Chapter 4 - QbD Considerations for Excipient Manufacturing

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.

Quality by design approaches for topical dermatological dosage forms Arunprasad Sivaraman, Ajay K Banga Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, USA Abstract: The quality of a pharmaceutical dosage form is the foremost criterion during the development of a product. The quality by testing (QbT) technique used by the pharmaceutical industry to ensure the quality of a drug product is a rigid process with tight specifications. The specifications set by QbT are not essentially based upon the critical quality attributes of the materials and critical process parameters involved in development, but based upon recorded observation of manufactured batches. Room for flexibility is narrow as every level change requires submission of a supplement to the US Food Drug and Administration. Unlike QbT, the concept of quality by design (QbD) is a modern approach to ensure the quality of pharmaceutical products. It can identify the critical attributes of the material and the process parameters involved in development of the drug product through substantial scientific understanding with an established design space. QbD tools such as design of experiment, risk assessment, and process analytical technology help to establish a control strategy for every drug product with an option of continual monitoring and improvement for a quality drug product. Implementing the concept of QbD to topical dermatological dosage forms is in the initial stages. For a generic topical dermatological dosage form, establishing the required pharmaceutical and therapeutic equivalence with same components or qualitatively (Q1), same components with same concentration or quantitatively (Q2), and same components in same concentration with same arrangement (Q3) is a cumbersome process. Applying QbD approaches by defining a quality target product profile and identifying critical quality attributes with establishment of a design space and control strategy can guide the design of a quality-based generic topical dermatological product. Keywords: quality by design, topical dermatological dosage forms, design of experiment, risk assessment, process analytical technology

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

In 2004, Quality by Design (QbD) framework was implemented in chemistry, manufacturing and controls review process in Pharmaceutical Current Good Manufacturing Practices for the 21st Century initiative to achieve a desired state in quality pharmaceutical manufacturing. In 1997, three pivotal scientific organizations, American Association of Pharmaceutical Sciences, United States Food and Drug Administration and United States Pharmacopeia jointly organized a workshop to revisit the regulatory principles governing transdermal drug product development. Through sound science and quality risk management, QbD mediated development lay emphasis on thorough product, process understanding and enhanced process control. The International Conference on Harmonization guidelines have helped to transform conventional, univariate, trial and error-based product development approach into multivariate, science-based and risk-based practices governed by the principles of QbD. Plethora of case studies has been documented in literature for inception of QbD in development of several drug products.

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.

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.

Quality by design (QbD) is utilized in the event of pharmaceutical processes to create certain predefined product quality. QbD ideas unit of measurement explained in International Conference on Harmonization (ICH) pointers Q8 (R1) (Pharmaceutical development), Q9 (Quality risk management [QRM]), and Q10 (Pharmaceutical quality system). ICH Q8 (R1) guideline defines QbD as “a systematic approach to develop that begins with predefined objectives and emphasizes product and methodology, understanding, and methodology management, supported sound science and QRM.” QbD approach studied the implications of various input variables (e.g. methodology parameters, and materials) of the merchandise development methodology, on the final word product (active pharmaceutical ingredient or drug product). The late QbD approach integrates the principles of QRM, and methodology analytical technology (PAT). QbD combined with methodology analytical technology (PAT) tools modify methodology management and increase assurance that the merchandise quality attributes unit of measurement achieved consistently. An integrated and risk-based approach for review of the merchandise development methodology is also a future need of the QbD plan. Although implementing the QbD approach is not a restrictive demand, restrictive agencies to supply flexibility in their pointers for producing that unit of measurement developed by the QbD approach. Rising trends embody the growing interest in quantifying and managing the impact of raw materials’ attributes variability of methodology and product, what is more, as a result of the event of retrospective QbD approaches in complement to simple QbD. Thus, the QbD approach is also a tool for developing worth effective and quality pharmaceutical products.

A quality by design study applied to an industrial pharmaceutical fluid bed granulation

Biopharmaceutical manufacturing processes in which the product of interest is extracellularly expressed typically employ a clarification step following cell culture or fermentation. During clarification, crude cell culture fluid or fermentation broth is processed to remove insoluble solids, cells, debris, and other particulates, with the extracellular product of interest retained in the filtrate. Soluble impurities, such as host cell proteins (HCPs), may also be partially removed. Historically, the clarification process has been considered a limited contributor to Critical Quality Attributes (CQA). As part of upstream harvest, many biopharmaceutical companies have not fully developed quality control strategies from process development to manufacturing, complicating the application of Quality by Design (QbD) principles to this step. However, advancements in upstream and downstream processing (DSP) technologies, alongside increasing cell counts and titers, necessitate reevaluating clarification as a critical process contributing to drug product quality. Conducting controlled studies to define the process and establish parameters using QbD principles can improve control over process impurities and facilitate a logical quality control strategy, integrating quality into the process. This article describes a systematic approach to QbD for a harvest clarification process where the product of interest is extracellular and impurities are removed in the filtrate post-clarification. It highlights methods for optimizing the clarification unit operation using QbD principles, ensuring better process efficiency, and product quality.

The concept of Quality by Design (QbD) is of paramount importance in designing and developing reproducible and robust drug products, processes and analytical methods, thus enabling regulatory compliance and ensuring manufacturability. Risk assessment, design space, and control strategy constitute the key elements of the QbD framework. In this paper, a data-based approach to developing robust pharmaceutical processes is presented and illustrated with an application to a drug product during a site transfer process. The key objective in applying QbD principles is to ensure that the product is designed and manufactured to consistently meet quality requirements. The approach presented simultaneously considers the variability in raw materials, quality critical process parameters and critical quality attributes. By nature, large historical databases of raw material (active ingredients and excipients) and process data exists for legacy products. Multivariate statistical models were employed to extract knowledge on critical variables. Furthermore, a number of design of experiments (DOE) were performed in the joint space of the raw materials and the manipulated process variables to develop the design space and control strategy with feedback control. The result was a joint space that combines the interaction of all the input variables such as raw materials and process parameters that have been proven to provide high quality. Throughout this paper, the use of multivariate statistical analysis and DOE and how they are applied to define meaningful raw materials specification and design space to achieve QbD are discussed.

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.

Chapter 6 - Application of Quality by Design Paradigms for Development of Solid Dosage Forms

ABSTRACTIntroduction: Quality by design (QbD) encourages the pharmaceutical industry to use risk management and science-based manufacturing principles to gain process and product understanding and thus assures quality of the product. With the objective to curb the rising costs for development and regulatory barriers to innovation and creativity, QbD is being widely promoted by Food and Drug Administration (FDA) and International Conference on Harmonization (ICH).Areas covered: This review describes the elements, different design and tools of QbD as well as multidimensional applications of QbD ranging from dosage form and method development to meeting latest regulatory requirements.Expert opinion: The understanding of a process is facilitated by proper identification of sources of variation, management of variability by process design, and prediction of product quality attributes using design space. The pharmaceutical industry is rapidly adopting the QbD principles for fabrication of safe, effective and quality products; however, we are still on a journey and the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress. Understanding the formulation and process parameters with the philosophy of QbD will be useful for the optimization of complex drug delivery systems in the near future.

Although various quality by design (QbD) approaches have been used to establish a design space to obtain robust drug formulation and process parameters, the effect of excipient variability on the design space and drug product quality is unclear. In this study, the effect of microcrystalline cellulose (MCC) variability on drug product quality was examined using a design space for immediate-release tablets of amlodipine besylate. MCC variability was assessed by altering the manufacturer and grade. The formulation was developed by employing the QbD approach, which was optimized using a D-optimal mixture design. Using 36 different MCCs, the effect of MCC variability on the design space was assessed. The design space was shifted by different manufacturers and grades of MCC, which resulted in associations between the physicochemical properties of MCC and critical quality attributes (CQAs). The correlation between the physicochemical properties of MCCs and CQAs was assessed through a statistical analysis. A predictive model correlating the physicochemical properties of MCCs with dissolution was established using an artificial neural network (ANN). The ANN model accurately predicted dissolution with low absolute and relative errors. The present study described a comprehensive QbD approach, statistical analysis, and ANN to comprehend and manage the effect of excipient variability on the design space.

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.