. The stability of the analyte in stress conditions was determined. All experiments were performed using reverse-phase Acquity UPLC BEH C18 (1.7 µm, 1 mm X 50 mm) column coupled in-line with Synapt G2 mass spectrometer in positive electrospray ionization (ESI) mode with electron multiplier analog-to-digital detector.
 Results: Optimized method condition eluted analyte at 3.40 min and the m/z 520 ratified the analyte peak. The method was validated and was found to be specific, linear in the range of 20-100 µg/ml (R2 = 0.9998) with accuracy between 98.71% - 101.17% and precise. The limit of detection and quantification were 5.50 µg/ml and 16.68 µg/ml respectively. Analyte degraded completely in acid and basic environment, however, stable in oxidative and photolytic conditions.
 Conclusion: The validated method developed through the systematic and rational QbD approach bespoke superior quality. The QbD approach not only justified the entire process but also eliminated uncertainties.

Quality by design (QbD) represents the modern approach to ensuring pharmaceutical quality. This concept has significantly influenced the progress of pharmaceutical sciences, having been established and applied globally in accordance with the International Conference on Harmonization (ICH) Guidelines. The proposed ICH guidelines—Q8 for pharmaceutical development, Q9 for quality risk management, and Q10 for pharmaceutical quality systems—provide a foundation for integrating quality into products. In the QbD framework, it is crucial to define the desired product performance profile, known as the Target Product Profile (TPP), and the Target Product Quality Profile (TPQP), as well as to identify Critical Quality Attributes (CQA). Based on this, we can design both the product formulation and the process to meet these attributes. This leads to recognizing the impact of raw material Critical Material Attributes (CMA) and Critical Process Parameters (CPP) on the CQAs, and identifying sources of variability

Quality by Design (QbD) is a new paradigm of quality to be applied to pharmaceutical products and processes, recently encouraged by International Conference on Harmonisation guidelines. In this paper QbD approach was applied to the development of a CE method for the simultaneous assay of metformin hydrochloride (MET) and its main impurities. QbD strategy was focused on electrophoretic process understanding, and the analytical method was thoroughly evaluated by applying risk assessment and chemometric tools. Method scouting allowed CD-CZE based on the addition of carboxymethyl-β-CD to Britton-Robinson acidic buffer to be chosen as operative mode. Seven critical process parameters (CPPs) were selected, related to capillary, injection, BGE and instrumental settings. The effect of the different levels of the CPPs on critical quality attributes (CQAs), e.g. critical resolution values and analysis time, was evaluated in a screening study. Response surface methodology led to draw contour plots and sweet spot plots. The definition of design space was accomplished by applying Monte-Carlo simulations, thus identifying by risk of failure maps a multivariate zone where the CQAs fulfilled the requirements with a selected probability. Finally, a control strategy was designed and the method was applied to a real sample of MET tablets.

To understand the role of analytics in drug development, regulatory bodies also started using the approach of Quality by Design (QbD) during analytical method developments. The present study deals with the development of the "Method Operable Design Region" for assay and purity determination of risperidone in risperidone drug substance and formulations usingy UHPLC. Five different column chemistries, five different pH buffers, oven temperatures from 25 to 45°C, and different organic modifier composition, column lengths and flow rates were studied and statistically evaluated using Fusion QbD software. The final method parameters were selected by performing multivariable changes in a single run and evaluated using the Monte Carlo simulation approach. The uniqueness of this method is that it is mass compatible, a total of 10 peaks are separated within a short run time of 12.0min and it uses a "Platforming approach", which means the use of a single method for testing the drug substance, different strengths of a drug product and different formulations. The same method can be also used for the determination of the preservative (benzoic acid) in risperidone 1mg/ml oral solution. The use of the QbD approach is aligned with the US Pharmacopeia <1220>, BP supplementary chapter 2022 and the International Conference on Harmonization Q14 guidelines for life cycle management of analytical methods.

INTRODUCTION. In 2023, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published a new Guideline on Analytical Procedure Development (ICH Q14) and a revised version of the Guideline on Validation of Analytical Procedures (ICH Q2(R2)). Consequently, there is a need for a considerable revision of the approach to the development and validation of analytical procedures that is currently used in the Eurasian Economic Union (EAEU). A revision is also needed for the processes for evaluating and introducing variations to the analytical procedures described in medicinal product registration dossiers.AIM. This review aimed to analyse the significant changes made to international approaches to the development of analytical procedures, as well as to study the advantages and disadvantages of these approaches for pharmaceutical manufacturers and regulatory agencies in the EAEU.DISCUSSION. This review covers the key provisions and practical aspects of the enhanced approaches to the development of analytical procedures introduced by the ICH Q14 guideline. In particular, the review addresses the concepts of the analytical procedure life cycle (APLC) and the modified analytical quality-by-design (AQbD) approach; the development of the analytical target profile (ATP); analytical quality risk management; planning of the design of experiments (DoE) and the analytical procedure control strategy; and the validation, subsequent verification, transfer, and change management of analytical procedures. Additionally, the review describes the ICH Q2(R2) updates that accompany this new regulatory paradigm.CONCLUSIONS. The above guidelines fill the existing gap in recommendations for the development of analytical procedures. The use of the APLC and AQbD concepts provides both pharmaceutical companies and regulatory authorities with flexible approaches that are applicable to analytical procedures both during the development phase and once they have been implemented. Effective implementation of these international approaches in the Russian pharmaceutical industry and regulatory system requires a broad discussion between pharmaceutical industry professionals and regulatory agency experts, possibly, as part of a pilot project. After that, there will be a necessity to provide training for specialists involved in the development of analytical procedures and to amend the EAEU Rules for Marketing Authorisation and Expert Assessment of Medicinal Products for Human Use.

This review explains the idea of pharmaceutical Quality by Design (QbD) more clearly and talks about its main goals. QbD focuses on making sure that medicines are designed and made with high quality from the beginning. It includes several important parts. First, it starts with a Quality Target Product Profile (QTPP), which describes the key features the final drug should have. Then, it involves understanding the product and identifying important materials, called Critical Material Attributes (CMAs). It also includes designing the manufacturing process and identifying the key steps, known as Critical Process Parameters (CPPs) that can affect the drug’s quality. These materials and steps are linked to the Critical Quality Attributes (CQAs) of the drug. [1,2] A control strategy is also part of QbD. This means setting standards for the drug ingredients, added substances (excipients), the final product, and each step of the manufacturing process to make sure everything stays on track. QbD also focuses on how capable the process is and encourages continuous improvement over time

Objective This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions. Methods Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs’ and CPPs’ impact on identified CQAs was further assessed through a 22 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile. Conclusions The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

This paper gives idea about the Pharmaceutical Quality by Design (QbD) and describes use of Quality by Design to ensure quality of Pharmaceuticals. Quality cannot be tested into products but quality should be built in by design. The concept of QbD can be extended to analytical methods. The emphasis of AQbD approach is on understanding of the operation and the variables affecting Analytical Methods employed in product development. The variables which affect the output are identified and subjected to thorough risk assessment employing various tools and techniques discussed in the article, after which the variables are optimized. The final method is validated and a control strategy is put in place. Pharmaceutical firms increased the number of product development by using scientific tools such as QbD (Quality by Design). ICH Q11 guidelines clearly discussed QbD approach for API synthesis with examples. It is a current trend among pharmaceutical industry to implement analytical quality by design (AQbD) in method development process as a part of risk management, pharmaceutical development, and pharmaceutical quality system (ICH Q10). QbD has its perspectives to contribute the drug design, development, and manufacture of high-quality drug products.

Background/Objectives: Quality by Design (QbD) has revolutionized pharmaceutical development by transitioning from reactive quality testing to proactive, science-driven methodologies. Rooted in ICH Q8-Q11 guidelines, QbD emphasizes defining Critical Quality Attributes (CQAs), establishing design spaces, and integrating risk management to enhance product robustness and regulatory flexibility. This review critically examines QbD's theoretical frameworks, implementation workflows, and industrial applications, aiming to bridge academic research and commercial practices while addressing emerging challenges in biologics, advanced therapies, and personalized medicine. Methods: The review synthesizes regulatory guidelines, case studies, and multidisciplinary tools, including Design of Experiments (DoE), Failure Mode Effects Analysis (FMEA), Process Analytical Technology (PAT), and multivariate modeling. It evaluates QbD workflows-from Quality Target Product Profile (QTPP) definition to control strategies-and explores advanced technologies like AI-driven predictive modeling, digital twins, and continuous manufacturing. Results: QbD implementation reduces batch failures by 40%, optimizes dissolution profiles, and enhances process robustness through real-time monitoring (PAT) and adaptive control. However, technical barriers, such as nonlinear parameter interactions in complex systems, and regulatory disparities between agencies hinder broader adoption. Conclusions: QbD significantly advances pharmaceutical quality and efficiency, yet requires harmonized regulatory standards, lifecycle validation protocols, and cultural shifts toward interdisciplinary collaboration. Emerging trends, including AI-integrated design space exploration and 3D-printed personalized medicines, promise to address scalability and patient-centric needs. By fostering innovation and compliance, QbD remains pivotal in achieving sustainable, patient-focused drug development.

Based on the concept of quality by design( QbD),the design space of Meiyan Shuqi Prescription extraction process was established,and its granules forming process was optimized. The content of total flavonoids was the critical quality attribute( CQA).The amount of water,extraction time and frequency were used as the critical process parameters( CPPs). Box-Behnken experimental design was used to optimize the extraction process. The design space of Meiyan Shuqi Prescription extraction process was established and verified. The results of variance analysis showed that the P value of the quadratic regression model was less than 0. 01,which indicated that the model had a statistical significance,and the relationship between each factor and response value could be functionalized by the established model. Through further optimization of design space,the optimal extraction process of Meiyan Shuqi prescription was13-fold volume of water,extraction for 3 times and each extraction time of 1. 4 hours. Furthermore,the forming process optimized by single factor was as follows: the excipient was dextrin; the ratio of extract powder to excipient was 1 ∶1; the wetting agent was 70% ethanol; and the amount of wetting agent was 0. 3 m L·g-1. The Meiyan Shuqi Prescription extraction process and the forming process based on QbD concept provide reference for the study of other traditional Chinese medicine prescriptions.