Pharmaceutical Quality by Design

A Practical Approach

Walkiria S. Schlindwein, Mark Gibson, Walkiria S. Schlindwein, Mark Gibson

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781118895207
• eBook ISBN: 9781118895214
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

A practical guide to Quality by Design for pharmaceutical product development

Pharmaceutical Quality by Design: A Practical Approach outlines a new and proven approach to pharmaceutical product development which is now being rolled out across the pharmaceutical industry internationally. Written by experts in the field, the text explores the QbD approach to product development. This innovative approach is based on the application of product and process understanding underpinned by a systematic methodology which can enable pharmaceutical companies to ensure that quality is built into the product.

Familiarity with Quality by Design is essential for scientists working in the pharmaceutical industry. The authors take a practical approach and put the focus on the industrial aspects of the new QbD approach to pharmaceutical product development and manufacturing. The text covers quality risk management tools and analysis, applications of QbD to analytical methods, regulatory aspects, quality systems and knowledge management. In addition, the book explores the development and manufacture of drug substance and product, design of experiments, the role of excipients, multivariate analysis, and include several examples of applications of QbD in actual practice. This important resource:

• Covers the essential information about Quality by Design (QbD) that is at the heart of modern pharmaceutical development
• Puts the focus on the industrial aspects of the new QbD approach
• Includes several illustrative examples of applications of QbD in practice
• Offers advanced specialist topics that can be systematically applied to industry

Pharmaceutical Quality by Design offers a guide to the principles and application of Quality by Design (QbD), the holistic approach to manufacturing that offers a complete understanding of the manufacturing processes involved, in order to yield consistent and high quality products.

1
Introduction to Quality by Design (QbD)

Bruce Davis¹ and Walkiria S. Schlindwein²

¹ Bruce Davis Ltd, United Kingdom

² De Montfort University, Leicester, United Kingdom

1.1 Introduction

The aim of this chapter is to introduce the principles of Quality by Design (QbD) to those who want to understand pharmaceutical QbD, and that may include readers from industry, academia, regulators or indeed anyone interested in finding out more about this important subject.

The content is applicable to development scientists, manufacturing specialists and those in supporting roles, such as quality, analytical, engineering, validation and more. It is intended to be helpful, practical and wide‐ranging and for use by novices, experienced practitioners or those who want to expand their current knowledge.

Each of the subsequent chapters is written by experts in their field and provide relevant, up‐to‐date and tailored information. Each part will stand alone, but it is the sum of these individual parts that makes QbD whole and provides the compelling story that will ultimately benefit patients and give clarity of understanding in what is important when designing, manufacturing and supplying products to our customers.

So, who are these customers? Some may be our family or friends or colleagues, but most will be individuals we do not know and will never meet. A customer may choose a generic medicine from a shelf in the pharmacy, their choice perhaps being influenced by the descriptions on the packaging or by marketing and advertising, or, alternatively, they may have their medicine prescribed and administered by healthcare professionals. Some may be supporting others, for example, a parent helping their child, or an adult helping an elderly relative or colleague.

But no matter what the circumstances are in which someone takes a medicine, there is one overriding principle: that every patient, healthcare professional, parent or career has to trust the pharmaceutical industry to provide what is intended and that the medicine will be safe, efficacious and of the required quality.

So it is important that we value this trust we have been given. History says that most of the time the pharmaceutical industries have delivered on this trust, but there have been occasions when the industries have not, and such mistakes, albeit small in number compared with all the medicines that are taken, have sadly damaged the trust that customers put in the industry.

So how does this impact the development, manufacturing and distribution of pharmaceuticals? First, we should recognise that we in industry have the detailed technical knowledge, and the customers usually do not. Second, we should ensure strong linkages across the product lifecycle, from development to manufacturing to supply. Third, we not only have to understand the underlying science, what risks there might be and mitigate these risks proactively before products reach the patient, but we have to communicate these risks effectively. So, for example, if there are a million tablets in a batch, we have to be sure, to the best of our ability, that these tablets have been produced of the appropriate quality, as each one may go to a different customer.

And this is where the term QbD comes in – sometimes referred to as ‘a science and risk‐based approach’, and this set of words gives a little more insight into what QbD is about.

The definition of QbD [1] is:

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

The term ‘Quality by Design’ was first used by Juran in 1985 when the first draft of his book [2], published in 1992, was available for consultation by 50 senior representatives of industry. The Juran Trilogy stated: ‘Managing for quality is done by use of the same three managerial processes: planning, control and improvement’ [3].

This book will provide detail to expand this same idea into a practical reality, but for this introduction, we can consider QbD as helping the pharmaceutical industry to continue to take a science‐ and risk‐based approach to enable safe and efficacious medicines to be developed and produced over the product lifecycle, that lifecycle being from the time the product is being conceived to the time it is finally withdrawn from the market, including managing the impact of any changes that may occur during this period.

1.2 Background

Historically, an ultra‐compliant approach had dominated the way the pharmaceutical industry operated, perhaps even threatening, wrongly, to potentially swamp the underlying science, rather than compliance being seen as a partnership with science. Fear of seeking change for already approved regulatory documents, even when new enhanced science or technology developments came to light, has meant that industry continued to operate within compliance‐driven, historically established boundaries. One example might be where manufacturing limits had been approved in a regulatory submission. Yet, over time, as more product and process knowledge accumulated to support widening – or maybe tightening – the original limits, industry had a fear of discussing this new knowledge with regulators. Sadly, this fear still partly exists today, though it is not as prevalent.

So why did compliance come to have such an overbearing role? Maybe it was a perceived fear of regulators? Or business pressure to have approvals in place to meet rapid launch of products ahead of competitors? Or was it to assess matters as either ‘right’ or ‘wrong’, rather than recognising there is a continuum of risk in regard to pharmaceuticals – or indeed in any product that is designed, manufactured and supplied to customers? It could be none, any or all of these reasons; one will never know.

This compliance‐focussed mindset did not mean that quality problems were not occurring. Indeed, one could sense, looking back, some frustration within industry and also for regulators, particularly when things did go wrong, as they occasionally did. Regulators started to impose increasingly large fines, but this did not seem to resolve recurrence of quality issues.

This point was captured in a Wall Street Journal article of 3 September 2003 [4]:

Dr. Woodcock had been among the architects of an FDA crackdown under which the agency fined drug makers as much as $500 million for manufacturing failures in recent years. Yet ‘we still weren't seeing acceptable levels of quality’, she says, because ‘production techniques were outmoded. Just refining procedures and documentation wasn't going to change that’.

This article was significant as it gave a reflection of what was happening at that time both within the industry and for regulators, but it also recognised that the public were beginning to take a keener interest in the pharmaceutical industry and expecting regulators to continue to play their part in ensuring quality.

One other important factor was that the pharmaceutical market was becoming increasingly international, yet regulators, who were normally based in one country, were, understandably, focussed on ensuring their own particular local interest was protected, both for imports and for products made within their national boundaries.

Gradually it became apparent that a less local perspective would be beneficial, and in 1990 the International Conference on Harmonisation (ICH) was created [5].

ICH is an interesting concept as it brings together regulators, industry associations and observers from different parts of the world to meet and jointly write guidance documents. The members include US, EU and Japanese regulators and industry bodies, as well as...

Table of contents

• Cover
• Title Page
• Table of Contents
• List of Figures
• List of Tables
• List of Contributors
• Advances in Pharmaceutical Technology: Series Preface
• Preface
• 1 Introduction to Quality by Design (QbD)
• 2 Quality Risk Management (QRM)
• 3 Quality Systems and Knowledge Management
• 4 Quality by Design (QbD) and the Development and Manufacture of Drug Substance
• 5 The Role of Excipients in Quality by Design (QbD)
• 6 Development and Manufacture of Drug Product
• 7 Design of Experiments
• 8 Multivariate Data Analysis (MVDA)
• 9 Process Analytical Technology (PAT)
• 10 Analytical Method Design, Development, and Lifecycle Management
• 11 Manufacturing and Process Controls
• 12 Regulatory Guidance
• Index
• End User License Agreement