Applications and Principles of Quality by Design (QbD) in European Union Regulatory Dossiers for Medicinal Products from 2020 to 2023

Quality by Design (QbD) is a structured approach to pharmaceutical development that ensures predefined product quality by understanding and controlling manufacturing processes from the outset. Unlike traditional methods focusing on end-product testing, QbD emphasizes building quality into the product design itself, enhancing manufacturing efficiency and regulatory compliance. This review highlights the application of QbD in developing generic solid oral drug products, emphasizing tools like risk assessment, process design, and control strategies to achieve consistent quality. Key components include identifying and managing Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and Critical Material Attributes (CMAs), which influence formulation, process development, and overall performance. The integration of Design of Experiments (DoE) to systematically study the effects of multiple variables on product and process performance, enabling optimization and robust development and effective control strategies are also discussed in this article. Addressing regulatory expectations, particularly those from the International Council for Harmonisation (ICH), this review outlines how QbD principles help generics meet bioequivalence standards, ensuring consistent quality and performance. Applying QbD not only enhances product robustness and manufacturing efficiency but also improves patient safety through better process understanding and continuous improvement. This review article outlines the various steps involved in the development of generic drug products using the QbD approach from analysis of brand product to product lifecycle management and continual improvement.

Green LC-MS/MS method for in-vivo pharmacokinetics of mirabegron-encapsulated nanostructured lipid carriers in rat plasma: Integrating white analytical chemistry and analytical quality by design approach

BackgroundQuality by Design (QbD) is a systematic risk-based approach to development, with predefined characteristics and quality risk management throughout the life cycle of a product. International Conference on Harmonization (ICH) guidelines Q8–Q11 give guidance on QbD applications with ICH Q8 (R2)—approved in 2009—describing the principles of QbD in detail. Since its adoption over 10 years ago, more information about QbD usage for the development of medicinal products is expected to be written in regulatory dossiers by companies.MethodsThe present study set out to evaluate the implementation of QbD principles and elements in all EU approved marketing applications (MA) (n = 494), based on information available in the European Public Assessment Reports (EPARs), for a period of six years (2014–2019), starting 5 years after QbD adoption.ResultsOf the 494 MAs, 271 were submitted with a full dossier (article 8(3)). According to EMA (38%), out of the 271 full dossier submissions, only 104 were developed using full QbD. This figure did not increase during this period. Interestingly, between 2014 and 2019, several MAs were not developed via full QbD implementation but used one or more QbD elements during development, including design space. In addition, a higher percentage of small molecule products were developed with QbD as opposed to biotechnology-derived products (78% vs. 22%, respectively).ConclusionOverall, QbD during development of medicinal products is still not commonly described in dossiers. However, more companies started mentioning QbD elements, thus making it a promising step toward QbD as the standard for development in the future.

Chapter 4 - Pharmaceutical product development: A quality by design (QbD) approach

A pharmaceutical industry is highly regulated by a quality policy in its management. The principles of Quality by Design (QbD) must be applied to ensure the development of pragmatic and systematic methods while managing the risks associated with analytical methods. Quality by Design (QbD) is a scientific way to develop easy and robust analytical techniques for critical analysis. Quality by Design (QbD) is a systematic approach to product or method development that starts with predetermined goals and uses a science and risk management approach to achieve product and method understanding. The concept of risk management is deeply integrated into the quality assurance system to ensure pharmaceutical quality and patient safety. In the context of quality control, detecting impurities in raw materials and finished products is a major concern. Analytical Quality by Design (AQbD) aims to achieve quality in measurement. The main objectives are to explain the various steps involved in developing a method using a Quality by Design (QbD) approach for the development of analytical methods and to explain the implementation of Quality by Design (QbD) in the validation of analytical procedures. The advantages of applying Quality by Design (QbD) principles to analytical techniques include finding and minimizing sources of variability that could lead to poor method robustness and ensuring that the method meets the desired performance requirements over the product and method life cycle. The Analytical Quality by Design (AQbD) strategy is increasingly being adopted as it allows an early understanding of the method and guarantees the determination of a wider set of experimental conditions.

Chapter 4 - QbD Considerations for Excipient Manufacturing

INTRODUCTION. Quality by design (QbD) is a systematic approach to pharmaceu­tical development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management. The QbD approach facilitates the production of medicinal products with target characteristics and quality profiles. There are currently no specific guidelines for the application of QbD principles to the development of individual dosage forms.AIM. This study aimed to evaluate the possibility of and propose an algorithm for using QbD at the laboratory stage of pharmaceutical development for solid dosage forms, with tablets as a case study.MATERIALS AND METHODS. This study analysed publicly available regulatory documents, scientific publications, and guidelines on pharmaceutical development using general scientific methods, including comparative and logical analysis. The regula­tory documents analysed included those issued by the International Council for Harmonisation (ICH), the Eurasian Economic Commission, and the State Pharmacopoeia of the Russian Federation. The sources searched included electronic databases, such as PubMed, Web of Science, eLIBRARY.RU, and Google Scholar.RESULTS. Developing the quality target product profile (QTPP) and composition of tablets requires a comprehensive study of the active substance, as well as an assessment of its compatibility with the excipients. At the laboratory stage of pharmaceu­tical development, it is necessary to select and optimise the medicinal product composition while assessing potential risks. This approach provides for the preliminary identification of critical quality attributes, critical process parameters, and critical material parameters. This article presents an algorithm for applying QbD to tablet formulations at the laboratory stage of pharmaceutical development.CONCLUSIONS. When implemented at the laboratory stage, the proposed algorithm with QbD elements will improve the overall efficiency of pharmaceutical development.

Over the last years, the pharmaceutical industry has faced real challenges regarding quality assurance. In this context, the establishment of more holistic approaches to the pharmaceutical development has been encouraged. The emergence of the Quality by Design (QbD) paradigm as systematic, scientific and risk-based methodology introduced a new concept of pharmaceutical quality. In essence, QbD can be interpreted as a strategy to maximize time and cost savings. An in-depth understanding of the formulation and manufacturing process is demanded to optimize the safety, efficacy and quality of a drug product at all stages of development. This innovative approach streamlines the pharmaceutical Research and Development (R&D) process, provides greater manufacturing flexibility and reduces regulatory burden. To assist in QbD implementation, International Conference on Harmonisation (ICH), U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) organized and launched QbD principles in their guidance for industry, identifying key concepts and tools to design and develop a high-quality drug product. Despite the undeniable advantages of the QbD approach, and the widespread information on QbD regulatory expectations, its full implementation in the pharmaceutical field is still limited.The present review aims to establish a crosswise overview on the current application status of QbD within the framework of the ICH guidelines (ICH Q8(R2) - Q14 and ICH Q2(R2)). Moreover, it outlines the way information gathered from the QbD methodology is being harmonized in Marketing Authorization Applications (MAAs) for European market approval. This work also highlights the challenges that hinder the deployment of the QbD strategy as a standard practice.

QbD, or Quality by Design, is a cutting-edge methodology adopted extensively in the pharmaceutical industry. It is defined objects, such as the product's safety and effectiveness. QbD's primary focus in the pharmaceutical industry is ensuring the product's security and usefulness. Quality by Design (QbD) seeks to instill high standards of excellence in the blueprinting process. The International Council for Harmonization (ICH) has developed guidelines and elements that must be adhered to guarantee the consistent, high-quality development of pharmaceuticals. This chapter provides updated guidelines and elements, including quality risk management, pharmaceutical quality systems, QbD in analytical methods and pharmaceutical manufacturing, process control, vaccine development, pharmacogenomic, green synthesis, etc. QbD was briefly defined, and several design tools, regulatory-industry perspectives, and QbD grounded on science were discussed. It was portrayed that significant effort was put into developing drug ingredients, excipients, and manufacturing processes. Quality by design (QbD) is included in the manufacturing process's development, and the result is steadily improving product quality. Quality target product profiles, critical quality attributes, analytical process techniques, critical process parameters control strategy and design space are elements of many pharmaceutical advancements. Some of the topics covered included the application of QbD to herbal products, food processing, and biotherapeutics through analytical process techniques. We are still exploring and compiling all the data and metrics required to link and show the benefits of QbD to all stakeholders. Nevertheless, the pharmaceutical sector is quickly using the QbD process to create products that are reliable, efficient, and of high quality. Soon, a more profound comprehension of the dosage form parameters supported by the notion of QbD will benefit Risk management and process and product design, optimizing complex drug delivery systems.

Introduction: The traditional development processes use a quality by testing (QbT) approach that needs continuous testing to determine quality. Such processes are fixed, averse to change, and focus only on process reproducibility. This approach does not allow variation in material and process controls. In order to overcome the shortcomings of the traditional process, regulatory bodies have issued guidelines for the industries to improve the understanding of the process and the quality of the product. It aims to shift from traditional process QbT to a scientific approach quality by design (QbD) to assure product quality in the pharmaceutical industry.
 Methodology: Articles related to QbD published in many search engines such as Scopus, Google Scholar, and PubMed were reviewed.
 Review Findings: In order to ensure the quality of pharmaceutical products, regulatory bodies have emphasized on the implementation of QbD. For this, various guidelines have been published from time to time. The Indian pharmaceutical industry has started to apply the principles of QbD. Implementation of QbD develops a detailed understanding of the manufacturing process. The design space is achieved by QbD within which the expected quality is achieved even with changes in process parameters.
 Conclusion: In short, the QbD approach is a great tool for assuring pharmaceutical product quality and better understanding of the manufacturing process. Therefore, it is imperative to have a successful implementation of the QbD approach.

The present study draw a bead on preparing single core osmotic pump with improved water transplant by employing Quality by Design (QbD) principles to achieve zero order drug release for prolonged period of time. QbD principles were employed in preparing single core osmotic pump by deriving quality target product profile (QTPP), critical quality attributes (CQA) followed by risk assessment using ishikawa diagram and risk estimation matrix. Box-Behnken Design was employed to study the effect of various independent parameters like concentration of Natrosol 250 HX (X1) and concentration of Xylitab (X2) no. of orifice (X3), on various dependent parameters like lag time (Y1) and time required for release 25%, 50%, 75% and 100% drug (Y2, Y3, Y4 and Y5). A controlled space was designed where each criteria or CQA was satisfied. Optimized formulation was further characterized for its efficiency. The results of design suggest the suitability of design for optimization of single core osmotic pump. In the initial period, drug release was driven by no. of orifice which on later stage depends on concentration of swellable polymer and concentration of osmogen. Optimized design was validated by preparing check point batch having less than 5% predicted error. Model fitting with drug release kinetics showed that optimized single core osmotic pump released drug in zero order. Stability data suggested that prepared formulation was stable for 3 month period without significant changes in the CQA. Single core osmotic pump using water transplant was successfully developed for a poorly soluble drug using QbD principles.

In the last few years, several quality by design (QbD) studies demonstrated the benefit of systematic approaches for biopharmaceutical development. However, only very few studies identified biosimilars as a special case of product development. The targeted quality profile of biosimilars is strictly defined by the originator's product characteristic. Moreover, the major source of prior knowledge is the experience with the originator product itself. Processing this information in biosimilar development has a major effect on risk management and process development strategies. The main objective of this contribution is to demonstrate how risk management can facilitate the implementation of QbD in early-stage product development with special emphasis on fitting the reported approaches to biosimilars. Risk assessments were highlighted as important tools to integrate prior knowledge in biosimilar development. The risk assessment process as suggested by the International Conference on Harmonization (ICH Q9) was reviewed and three elements were identified to play a key role in targeted risk assessment approaches: proper understanding of target linkage, risk assessment tool compliance, and criticality threshold value. Adjusting these steps to biosimilar applications helped to address some unique challenges of these products such as a strictly defined quality profile or a lack of process knowledge. This contribution demonstrates the need for tailored risk management approaches for the risk-based development of biosimilars and provides novel tools for the integration of additional knowledge available for these products. The pharmaceutical industry is facing challenges such as profit loss and price competition. Companies are forced to rationalize business models and to cut costs in development as well as manufacturing. These trends recently hinder the implementation of any concepts that do not offer certain financial benefit or promise a long return of investment. Quality by design (QbD) is a concept that is currently struggling for more acceptance from the side of the pharmaceutical industry. To achieve this, the major goals of QbD have to be revisited and QbD tools have to be subsequently developed. This contribution offers an example as to how implement risk management in early-stage biosimilar development as part of the QbD concept. The main goal was to go beyond the conventional QbD workflow and to adjust risk management to the challenges of biosimilar products. Accordingly, instead of using methods like failure mode and effects analysis, recommendations of the ICH Q9 guideline were reviewed and put into practice by creating tailored risk assessment tools. The novelty of this contribution is to report those tailored tools ready-to-use for early bioprocess development of biosimilars along QbD principles.

The application of quality by design (QbD) in pharmaceutical product development is now a thrust area for the regulatory authorities and the pharmaceutical industry. International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the principles and applications of QbD in pharmaceutical development in their guidance for the industry. QbD attributes are addressed in question-based review, developed by USFDA for chemistry, manufacturing, and controls section of abbreviated new drug applications. QbD principles, when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are discussed to understand the performance of dosage forms within design space. Design of experiments, risk assessment tools, and process analytical technology are also discussed for their role in QbD. This review underlines the importance of QbD in inculcating science-based approach in pharmaceutical product development.

The present research outlines a comprehensive and systematic approach for the development and validation of a bioanalytical Liquid chromatography–mass spectrometry (LC-MS) method to quantify ranolazine in human plasma. The study employs principles of quality by design (QbD) to enhance method robustness, precision, and accuracy. The primary goals of this research were to create a reliable LC-MS method for the accurate quantification of ranolazine in human plasma and to validate this approach in accordance with established standards set by regulatory bodies. A secondary objective was to explore the application of QbD principles to optimize method performance. The study resulted in the successful development of an LC-MS method that exhibits exceptional specificity, sensitivity, accuracy, and precision in the quantification of ranolazine in human plasma. Specificity tests revealed no interference from endogenous plasma components. The method demonstrated good sensitivity with limit of quantitation (LoQ) of 5 ng/mL and limit of detection (LoD) of 2 ng/mL. Accuracy, as assessed through recovery studies, showed mean recoveries of 98, 99, and 101% for three different spiked concentrations. Precision, expressed as RSD, was below 5% for both intra-day and inter-day analyses. Linearity studies resulted in a calibration curve with an R² value of 0.9998. By employing QbD principles, the method demonstrated improved robustness, thus minimizing the impact of variability during sample analysis. Robustness experiments revealed minimal effects on precision and accuracy when varying critical parameters. This research not only presents a reliable LC-MS method for ranolazine quantification but also underscores the importance of incorporating QbD principles in bioanalytical method development. The validated method holds significant implications for clinical research, pharmacokinetic studies, and therapeutic drug monitoring. By enhancing the accuracy and robustness of ranolazine quantification, this method contributes to the advancement of pharmaceutical and clinical research, ultimately benefiting patient care and treatment outcomes.

Pharmaceutical has vast areas of formulation and development which design different formulations for different disease conditions and their treatment. Each product developed in the pharmaceutical has to pass the standard prescribed in the monographs. QbD plays an important role in drug product development that is very important because it ensures the stability, safety, and quality of the product. The product quality should be best so that it has per patient compliance. QbD ensures all the safety procedures in the industries that make the stable and good quality and validate the procedure. It also helps in the design of the product and its procedures. It controls all the manufacturing processes and understanding that develops the best quality product. Its modern approach in the pharmaceuticals which aims to develop and design a quality product using its manufacturing process that is intended to deliver constantly and shows good performance. Quality by Design (QbD) is a methodical approach to drug development that emphasizes comprehending and managing the production process to guarantee constant product quality. Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), and Critical Process Parameters (CPPs) are all identified in this examination, which offers a thorough summary of QbD concepts. It talks about how to optimize pharmaceutical formulations and manufacturing processes by using risk assessment tools, Design of Experiments (DoE), and multivariate analysis. It is emphasized how important regulatory guidelines—like those provided by the International Council for Harmonization (ICH) Q8–Q11—are to maintaining compliance and improving product lifecycle management. Additionally, the study examines how QbD might enhance product effectiveness, lower variability, and speed up regulatory approvals. The difficulties in putting QbD into practice, such as the lack of resources and the complexity of data processing, are also discussed. Insights into the strategic application of QbD to improve pharmaceutical product development and production are the goal of this research.