Pharmaceutical Quality by Design: A Practical Approach

Advances in Pharmaceutical Technology: Series Preface

The series Advances in Pharmaceutical Technology covers the principles, methods and technologies that the pharmaceutical industry uses to turn a candidate molecule or new chemical entity into a final drug form and hence a new medicine. The series will explore means of optimizing the therapeutic performance of a drug molecule by designing and manufacturing the best and most innovative of new formulations. The processes associated with the testing of new drugs, the key steps involved in the clinical trials process and the most recent approaches utilized in the manufacture of new medicinal products will all be reported. The focus of the series will very much be on new and emerging technologies and the latest methods used in the drug development process.

The topics covered by the series include the following:

Formulation: The manufacture of tablets in all forms (caplets, dispersible, fast‐melting) will be described, as will capsules, suppositories, solutions, suspensions and emulsions, aerosols and sprays, injections, powders, ointments and creams, sustained release and the latest transdermal products. The developments in engineering associated with fluid, powder and solids handling, solubility enhancement, colloidal systems including the stability of emulsions and suspensions will also be reported within the series. The influence of formulation design on the bioavailability of a drug will be discussed, and the importance of formulation with respect to the development of an optimal final new medicinal product will be clearly illustrated.

Drug Delivery: The use of various excipients and their role in drug delivery will be reviewed. Among the topics to be reported and discussed will be a critical appraisal of the current range of modified‐release dosage forms currently in use and also those under development. The design and mechanism(s) of controlled release systems including macromolecular drug delivery, microparticulate controlled drug delivery, the delivery of biopharmaceuticals, delivery vehicles created for gastrointestinal tract targeted delivery, transdermal delivery and systems designed specifically for drug delivery to the lung will all be reviewed and critically appraised. Further site‐specific systems used for the delivery of drugs across the blood–brain barrier including dendrimers, hydrogels and new innovative biomaterials will be reported.

Manufacturing: The key elements of the manufacturing steps involved in the production of new medicines will be explored in this series. The importance of crystallization; batch and continuous processing, seeding; and mixing including a description of the key engineering principles relevant to the manufacture of new medicines will all be reviewed and reported. The fundamental processes of quality control including good laboratory practice, good manufacturing practice, Quality by Design, the Deming Cycle, regulatory requirements and the design of appropriate robust statistical sampling procedures for the control of raw materials will all be an integral part of this book series.

An evaluation of the current analytical methods used to determine drug stability, the quantitative identification of impurities, contaminants and adulterants in pharmaceutical materials will be described as will the production of therapeutic bio‐macromolecules, bacteria, viruses, yeasts, moulds, prions and toxins through chemical synthesis and emerging synthetic/molecular biology techniques. The importance of packaging including the compatibility of materials in contact with drug products and their barrier properties will also be explored.

Advances in Pharmaceutical Technology is intended as a comprehensive one‐stop shop for those interested in the development and manufacture of new medicines. The series will appeal to those working in the pharmaceutical and related industries, both large and small, and will also be valuable to those who are studying and learning about the drug development process and the translation of those drugs into new life‐saving and life‐enriching medicines.

Dennis Douroumis

Alfred Fahr

Jürgen Siepmann

Martin Snowden

Vladimir Torchilin

Preface

The Quality by Design (QbD) concept is not a new one, but it is only in recent years that it has been adopted by the pharmaceutical industry as a systematic approach to the development and control of drug products and their associated manufacturing processes. It became, and still is, a ‘hot topic’ after the US Food and Drug Administration (FDA) observed diminished drug approval rates, and recognized that something needed to be done to address the numerous quality manufacturing issues occurring post approval due to poorly developed products and manufacturing processes. As a result, the FDA outlined its initiative to address these concerns in its report ‘Pharmaceutical Quality for the 21st Century: A Risk‐Based Approach’, and subsequently, in collaboration with major pharmaceutical companies, established a series of pharmaceutical QbD guidance documents adopted by ICH (International Conference on Harmonization) to help streamline the drug development and regulatory filing process.

The term ‘Quality by Design’ with respect to pharmaceutical development is defined in ICH guideline Q8(R2) ‘Pharmaceutical Development’ as ‘a systematic approach to development that begins with predefined objectives, emphasizes product, process understanding and process control, based on sound science and quality risk management’ (ICH, 2009). A key principle is that quality should be built into a product with a thorough understanding of the product and the manufacturing process. This includes establishing a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. This new paradigm for pharmaceutical product development employing QbD varies a great deal from the traditional approach, which was extremely empirical; should result in better control of parameters and variables; and reduce the emphasis on end‐product testing. There are also potential opportunities to operate within a broader design space, post approval, without the need for additional regulatory scrutiny.

Due to the combination of regulatory pressure, the carrot of regulatory flexibility, and an acceptance by many pharmaceutical companies that QbD is an improved way of working for the development of new products, it has been adopted as the preferred way of working by many companies. However, implementation has often been found challenging because the FDA and ICH guidance documents are written at a fairly high level, and it is up to each company to interpret them. Some leading pharmaceutical companies have found a way forward and have obtained approval of QbD applications, but there are many others who still struggle to implement QbD in practice and are still feeling their way.

A new group specializing in Pharmaceutical Quality by Design was initiated in 2010 at De Montfort University, Leicester School of Pharmacy, led by Walkiria S. Schlindwein, in recognition of an opportunity to fill a perceived gap in education and learning associated with QbD. A distance learning postgraduate certificate programme was launched in 2010 and expanded into a full validated MSc programme in 2012. This programme has been specifically designed with the needs of the pharmaceutical and allied industries in mind and has been created through a unique collaboration between industry and academia. A wide range of experienced industrial and regulatory experts have been engaged in preparing and delivering pre‐recorded lectures that form the core of the programme. They represent manufacturing and development companies, excipient suppliers, process equipment suppliers, data analysis software suppliers, consultancies and regulators. In addition, DMU has developed a dedicated online platform to deliver online short courses tailored to the needs of industry.

The most significant departure in the creation of a QbD training for industry programme, however, has been the completion of a dedicated laboratory to simulate the conditions for QbD in action. Here, programmes can be designed to address the specific training needs of companies from the United Kingdom and the rest of the world, to give support to institutions of all sizes within the industry.

This book, Pharmaceutical Quality by Design: A Practical Approach, is intended to complement the DMU QbD teaching materials already available to support the MSc course and distance learning modules, and also, to be consistent in terms of interpretation of the principles, approach and their application in practice.

Pharmaceutical Quality by Design: A Practical Approach includes 12 different chapters covering a broad scope of QbD aspects that are considered important by the editors and contributors. Each of the subsequent chapters are 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 Quality by Design 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.

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.

Walkiria S. Schlindwein

Mark Gibson

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 observers from the World Health Organisation (WHO) and others.

As is stated on the ICH web site [5]:

The ICH Parties comprise representatives from the following regulatory parties:

European Union, the Regulatory Party is represented by the European Commission (EC) and the European Medicines Agency (EMA).

Japan, the Regulatory Party is the Ministry of Health, Labour and Welfare (MHLW).

USA, the Regulatory Party is the Food and Drug Administration (FDA).

Canada, the Regulatory Party is the Health Products and Food Branch (HPFB).

Switzerland, the Regulatory Party is the Swissmedic.

As well as from the following industry parties:

Europe, the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Japan, the Japan Pharmaceutical Manufacturers Association (JPMA).

The United States, the Pharmaceutical Research and Manufacturers of America (PhRMA).

ICH produces guidelines under headings of Safety, Quality and Efficacy. It has eminent and broad‐ranging groups of experts involved in producing these guidelines, so these guidances are as near to global as one can obtain, even though they are neither global nor mandatory, unless – as happens in some cases – regulatory agencies include them in their national Good Manufacturing Practices (GMPs). Most can be considered, to all intents and purposes, as internationally applicable.

It was ICH that first brought the term QbD to the pharmaceutical industry when in 2009 it published ICH Q8 (R2) [1], ‘Pharmaceutical Development’.

This was a watershed moment for the industry, as, after this, the importance of taking a science‐ and risk‐based approach moved to front stage, and even terms like ‘manufacturing science’ began to be heard.

1.3 Science‐ and Risk‐Based Approaches

Science, of course, has always been a fundamental element of the development of pharmaceuticals and, historically, innovative application of science has been core to producing the many life‐saving and life‐enhancing drugs that the industry has produced over time.

So why all this supposedly new approach? What has changed?

Well, the fundamentals driving the need to understand pharmaceutical science remain the same, but perhaps the following are factors that influenced a change in perspective:

The application of science is becoming more complex; for example, biotechnology‐based drugs are more complicated to understand, make and analyse compared to small molecules; specialised therapies such as advanced therapeutic medicinal products, gene therapies, etc. are beginning to emerge.

The use and application of more sophisticated tools, for example, process analytical technology (PAT), [6] has become more commonplace – although this tool is relatively new for the pharmaceutical industry, it has been in use by other industries for many years.

More powerful data processing is now available to enable such tools to be used. An example is design of experiments (DoE) (see Chapter 7) and multivariate analysis (MVA) (see Chapter 8) can now be used for more sophisticated analysis than was possible previously.

The industry has become more global, often with many differing countries involved in the supply chain, which has made it necessary to maintain quality across various international boundaries and cultures.

The supply chain has become more fragmented and diverse, with many more parties involved, including contract research organisations (CROs), contract manufacturing organisations (CMOs) and external suppliers. ‘Virtual’ companies are now emerging, a role that did not exist a few years ago.

Internal organisations are being re‐structured. An ‘over the wall’ attitude for technology transfer, development and manufacturing is being heavily discouraged. Business benefits are being seen in having closer working internal partnerships.

Knowledge management is becoming increasingly important, from development to manufacturing to supply. Knowledge is not just about knowing the pure science but is also about embracing the application of that science through technology, manufacture, engineering, materials science and many other disciplines.

Regulatory pressures are continuing. The recent US Food and Drug Administration Safety and Innovation Act (FDASIA) law [7] and the current discussions about quality metrics is an example, as is the stronger emphasis on data integrity, lifecycle, process validation and many other topics.

Public pressure continues to grow. The pharmaceutical industry is expected to not only do things right but to also reduce costs.

Location of manufacture is moving east. India, China and other countries have more dominant and extensive pharmaceutical industries.

All these factors have reinforced the need to not only understand pharmaceutical science, but to also understand where any potential risks lie, to mitigate and control these risks, and to ensure clear communication over the lifecycle of the drug to deliver safe and efficacious products to patients.

So industry has always recognised the importance of science and that risks should be quantified.

But there is probably one major factor that has been a significant gap, and that is the rationale has not been as clearly articulated as it could have been.

So QbD is not just about doing the science‐ and risk‐based work; it is also about explaining the story clearly, both verbally and in written form. Everyone who is a part of a product’s lifecycle has to be made aware of their role in ensuring product quality is in place at all stages – be they a development scientist, an operator on the manufacturing plant, a business leader, a regulatory department, a third party supplier, an equipment vendor or anyone else involved in this, at times, complicated supply chain.

1.4 ICH Q8–Q12

The following published ICH Guidelines set forth the principles about how a science‐ and risk‐based approach should be delivered.

The key ICH documents that make up the QbD ‘family’ are:

ICH Q8 (R2) – ‘Pharmaceutical Development’ [1].

ICH Q9 – ‘Quality Risk Management’ [8].

ICH Q10 – ‘Pharmaceutical Quality System’ [9].

ICH Q11 – ‘Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities’ [10].

ICH Q12 – Concept paper (at the time of writing this) – ‘Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management’ [11].

Taking each of these in turn, in brief:

ICH Q8 (R2) lays out the principles of using science for development of a drug product. It was the first ICH document to use the term ‘enhanced, Quality by Design’ approach. It includes two Parts and two Appendices. Part 1 is Pharmaceutical Development; Part 2 gives the Elements of Pharmaceutical Development, also introducing the terms laid out in the next section of this chapter, and details for Submissions; Appendix 1 is about differing approaches and gives examples of ‘minimal’ and ‘enhanced, Quality by Design’ approaches; Appendix 2 is Illustrative Examples. The development and manufacture of drug product with the application of ICH Q8 (R2) is discussed in detail in Chapter 6 of this book by Mark Gibson.

ICH Q9 lays out a framework on approaches for quality risk management, including risk initiation, assessment, control, review, communication and the tools to use. This framework is explained in more detail later in this book in Chapter 2 (Noel Baker). ICH Q9 has two Annexes: the first is on methods and tools to use, and the second is about applications. Importantly, ICH Q9 uses clear terms and definitions, and this author recommends being consistent and rigorous in using these terms, as they enable clearer communication both within a company and externally, be this to third parties or regulators.

ICH Q10, ‘Pharmaceutical Quality Systems’, lays out the fundamentals of what a quality system should cover, including management responsibility, and continual improvement of process performance and product quality and also of the quality system itself. Quality systems and knowledge management are discussed further in Chapter 3 of this book by Siegfried Schmitt.

ICH Q11, ‘Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)’, is a partner to Q8, and is based on similar principles, with extensive use of the term ‘enhanced’. Significantly, it covers API (active pharmaceutical ingredient) for both large and small molecules. It covers selection of starting materials, control strategy, process validation, submission and lifecycle and gives some examples. See Chapter 4 of this book by Gerry Steele for more details on the development and manufacture of small molecule drug substances.

ICH Q12, at the time of writing this book, is being drafted. The concept paper indicates it will cover the regulatory dossier, the quality system and lifecycle change management. Further reference to this and other regulatory guidance is given in Chapter 12 of this book.

All these guidelines form the basis of taking a science‐ and risk‐based approach to cover the product and process lifecycle.

1.5 QbD Terminology

The ICH Q8–Q11 documents have helped bring great clarity to terms and definitions. The pharmaceutical industry is complex and does not help itself when companies or individuals use different language to describe in essence the same thing. Indeed, there are examples where the regulators have been concerned when there has been a lack of clarity.

The following are some of the key terms on which QbD is founded:

Quality target product profile (QTPP).

Critical quality attribute (CQA).

Critical process parameter (CPP).

Critical materials attribute (CMA).

Design space (DS).

Control strategy (CS).

Lifecycle.

The following chapters in this book will expand, bring alive and give context to these terms.

Use of ICH terminology enables industry and regulators to use a common language both in‐house as well as, say, during regulatory applications. No longer it is acceptable to sloppily mix terms such as parameter and attribute. They mean completely different things and using terms precisely enables clarity of communication within development and on to manufacturing and, indeed, over the full product lifecycle. So, it is strongly recommended that ICH terminology is used wherever possible.

1.6 QbD Framework

The following ‘QbD framework’ given in Figure 1.1 will be used for this book.

Figure 1.1 A framework for QbD.

The following chapters will expand on and explain the elements of this diagram.

1.7 QbD Application and Benefits

QbD fundamentally links patient requirements to drug product and then drug substance. It is used to understand product specific requirements, which can then be supported by GMP [12].

QbD normally starts in development and progresses through to manufacturing, with the intent of producing a control strategy for commercial‐scale production. Sometimes, say, with a legacy product, QbD may start with an existing manufacturing process, for example, where a rich history of product and process knowledge is available.

QbD can be applied to small and large molecules, to drug substance and drug product, to vaccines, to combination products, to all or parts of a process, to novel drugs or to generics. It can be used by leading companies, by contract research or contract manufacturing companies or ‘virtual’ companies. It is up to the particular organisation to decide an appropriate level and application of QbD. QbD can be applied nationally or internationally.

Understanding the science underpinning a product and its associated risks helps prioritise what is important for manufacturing and so normally leads to efficiency gains and cost benefits. On the basis of a survey of several companies, Reference [13] concludes that companies found strong business benefits in using QbD. Part of the Concluding Remarks stated the following:

QbD seems strongly embedded in the companies interviewed. The benefits realized have met the expectations set by companies when they embraced QbD…. improved product and process understanding; a more systematic approach across the development portfolio; to continue to improve patient safety and efficiency; to improve manufacturing efficiency; and to improve development efficiency.

1.8 Regulatory Aspects

QbD is not mandatory, but product and process understanding is an expectation of regulators. So how does one obtain such understanding without considering QbD principles? With difficulty, is the answer!

As indicated earlier, legacy products with an established history can provide a wealth of qualitative data to confirm, for example, that ranges and acceptance criteria set during manufacturing have produced products of the appropriate quality. Such knowledge is extremely valuable, as regulators are not insisting that companies should go back and start doing experiments afresh to provide quantitative evidence (unless, of course, there is demonstrably a lack of product and process understanding), but they do expect an assessment has been made that products of the required quality can be produced.

It is significant that ICH documents are increasingly being referenced by regulators, in areas where compliance is expected. For example, validation is a regulatory requirement, and it is interesting that ICH Q8, Q9 and Q10 are referenced in guidelines for the United States, EU and elsewhere.

One other matter of importance relative to this area is the US FDA internal guideline Manual of Policies and Procedures, MAPP 5016.1, Applying ICH Q8(R2), Q9, and Q10 Principles to CMC Review [14]. As it says: ‘This MAPP outlines and clarifies how the chemistry, manufacturing, and controls (CMC) reviewers in the Office of Pharmaceutical Science (OPS) should apply the recommendations in the ICH Q8 (R2), Q9, and Q10 guidances to industry’. It also interestingly says: ‘OPQ product quality reviewers will consider ICH Q8(R2), Q9, and Q10 recommendations when reviewing applications that may or may not include QbD approaches’.

1.9 Summary

This book includes chapters on quality risk management, quality systems, knowledge management, development and manufacture of drug product and drug substance, the role of excipients, DoE, multivariate analysis, process analytical technology, manufacturing and process controls, analytical QbD and regulatory guidance. Within each of these chapters is a wealth of information written by practitioners who have been and are actively involved in this important subject.

So, in summary, QbD is about gaining product and process understanding, communicating it and delivering it, such that patients can continue to benefit from the medicines they may take.

Hopefully this book will help provide some tools to enable this to be put into practice.

1.10 References

[1] ICH Q8 (R2) (2009) Pharmaceutical Development, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf (accessed 30 August 2017).

[2] Juran, J.M. (1986) The Quality Trilogy: A Universal Approach to Managing for Quality, Quality Progress, Volume 19 (8), pp. 19–24.

[3] Juran, J.M. (1992) Juran on Quality by Design: The New Steps for Planning Quality into Goods and Services, 1st ed., The Free Press, New York, USA.

[4] Abboud, L. and Hensley, S. (2003) New Prescription for Drug Makers: Update the Plants, http://www.wsj.com/articles/SB10625358403931000 (accessed 30 August 2017).

[5] ICH (1990) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, http://www.ich.org/home.html (accessed 30 August 2017).

[6] FDA (2004) Guidance for Industry PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070305.pdf (accessed 30 August 2017).

[7] FDA (2012) Safety and Innovation Act (FDASIA), http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm (accessed 30 August 2017).

[8] ICH Q9 (2005) Quality Risk Management, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf (accessed 30 August 2017).

[9] ICH Q10 (2008) Pharmaceutical Quality System, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf (accessed 30 August 2017).

[10] ICH Q11 (2012) Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf (accessed 30 August 2017).

[11] ICH Q12 (2014) Concept paper: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (accessed 30 August 2017).

[12] MHRA (2014) Good Manufacturing Practice and Good Distribution Practice, https://www.gov.uk/guidance/good‐manufacturing‐practice‐and‐good‐distribution‐practice (accessed 30 August 2017).

[13] Kourti, T. and Davis, B. (2012) The Business Benefits of Quality by Design (QbD), Pharmaceutical Engineering – The Official Magazine of ISPE32 (4), 1–10.

[14] FDA (2011) Manual of Policies & Procedures (CDER) – Office of Pharmaceutical Science MAPP5016.1, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM242665.pdf (accessed 30 August 2017).

2

Quality Risk Management (QRM)

Noel Baker

AstraZeneca, United Kingdom

2.1 Introduction

Risk management principles have been established for several decades and are utilised by many business and government sectors to control and mitigate harm to the consumer. Examples of these sectors – though this is not an exhaustive list – include finance, insurance, occupational safety and public health as well as the government and independent agencies regulating these sectors [1].

Risk in the pharmaceutical sector is defined as the combination of the probability of occurrence of harm and the severity of the harm. For example, the well‐established law for Control of Substances Hazardous to Health (COSHH) implemented by the Health and Safety Executive (HSE) [2] in the United Kingdom requires businesses that undertake activities with hazardous substances to prevent or reduce exposure of workers to risks to health. The health risks associated with these hazardous substances are typically detailed in a Chemical Safety data sheet, which businesses can use to:

Find out what the health hazards are.

Decide how to prevent harm to health (perform a risk assessment).

Provide control measures to reduce harm to health.

Make sure they are used.

Keep all control measures in good working order.

Provide information, instruction and training for employees and others.

Provide monitoring and health surveillance in appropriate cases.

Plan for emergencies.

It is this shared understanding of COSHH, to determine and control risk to harm, which has enabled both industry and the regulators to effectively communicate and maintain appropriate awareness of, and control and prevent, risks to health.

A reason for using COSHH as an example here is to demonstrate that risk management is more than performing a one‐off risk assessment, this is important to understand the principles of quality risk management (QRM) described later in this chapter.

Specific definitions to help consolidate the differences between risk management and risk assessment are as follows:

Risk management is a systematic and methodical approach to developing an understanding of the variability of a process or procedure, including all associated hazards and failure modes, and implementing means of controlling or eradicating the risk in a given process or procedure.

Risk assessment is a one‐off activity that utilises an appropriate tool to capture perceived risks to a process or procedure and then with appropriate expertise to determine options to control or mitigate the risk. The output from the assessment will inform the business on appropriate mitigation plans and associated controls.

It was agreed by the International Conference on Harmonisation (ICH) members in 2003 that a shared understanding of risk management was generally absent across the pharmaceutical industry and associated regulating agencies. In addition, the ICH members felt that the pharmaceutical industry underutilised both risk management and risk assessment through a medicinal products lifecycle. Maintenance of the quality of a medicinal product supplied to the consumer, in this case a patient requiring a medicine to address an urgent need, is of critical importance to understanding sources of harm and ultimately prevent harm from occurring.

It was expected that without this shared understanding of QRM, resources and time could be consumed inefficiently by both Pharma and regulators while discussing potential and/or realised causes of harm, even as supply of product to patients declines. Achieving a shared understanding of the application of risk among stakeholders is extremely important, otherwise each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each