Quality by Design-Driven Process Development of Cell Culture in Bioreactor for the Production of Foot-And-Mouth Veterinary Vaccine

Quality by design (QbD) principle has been established as a guideline to emphasize the understanding of the relationship of product quality with process control. Vaccine product have characteristics of security and high efficiency, but it also has features such as complexity and rigorous regulatory for production. This case study describes an example of QbD-driven process development for manufacturing a veterinary vaccine produced with baby hamster kidney-21 cells. The study revealed that cell culture duration was the most significant factor affecting 50% tissue culture infectious doses (TCID₅₀) and antigenic titer, and the factors of culture temperature and pH at infection phase exhibited less effect. Culture temperature at infection phase was the only significant factor for total protein. Through the Monte Carlo simulation, the design spaces of process parameters were determined. Meanwhile, the excellent and robust performance in manufacturing scale (4000-L) validated the effectiveness of this strategy. A reliable and robust multivariate process parameter range, that is, design space, was identified by this systematic approach. Our investigation presents a successful case of QbD principle, which encourages other researchers to combine the methodology into other biopharmaceutical manufacturing process.     

Evaluation of the microbial growth potential of pharmaceutical drug products and quality by design

The microbial growth potential of a pharmaceutical drug product refers to the ability of microorganisms to survive and proliferate in the product. Each drug formulation possesses a different potential for supporting or inhibiting microbial growth. Understanding this microbial growth potential can have a significant effect on the development and design of the drug manufacturing process. This article describes how this attribute can exert this effect on manufacturing process development and design through real examples and case studies obtained from the regulatory review of new drug and biologics license applications. In addition, this article describes how understanding the microbial growth potential of a pharmaceutical drug product is an element of the Quality by Design paradigm and how this understanding can simplify the drug development process and lead to better process design. LAY ABSTRACT: The microbial growth potential of a pharmaceutical drug product refers to the ability of microorganisms to survive and proliferate in the product formulation. Each drug product formulation possesses a different potential for supporting or inhibiting microbial growth depending on its components. Understanding this microbial growth potential can have a significant effect on the development and design of the drug manufacturing process. This article describes how this attribute can affect manufacturing process development and design through real examples and case studies obtained from the regulatory review of new drug and biologics license applications. In addition, this article describes how understanding the microbial growth potential of a pharmaceutical drug product is an element of the Quality by Design paradigm and how this understanding can simplify the drug development process and lead to better process design.     

Overcoming Inherent Limits to Pharmaceutical Manufacturing Quality Performance with QbD (Quality by Design)

Pharmaceutical development and manufacturing systems typically rely on a Quality by Testing (QbT) model that use release testing and other measures to ensure product quality. However, there is a significant gap between typical pharmaceutical production system capability and supplied quality. To sustain high levels of product supply quality, the industry incurs a high cost of quality and retains value at risk. This paper presents research results from a systems engineering perspective using case study data that quantitatively evaluates the gap between pharmaceutical production system sigma and supplied quality. It also identifies the extent to which emerging Quality by Design (QbD) eliminates system contradictions that prohibit higher production system sigma performance.     

人乳头瘤病毒重组蛋白疫苗酶联免疫检测法的建立及其应用

目的建立人乳头瘤病毒重组蛋白疫苗(HPV16 L2E6E7)酶联免疫的检测方法,用于疫苗发酵过程中的重组蛋白表达的监控。方法用常规方法制备兔抗HPV16 L2E6E7多克隆抗体作为包被抗体,商品化小鼠抗HPV16 E7单克隆抗体为检测抗体,夹心ELISA方法检测HPV16 L2E6E7抗原参考品,建立抗原标准曲线,确定线性范围及检测限,同时验证该方法的特异性。结果建立了检测HPV16 L2E6E7抗原含量的夹心ELISA方法,抗原参考品系列浓度在19.53~1 250 ng·m L-1内有很好的线性(R2>0.99)和回收率(90%~110%);特异性好,不受发酵液中宿主菌蛋白的干扰。结论建立了人乳头瘤病毒重组蛋白疫苗重组抗原含量的测定方法,为该疫苗的发酵工艺的质控提供了有效技术手段。     

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.     

Population Balance Model Validation and Predictionof CQAs for Continuous Milling Processes: toward QbDin Pharmaceutical Drug Product Manufacturing

Continuous tablet manufacturing has been investigated for its potential advantages (e.g., cost, efficiency, and controllability) over more conventional batch processes. One avenue for tablet manufacturing involves roller compaction followed by milling to form compactible granules. A better understanding of these powder processes is needed to implement Quality by Design in pharmaceutical manufacturing. In this study, ribbons of microcrystalline cellulose were produced by roller compaction and milled in a conical screen mill. A full factorial experiment was performed to evaluate the effects of ribbon density, screen size, and impeller speed on the product size distribution and steady-state mass holdup of the mill. A population balance model was developed to simulate the milling process, and a parameter estimation technique was used to calibrate the model with a subset of experimental data. The calibrated model was then simulated at other processing conditions and compared with additional unused experimental data. Statistical analyses of the results showed good agreement, demonstrating the model’s predictive capability in quantifying milled product critical quality attributes within the experimental design space. This approach can be used to optimize the design space of the process, enabling Quality by Design.     

Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: Towards a global multi-step design space

The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Similarly, process parameters that have a potential impact on critical quality attributes (CQAs) were also identified through a risk assessment. Critical process parameters were then evaluated for their impact on CQAs, individually and in interaction with each other, using multivariate design of experiment techniques during the process characterisation phase. The global multi‐step Design Space, defining operational limits for the entire drug substance manufacturing process so as to ensure that the drug substance quality targets are met, was devised using predictive statistical models developed during the characterisation study. The validity of the global multi‐step Design Space was then confirmed by performing the entire process, from cell bank thawing to final drug substance, at its limits during the robustness study: the quality of the final drug substance produced under different conditions was verified against predefined targets. An adaptive strategy was devised whereby the Design Space can be adjusted to the quality of the input material to ensure reliable drug substance quality. Finally, all the data obtained during the process described above, together with data generated during additional validation studies as well as manufacturing data, were used to define the control strategy for the drug substance manufacturing process using a risk assessment methodology.     

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.     

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.     

Process Analytical Technologies (PAT) in freeze-drying of parenteral products

Quality by Design (QbD), aims at assuring quality by proper design and control, utilizing appropriate Process Analytical Technologies (PAT) to monitor critical process parameters during processing to ensure that the product meets the desired quality attributes. This review provides a comprehensive list of process monitoring devices that can be used to monitor critical process parameters and will focus on a critical review of the viability of the PAT schemes proposed. R&D needs in PAT for freeze-drying have also been addressed with particular emphasis on batch techniques that can be used on all the dryers independent of the dryer scale.     

Integration of Continuous Flow Reactors and Online Raman Spectroscopy for Process Optimization

The pharmaceutical industry has great need to reduce costs and improve manufacturing efficiency while consistently manufacturing quality drug product. Continuous flow reactors (CFRs) offer an option for a flexible, leaner, and cleaner process. CFRs are flow cells optimized for the continuous production of a target compound. Small-volume CFRs avoid some of the reaction control problems associated with scale-up to large-batch chemistry, while still allowing for process intensification through modular scale-out. Compared to batch reactors, CFRs are more energy efficient due to their superior mixing schemes and heat transfer properties. Reactions typically proceed much faster than in batch and require less excess solvent. Currently, CFRs are limited by the technologies available for online monitoring, which require product stream sampling and off-line analytics. This work addresses the analytical challenges inherent to CFRs by demonstrating the ability to assess the quality of product from a reactor stream rapidly, using effective online sampling and monitoring systems. Additionally, following the Quality by Design paradigm, techniques such as statistically based design of experiments, process analytical technologies, and multivariate statistical modeling methods were implemented to facilitate enhanced product and process understanding. An online sampling system that is able to interface with CFRs was developed, with custom software to monitor and control process variables using online analytics. Knowledge of these in-process parameters, combined with appropriate online process analytical technologies, provided a complete understanding of both the physical and chemical system. These improvements reduced the time and effort required to develop and optimize a chemical reaction for large-scale continuous production.     

Generic Development of Topical Dermatologic Products, Part II: Quality by Design for Topical Semisolid Products

The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products.     

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)     

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。     

Development,validation and transfer of a Near Infrared method to determine in-line the end point of a fluidised drying process for commercial production batches of an approved oral solid dose pharmaceutical product

Pharmaceutical companies are progressively adopting and introducing the principles of Quality by Design with the main purpose of assurance and built-in quality throughout the whole manufacturing process. Within this framework, a Partial Least Square (PLS) model, based on Near Infrared (NIR) spectra and humidity determinations, was built in order to determine in-line the drying end point of a fluidised bed process. The in-process method was successfully validated following the principles described within The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – ICH Q2 (r1) – Validation of Analytical Procedures: Text and Methodology. However, in some aspects, the cited guidelines were not appropriate to in-process methods developed and validated exclusively with in-line samples and implemented in dynamic systems, such as drying processes. In this work, a customized interpretation of guidelines has been adopted which provided the framework of evidence to support a validated application.     

Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues

The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.     

Application of a tablet film coating model to define a process-imposed transition boundary for robust film coating

A scientific understanding of interaction of product, film coat, film coating process, and equipment is important to enable design and operation of industrial scale pharmaceutical film coating processes that are robust and provide the level of control required to consistently deliver quality film coated product. Thermodynamic film coating conditions provided in the tablet film coating process impact film coat formation and subsequent product quality. A thermodynamic film coating model was used to evaluate film coating process performance over a wide range of film coating equipment from pilot to industrial scale (2.5–400?kg). An approximate process-imposed transition boundary, from operating in a dry to a wet environment, was derived, for relative humidity and exhaust temperature, and used to understand the impact of the film coating process on product formulation and process control requirements. This approximate transition boundary may aid in an enhanced understanding of risk to product quality, application of modern Quality by Design (QbD) based product development, technology transfer and scale-up, and support the science-based justification of critical process parameters (CPPs).     

Development of a Design Space for a Unit Operation: Illustration Using Compression-Mix Blending Process for the Manufacture of a Tablet Dosage Form

This paper describes the development of an orthogonal design space for a compression-mix blending unit operation for the manufacture of tablet dosage form using an empirical approach. Potential critical process parameters identified through a risk assessment process were assessed through a full-factorial design of experiment for impact on material attributes and drug product critical quality attributes (DP CQA). The impact on each individual attribute measured as responses were subjected to statistical analysis by analysis of variance and regression models were built on the statistically significant effects (p < 0.05). Design space for relevant DP CQA was created using 95% predicted interval estimates. Orthogonal design space for the unit operation was proposed by overlaying design spaces generated for individual DP CQAs. The resulting orthogonal design space made implementation of manufacturing flexibility in to routine manufacturing process and into control strategy simpler and straightforward.     

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process.     

FDA有关“质量源于设计”的初步实施情况介绍

为更加有效地控制药品质量,应不断寻找更适合药品研发实际的质量控制手段。近年来,药品初始设计决定最终药品质量的理念逐渐为业界所接受,国外已就此开展了部分实践性工作并取得了一些经验和教训。介绍FDA关于"质量源于设计"实施的具体情况,希望为药品研发者和评价者提升质量控制水平提供参考。