API Quality by Design Example from the Torcetrapib Manufacturing Process

The concept and application of quality by design (QbD) principles has been and will undoubtedly continue to be an evolving topic in the pharmaceutical industry. However, there are few and limited examples that demonstrate the actual practice of incorporating QbD assessments, especially for active pharmaceutical ingredients (API) manufacturing processes described in regulatory submissions. We recognize there are some inherent and fundamental differences in developing QbD approaches for drug substance (or API) vs drug product manufacturing processes. In particular, the development of relevant process understanding for API manufacturing is somewhat challenging relative to criteria outlined in ICH Q8 (http://www.ich.org/cache/compo/276–254–1.html) guidelines, which are primarily oriented toward application of QbD for drug product manufacturing. This position paper provides a perspective of QbD application for API manufacture using an example from the torcetrapib API manufacturing process. The work includes a risk assessment, examples of multivariate design, and a proposed criticality assessment, all of which coalesce into an example of design space. Torcetrapib was a project in phase III development as a potent and selective inhibitor of cholesteryl ester transfer protein before being terminated in late 2006. The intent of Pfizer was to submit torcetrapib under the QbD paradigm (route selection, robustness, and reagent/solvent selection during phases I to III are significantly important in establishing a manufacturing process that would have the most flexibility in the final design space. For more information on this development phase for torcetrapib see Damon et al., Org Process Res Dev, 10(3):464–71, 2006, Org Process Res Dev, 10(3):472–80, 2006).     

智能制造理念在血液制品产业的应用研究

目的：通过分析智能制造理念下,质量源于设计（quality by design,QbD）与血液制品生产的相关性、过程分析技术（process analytical technology,PAT）在血液制品QbD中的应用以及关键质量环节的QbD实施,以期推动我国血液制品行业升级,实现血液制品的智能生产。方法：采取前瞻性研究方法,查阅、检索以"智能制造" "血液制品" "质量源于设计"过程分析技术"为关键词的文献,对智能制造理念在血液制品的应用研究进行论述。结果与结论：基于我国制药工业的自动化与信息化的水平与现状,制药工业的"智能制造"已逐步发展起来,QbD已被引入我国新版药品GMP,强调了与药品注册、上市制度的有效衔接。在科学监管的要求下,QbD理念已成为血液制品行业界的共识,实施QbD,通过基于问题的审核（question-based review,QbR）,将有助于全面提高我国血液制品的质量,提升产品的竞争力。     

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

PURPOSE: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. MATERIALS AND METHODS: The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. RESULTS: The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile; Designing product and manufacturing processes; Identifying critical quality attributes, process parameters, and sources of variability; Controlling manufacturing processes to produce consistent quality over time. CONCLUSIONS: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.     

Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.     

Understanding Pharmaceutical Quality by Design

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.     

Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm

Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.KEY WORDS: absorption modeling, PBPK, pharmacokinetics, Quality by Design (QbD), quality target product profile (QTPP)     

Quality by Design-Driven Process Development of Severe Fever With Thrombocytopenia Syndrome Vaccine

Owing to the biological activity of the vaccine, the complicated production process, sterility, and uniformity of the product, the producing process of the vaccine is complicated and the product quality hard to control. In recent years, with the development of basic science such as cell biology, molecular biology, and metabolic engineering, bioprocess engineering research has developed rapidly. Therefore, U.S. Food and Drug Administration and European Medicines Agency conduct stringent control over the development of biomedical process engineering and product quality. This case study describes an example of Quality by Design–driven process development for manufacturing a human vaccine produced with Vero cells. Cell density in harvest fermentation broth and antigenic titer were chosen as 2 critical quality attributes. The study through 3 rounds design of experiment revealed that H₂O₂ and cell boost 4 had a significant effect on antigenic titer. Ethanolamine had significant improvement in the final concentration of cells. Through the Monte Carlo simulation, the design spaces and control space of process parameters were determined. A successful validation in a bioreactor was executed to verify the results of a spinner flask. Our investigation presents a successful case of Quality by Design principle, which encourages other researchers to combine the methodology into other biopharmaceutical manufacturing process.     

Application of Quality by Design Principles to Legacy Drug Products

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.     

Misunderstanding <Emphasis Type="Italic">Design Space</Emphasis>: a Robust Drug Product Control Strategy Is the Key to Quality Assurance

ICH guidelines Q8/11, Q9, and Q10 introduced risk-based approaches and enhanced scientific understanding as an opportunity to encourage continuous process improvement for pharmaceutical manufacturing. Conceptually, Quality by Design (QbD) promised to improve confidence in quality through the lifecycle of pharmaceutical products. A primary incentive for industry is the prospect of global regulatory concordance for new applications and post approval changes. Unfortunately, during the last decade, the industry has experienced regulatory divergence regarding the interpretation of ICH guidelines across geographic regions. Rather than truly harmonized regulatory expectations, localized interpretations of ICH guidance have resulted in different technical requirements posing significant challenges for a global industry. As a result, the increased complexity of manufacturing supply chains and the regulatory burden associated with maintaining compliance with these diverse regulatory expectations serves as a barrier to continual improvement and innovation. The QbD paradigm has effectively demonstrated a risk-based link between a product’s control strategy and patient needs that has prompted meaningful improvement in the industry’s approach to product quality assurance. Divergent interpretations of the concepts and definitions used in the modern QbD approach to product development and manufacturing, however, has led to challenges in achieving a common implementation of design space, control strategy, prior knowledge, proven acceptable range, and normal operating range. While the concept of design space remains an appealing focal point for demonstrating process understanding, the authors suggest that Control Strategy is the most important QbD concept, and one that assures product quality for patients. A focus by both regulators and manufacturers on the significance of Control Strategy could facilitate management of post approval changes to improve manufacturing processes and enhance product quality while also engendering regulatory harmonization.     

A Quality by Design Approach to Developing and Manufacturing Polymeric Nanoparticle Drug Products

The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines—using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform. This article exemplifies a QbD approach used by BIND Therapeutics, Inc., to industrialize a polymeric targeted nanoparticle drug delivery platform. The focus of the approach is on CMC affairs but consideration is also given to preclinical, clinical, and regulatory aspects of pharmaceutical development. Processes are described for developing a quality target product profile and designing supporting preclinical studies, defining critical quality attributes and process parameters, building a process knowledge map, and employing QbD to support outsourced manufacturing.     

Quality by design (QbD) approaches in current pharmaceutical set-up

Introduction: 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.     

A Tutorial for Developing a Topical Cream Formulation Based on the Quality by Design Approach

The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test system have been widely acknowledged. The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development. The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner.     

模型设计在制剂研发及生产过程质量控制中的应用

“质量源于设计”概念的提出,将药品的质量控制从生产过程扩展至整个药品生命周期中,而这一概念的核心便是模型设计。介绍模型设计在制剂研发和及生产过程工艺阶段质量控制中的应用情况及模型建立的原理和模型预测结果,并结合笔者所在实验室的模型预测结果,对模型设计在制剂研发生产过程质量控制中的应用进行了评价和展望。     

Impact of Quality by Design in Process Development on the Analytical Control Strategy for a Small-Molecule Drug Substance

Development of the arzoxifene hydrochloride drug substance manufacturing process, first via a traditional approach and subsequently via an enhanced approach, provides an informative case study in quality by design (QbD). The primary focus of this paper is to illustrate the impact and advantages of QbD on the impurity control strategy. By operating the process at the extremes during design space studies, a larger collection of organic impurities and higher levels of typical impurities are observed in the intermediates. This enables a more thorough understanding of the ability of the process to purify the drug substance and results in a more complete and robust set of intermediate specifications as well as broader and more robust analytical methods. We demonstrate that, when each of the synthetic steps are operated within the design space, the byproduct impurities in the intermediates will not exceed levels found to be rejected in subsequent steps, ensuring that the drug substance will meet its critical quality attributes. Through the rigorous application of an enhanced process development approach, we have designed quality into the arzoxifene hydrochloride drug substance. As a result, real-time release of the intermediate batches is proposed to increase the process throughput and avoid the expense of nonvalue-added testing.     

Minimisation of the capping tendency by tableting process optimisation with the application of artificial neural networks and fuzzy models

The pharmaceutical industry is increasingly aware of the advantages of implementing a quality-by-design (QbD) principle, including process analytical technology, in drug development and manufacturing. Although the implementation of QbD into product development and manufacturing inevitably requires larger resources, both human and financial, large-scale production can be established in a more cost-effective manner and with improved efficiency and product quality. The objective of the present work was to study the influence of particle size (and indirectly, the influence of dry granulation process) and the settings of the tableting parameters on the tablet capping tendency. Artificial neural network and fuzzy models were used for modelling the effect of the particle size and the tableting machine settings on the capping coefficient. The suitability of routinely measured quantities for the prediction of tablet quality was tested. Results showed that model-based expert systems based on the contemporary routinely measured quantities can significantly improve the trial-and-error procedures; however, they cannot completely replace them. The modelling results also suggest that in cases where it is not possible to obtain sufficient number of measurements to uniquely identify the model, it is beneficial to use several modelling techniques to identify the quality of model prediction.     

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.     

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices.     

Quality by design (QbD) approach for design and development of drug-device combination products: a case study on flunisolide nasal spray

Abstract

The objective of the present study was to design and develop drug-device combination product in particular flunisolide nasal spray (FNS) using quality by design (QbD) approach. Quality target product profile (QTPP) of FNS was defined and critical quality attributes (CQAs), i.e. viscosity (cp) (Y₁) and D₅₀ droplet size distribution (DSD) (μm) (Y₂) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tools. Plackett–Burman and Box–Behnken designs were used for screening the significant factors and optimizing the variables range, respectively. It was observed that viscosity (cp) (Y₁) was significantly impacted by formulation variables X₁: propylene glycol (PG) (%) and X₂: polyethylene glycol (PEG) 3350 (%), while D₅₀ DSD (μm) (Y₂) was significantly impacted by formulation variables X₁: PG (%), X₂: PEG 3350 (%) and device variable X₈: delivery volume (μl). A design space plot within which the CQAs remained unchanged was established at laboratory scale. In conclusion, this study demonstrated how QbD based development approach can be applied to the development of drug-device combination products with enhanced understanding of the impact of formulation, process and device variables on CQAs of drug-device combination products.