Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture

Gintaras V. Reklaitis, Christine Seymour, Salvador García-Munoz, Gintaras V. Reklaitis, Christine Seymour, Salvador García-Munoz

• Publisher: Wiley-AIChE
• Year: 2017
• Print ISBN: 9780470942376
• eBook ISBN: 9781119356172
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

Covers a widespread view of Quality by Design (QbD) encompassing the many stages involved in the development of a new drug product.

The book provides a broad view of Quality by Design (QbD) and shows how QbD concepts and analysis facilitate the development and manufacture of high quality products. QbD is seen as a framework for building process understanding, for implementing robust and effective manufacturing processes and provides the underpinnings for a science-based regulation of the pharmaceutical industry.

Edited by the three renowned researchers in the field, Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture guides pharmaceutical engineers and scientists involved in product and process development, as well as teachers, on how to utilize QbD practices and applications effectively while complying with government regulations. The material is divided into three main sections: the first six chapters address the role of key technologies, including process modeling, process analytical technology, automated process control and statistical methodology in supporting QbD and establishing the associated design space. The second section consisting of seven chapters present a range of thoroughly developed case studies in which the tools and methodologies discussed in the first section are used to support specific drug substance and drug-product QbD related developments. The last section discussed the needs for integrated tools and reviews the status of information technology tools available for systematic data and knowledge management to support QbD and related activities.

Highlights

• Demonstrates Quality by Design (QbD) concepts through concrete detailed industrial case studies involving of the use of best practices and assessment of regulatory implications
• Chapters are devoted to applications of QbD methodology in three main processing sectors—drug substance process development, oral drug product manufacture, parenteral product processing, and solid-liquid processing
• Reviews the spectrum of process model types and their relevance, the range of state-of-the-art real-time monitoring tools and chemometrics, and alternative automatic process control strategies and methods for both batch and continuous processes
• The role of the design space is demonstrated through specific examples and the importance of understanding the risk management aspects of design space definition is highlighted

Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture is an ideal book for practitioners, researchers, and graduate students involved in the development, research, or studying of a new drug and its associated manufacturing process.

1
Introduction

Christine Seymour¹ and Gintaras V. Reklaitis²

¹ Global Regulatory Chemistry and Manufacturing Controls, Pfizer Inc., Groton, CT, USA

² Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, USA

1.1 Quality by Design Overview

QbD emerged as a cultural change in the pharmaceutical industry, which promoted a scientific and risk‐based approach to pharmaceutical product development and manufacturing. Historically, pharmaceutical development and manufacturing had emphasized checklist‐based operations rather than scientific understanding. The high attrition rates of drug candidates during development and the high value of pharmaceutical products, along with extremely high regulatory burden, had led to business practices that minimized risk and restricted process changes and the implementation of new technology.

Traditionally, pharmaceutical process and product development utilized empirical and univariate experimentation and pharmaceutical processes operated at fixed process conditions with offline analytical testing (with a long feedback timeline) and end‐product testing. In addition, it was typical of pharmaceutical companies to provide the regulatory agencies with minimal process and scientific information, and regulatory agencies responded with a wealth of detail queries.

QbD is a “systematic approach to pharmaceutical development and manufacturing that is based on science and quality risk management and begins with predefined objectives and emphasizes product and process understanding as well as process control” [1]. QbD emphasizes multivariable experimentation, design of experiments, process modeling, kinetics, thermodynamics, online analytical testing, and so on. In addition, it has become an improved regulatory paradigm in which the scientific understanding of the product and process has to be provided to the regulatory agencies. This new regulatory model is intended to allow for higher transparency, higher quality, and the implementation of modern manufacturing techniques, such as continuous processing, as well as continuous improvement of commercial pharmaceutical processes.

1.2 Pharmaceutical Industry

The active pharmaceutical ingredient or drug substance is the active component of the pharmaceutical product, and typically small‐molecule drug substances are produced by a multistep synthesis, which involves a sequence of chemical reactions followed by purification/isolation unit operations. Historically, drug substance pharmaceutical processes consisted of batch operations such as reactions, extraction, distillation, crystallization, filtration/centrifugation, drying, and milling.

The drug product is the pharmaceutical formulation that the patient receives and is often in the form of tablets or capsules; other common formulations are oral solutions, topical transdermal patches, and lyophiles or sterile solutions for injection. Historically, drug product processes also consisted of batch operations such as blending, granulation, drying, tableting, encapsulation, or filling depending on the final formulation.

The history of regulations [2, 3] shows an increase in regulatory control after catastrophes; one of the most tragic incidents in the United States was the elixir sulfanilamide incident of 1937 where diethylene glycol was used as a solvent in a pediatric cough syrup and resulted in more than a hundred deaths. This incident led to the Food, Drug, and Cosmetic Act, which increased the US Food and Drug Administration (FDA)’s authority to regulate drugs and required premarketing safety approval for new medications. Another tragic incident was the thalidomide disaster of 1961 where approximately 12 000 infants in over 50 countries were born with severe malformations. This incident led to the Kefauver–Harris Drug Amendment, which increased the FDA’s authority to require safety and efficacy prior to marketing (and tighter controls of clinical trials). These and other incidents led to tighter regulations and, in the 1960s and 1970s, to a rapid increase in national pharmaceutical regulations; simultaneously, many pharmaceutical companies were also globalizing.

The global harmonization of pharmaceutical guidelines across the developed economics was initiated in 1990 through the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use [4]. ICH is cosponsored by regulatory agencies and industrial organizations, as well as many observing organizations. These include the European Commission; the US FDA; Ministry of Health, Labour and Welfare of Japan; the European Federation of Pharmaceutical Industries and Associations; the Japan Pharmaceutical Manufacturers Association; the Pharmaceutical Research and Manufacturers of America; Health Canada; Swissmedic; ANVISA of Brazil; Ministry of Food and Drug Safety of the Republic of Korea; the International Generic and Biosimilar Medicines Association; the World Self‐Medication Industry; and the Biotechnology Innovation Organization. ICH has set a structure and process for the proposal, review, and implementation for efficacy, safety, and quality guidelines as well as dossier format requirements. The initial ICH guidelines set common structure stability, analytical methods, impurity control and drug substance, and drug product specifications requirements for drug substance and drug product, and the early ICH guidelines emphasized testing for quality.

1.3 Quality by Design Details

QbD was introduced through the “QbD tripartite” of ICH guidelines: ICH Q8 (R2) Pharmaceutical Development, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality Systems. ICH Q8 Pharmaceutical Development describes the principles of QbD, outlines the key elements, and provides illustrative examples for pharmaceutical drug products. ICH Q9 Quality Risk Management offers a systematic process for the assessment, control, communication, and review of risks to the quality of the drug product. In addition, it states that “the evaluation of the risk to the quality should be based on scientific knowledge and ultimately linked to the protection of the patient” [5]. ICH Q10 Pharmaceutical Quality Systems describes a “comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization quality concepts and includes applicable Good Manufacturing Practices” [6]. The fourth QbD ICH guideline (considered the drug substance equivalent of ICH Q8) for enhanced active pharmaceutical ingredient synthesis and process understanding, Q11 Development and Manufacturing of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), was approved in November 2012 [7]. The fifth QbD ICH guideline (ICH Q12), Technology and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, is currently under development.

The QbD approach begins with Quality Target Product Profile, which is a prospective summary of the quality characteristics of the pharmaceutical product that ensures the desired quality, safety, and efficacy, and works backward through the drug product and drug substance processes establishing a holistic understanding of which attributes are linked to patients’ requirements and functional relationships of these attributes.

The next step in QbD is a systematic approach to determine the aspects of the drug substance and drug product manufacturing processes that impact the Quality Target Product Profile. A risk assessment is conducted to identify the quality attributes and process parameters that could potentially impact product safety and/or efficacy, utilizing prior scientific knowledge gained from first principles, literature, and/or similar processes.

The output of the risk assessment is a development plan, in which multivariable experiments, kinetics, and/or modeling is typically utilized. The goal of the plan is to establish a holistic understanding of how attributes and parameters are functionally interrelated throughout the entire drug substance and drug product processes. The result is control strategy, which links parameters and attributes to the Quality Target Product Profile.

This approach provides a comprehensive understanding of the critical quality attributes, which is a “physical, chemical, biological, or microbiological property or characteristic that should be in an appropriate limit, range or distribution to ensure the desired product quality,” and of how the process parameters are related to the quality attributes and how probable they can impact quality.

The enhanced understanding of products and processes, along with quality risk management, leads to a product control strategy, which might include a design space (that is optional in ICH Q8/11), which is “the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality.” The control strategy is a planned set of controls, which can be process parameters, process attributes, design space, facility and equipment operating conditions, and process testing that ensures process performance and product quality.

The regulatory QbD landscape continues to evolve, and AIChE conferences and sessions will continue to provide a platform to discuss and debate the latest QbD concepts and implementations.

1.4 Chapter Summaries

The contributions in this book can be divided into three sets: Chapters 2–6 address the role of key technologies, process models, process analytical technology (PAT), automatic process control, and statistical methodology, supporting QbD and establishing associated design spaces. Chapters 7–13 present a range of thoroughly developed case studies in which tools and methodologies are used to support specific drug substance and drug product QbD‐related developments. Finally, Chapter 14 discusses the needs for initial efforts toward systematic data and knowledge management to support QbD and related activities. More specifically:

Chapter 2, An Overview of the Role of Mathematical Models in Implementation of Quality by Design Paradigm for Drug Development and Manufacture (Chatterjee, Moore, and Nasr), reviews the categories of mathematical models that can be exploited to support QbD and presents literature examples of various types of model formulations and their use. The authors emphasize that models are valuable tools at every stage of drug development and manufacture. Examples presented span early‐stage risk assessment, design space development, process monitoring and control, and continuous improvement of product quality.

Chapter 3, Role of Automatic Process Control in Quality by Design (Braatz and coworkers), outlines how robust automatic control is an important element...

Table of contents

• Cover
• Title Page
• Table of Contents
• List of Contributors
• Preface
• 1 Introduction
• 2 An Overview of the Role of Mathematical Models in Implementation of Quality by Design Paradigm for Drug Development and Manufacture
• 3 Role of Automatic Process Control in Quality by Design
• 4 Predictive Distributions for Constructing the ICH Q8 Design Space
• 5 Design of Novel Integrated Pharmaceutical Processes: A Model-Based Approach
• 6 Methods and Tools for Design Space Identification in Pharmaceutical Development
• 7 Using Quality by Design Principles as a Guide for Designing a Process Control Strategy
• 8 A Strategy for Tablet Active Film Coating Formulation Development Using a Content Uniformity Model and Quality by Design Principles
• 9 Quality by Design: Process Trajectory Development for a Dynamic Pharmaceutical Coprecipitation Process Based on an Integrated Real-Time Process Monitoring Strategy
• 10 Application of Advanced Simulation Tools for Establishing Process Design Spaces Within the Quality by Design Framework
• 11 Design Space Definition: A Case Study—Small Molecule Lyophilized Parenteral
• 12 Enhanced Process Design and Control of a Multiple-Input Multiple-Output Granulation Process
• 13 A Perspective on the Implementation of QbD on Manufacturing through Control System: The Fluidized Bed Dryer Control with MPC and NIR Spectroscopy Case
• 14 Knowledge Management in Support of QbD
• Index
• End User License Agreement