Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing

Hamid Mollah, Harold Baseman, Mike Long, Hamid Mollah, Harold Baseman, Mike Long

• Publisher: Wiley
• Year: 2013
• ISBN:
  9781118514344
• Edition: 1
• Topic: Scienze biologiche
• Subtopic: Biotecnologia

Sets forth tested and proven risk management practices in drug manufacturing

Risk management is essential for safe and efficient pharmaceutical and biopharmaceutical manufacturing, control, and distribution. With this book as their guide, readers involved in all facets of drug manufacturing have a single, expertly written, and organized resource to guide them through all facets of risk management and analysis. It sets forth a solid foundation in risk management concepts and then explains how these concepts are applied to drug manufacturing.

Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing features contributions from leading international experts in risk management and drug manufacturing. These contributions reflect the latest research, practices, and industry standards as well as the authors' firsthand experience. Readers can turn to the book for:

• Basic foundation of risk management principles, practices, and applications
• Tested and proven tools and methods for managing risk in pharmaceutical and biopharmaceutical product manufacturing processes
• Recent FDA guidelines, EU regulations, and international standards governing the application of risk management to drug manufacturing
• Case studies and detailed examples demonstrating the use and results of applying risk management principles to drug product manufacturing
• Bibliography and extensive references leading to the literature and helpful resources in the field

With its unique focus on the application of risk management to biopharmaceutical and pharmaceutical manufacturing, this book is an essential resource for pharmaceutical and process engineers as well as safety and compliance professionals involved in drug manufacturing.

Chapter 1: Background and Introduction

Harold S. Baseman and A. Hamid Mollah

Companies wishing to manufacture and distribute regulated health care products to the population of the United States must comply with the U.S. Food and Drug Administration (FDA) regulations, better known as Current Good Manufacturing Practices (CGMPs). 21 CFR 211.100 of U.S. CGMPs states “There shall be written procedures for product and process control designed to assure that drug products have identity, strength, quality, and purity they purport or are represented to possess …”[1]. Regulations are a legal requirement and this CFR, among others, mandates that companies must take active steps to assure product quality.

Companies and individuals working for health care industries have an obligation to provide products that are safe and effective to their customers, users, and patients. The regulations codify this obligation, thus making it a legal requirement; but the obligation to provide safe and effective products is also a moral and ethical obligation that goes beyond the legal regulatory requirements. People working for pharmaceutical companies also have a duty of loyalty to operate for the welfare of the company. In other words, they have an additional obligation to operate efficiently and earn optimal profits within the framework of regulatory requirements and ethics. Companies and individuals must be able to align these legal requirements and business obligations.

The failure to provide safe and effective products will likely result in loss of business as well as other legal consequences. However, in recent years, it seems that the industry has faced pressure and challenges to balance these requirements and obligations. It has become more difficult to remain in compliance, serve customers, and be competitive. Companies have struggled with balancing regulatory requirements, scientific elements of product development and manufacture, and maintaining a productive business situation.

The pharmaceutical and biopharmaceutical industries are facing financial pressure because of the high cost of drug development and manufacturing as well as generic competition. There are business drivers and regulatory expectations for innovative approaches to speed up pharmaceutical product development and licensure, optimally use resources, and to assure continued product quality and patient safety. The industry must apply comprehensive risk management and innovative approaches to product life cycle not only to enhance patient safety but also to improve business outcomes. Hence, it is critical to understand appropriate risk management tools and approaches that would be acceptable to regulatory agencies. Other industries, including closely related ones such as the medical devices and food industries, have adopted a more structured approach to this subject than we have traditionally used. The application of risk management to medical devices is expected by medical device regulatory bodies [2–4]. Hazard analysis and critical control points (HACCP) is used in the food industry to identify potential food safety hazards, so that key actions, known as critical control points (CCPs), can be taken to reduce or eliminate the risk of the hazards being realized [5].

In the summer of 2002, the FDA announced an initiative to “enhance and modernize” pharmaceutical regulation. In the fall of 2004, it published the final report on Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach. This paper represented an attempt to “enhance and modernize” pharmaceutical regulation. It not only speaks of product quality and patient safety but also of the need for innovation and the cost of drug development and manufacture [6].

The paper offered initiatives and recommendations with the following objectives in mind:

1. Encourage the early adoption of new technological advances by the pharmaceutical industry.

2. Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance.

3. Encourage implementation of risk-based approaches that focus the attention of both industry and agency on critical areas.

4. Ensure that regulatory review, compliance, and inspection policies are based on the state-of-the-art pharmaceutical science.

5. Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by further integrating enhanced quality systems approaches into the agency's business processes and regulatory policies concerning review and inspection activities.

The reference to risk-based approaches mentioned in (3) is of particular interest to the subject of this book. Facing limited resources, the agency recognized that to best serve public interest, decisions on resource allocation, focus, and prioritization should be based on risk to patient safety and public safety. Those in the industry are impacted by the approach. For instance, a firm manufacturing over-the-counter (OTC) oral dosage products and having a relatively clean compliance record would likely be inspected less often or receive less attention than a firm aseptically manufacturing sterile injectables and having a more problematic compliance record.

The prioritization of resources based on risk to public safety make sense and it led to better productivity and effectiveness. It was logical that the agency would expect the industry to employ similar approach to make resource- and focus-related decisions. Firms are encouraged to use risk to product quality and patient safety as a criterion for decision making.

Risk management and assessment are not new. People use risk assessment as a way to help make decisions every day. When you walk across the street, drive through a yellow light, or order a meal—you employ a level of risk assessment, weighing the impact of a hazard and the likelihood of the hazard happening against anticipated benefit. Companies do the same in many aspects of corporate functioning from financial decisions, to investments, to plant locations, and product development. If their objective is to serve their customer, then it makes sense that they would employ this type of decision making to manufacturing and response to patient needs and safety.

In 2005, the ICH (International Conference for Harmonization) issued Q9 Guidance on quality risk management. ICH Q9 was later issued in 2006 as Guidance for Industry by the FDA and adopted by the EU as Annex 20 of the European GMPs in 2011. The guidance remains optional for pharmaceutical product manufacturers in the United States and Europe [7]. However, references to risk assessments and criticism for not employing such measures have appeared in FDA warning letters dating back to 2006 [8]. Regulatory citations indicated that companies face questions on how decisions related to product quality were made, if assessments of the risk of process steps and changes to product quality were not employed. If a company's obligation is product quality and patient safety, it should take such risks into account when making manufacturing decisions. How else could it make these decisions?

In the spring of 2005, at the PDA (Parenteral Drug Association) annual meeting in Chicago, the leaders of the Process Validation Interest Group asked its members for their topic of most interest or concern. The overwhelming answer was risk management. The leaders then asked how many of those individuals were currently utilizing or were aware of efforts within their respective organizations to utilize risk management. Only a few raised their hands. This was not unexpected. ICH Q9 was being issued and reviewed. Papers presented at the PDA annual meeting spoke about the need for risk management.

One person in the meeting noted that their risk assessment efforts were unsuccessful, as they were subject to criticism from local regulators, because of the misuse of the risk management. The misuse apparently involved using risk assessment to identify process-related risk, but then failing to take steps to mitigate that risk. The objective of risk management, as discussed later, is not just to identify risk, but to mitigate and reduce risk, thus improving the manufacturing process.

The outcome of the 2005 meeting was an initiative by the PDA Science Advisory Board to create a task force of industry professionals to investigate and develop a model for the use of risk management for aseptic processes. This would later become the basis of PDA Technical Report No. 44 Quality Risk Management for Aseptic Processes, as well as later efforts on companion documents and reports. The task force was made up of 15 individuals from sterile drug manufacturing within 15 different organizations and companies. Only a few had direct experience with formal risk management and that experience had largely come from the medical device industry. The use of formal risk assessment and management techniques for pharmaceutical and biopharmaceutical manufacturing appeared to be a work in progress at best.

In 2008, the PDA published Technical Report No. 44. The technical report presented concepts and a program for evaluating the risk of process failure in making decisions for the manufacture of sterile drug products using aseptic processing. One point presented in TR 44 was that aseptic processing was not necessarily risky. The hazards associated with aseptic processing were significant. However, if well controlled, the risk should not necessarily be high. In other words, determining the risk was the objective of risk management—rather, process improvement through control and mitigation were the key objectives [9].

Since 2004, more and more FDA guidance has included recommendations for risk management and assessments. In the 2008 draft version of the FDA Guidance for Industry on the General Principles of Process Validation, the FDA included a modest level of references to risk assessments in the text. Some industry comments questioned the apparent “lack” of focus on risk in the document. When asked, FDA representatives responded that they felt risk management principles and methodology were so prevalent in the fabric of industry operation that it was not necessary to emphasize it in the guidance. The number of references to risk management and assessment nearly doubled in the 2011 final version [10–12].

Throughout the next several years, industry standards, guidance, and technical reports were prepared to address risk-based decision-making. In 2001 through 2011, the ISPE (International Society of Pharmaceutical Engineering) published a series of industry guides, employing risk-based methods for design and qualification of pharmaceutical manufacturing facilities and processes, including Volume 5 of its Facilities Baseline Guides: Commissioning and Qualification (with revisions in progress) and the ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities, Systems, and Equipment. These guides presented methods for qualifying pharmaceutical manufacturing facilities incorporating risk to product-quality-based decision criteria. The baseline guide introduced the concept of evaluating systems based on their relative impact to product quality [13].

In 2007, the ASTM (American Society for Testing and Methodology) issued E2500-07, the Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. E2500-07 discussed a risk- and science-based approach to the qualification or verification of equipment used to manufacture and test pharmaceutical products. It was an effort to use risk to product quality and patient safety as important factors when deciding what to qualify, how to qualify, when to qualify, and who should be involved in the qualification and approval effort [14].

When the ASTM committee E55 was assembled to create and review what would become E2500-07, they discovered that while many, companies recognized that quality risk management was an important tool for making product manufacturing decisions, few, had real experience or input into practical means to accomplish this in an effective manner. As such, the committee was faced with creating desired state approaches rather than reflecting tried and true best practices. Throughout related meetings and discussions, it appeared that most companies had some appreciation for the need to manage risk to product quality and as a part of that to take steps to assess and document the assessment of that risk. However, it also appeared that companies did not always utilize risk management techniques optimally or effectively in making decisions. One is reminded of a company visited not long after the 2005 PDA meeting. The company had a vigorous risk management program, complete with corporate directives, policies, procedures, and a risk management department. They had volumes of carefully filled out risk assessments, which were placed in binders and displayed. When asked what these risk assessments were used for, the response was to assess risk. The assessment forms were meticulously filled in, reviewed, and approved. After that, they were placed in binders and placed on a shelf. Whether the information was used to help make any decisions was not apparent. This illustrates the misconception that the objective of risk management is to merely assess or categorize risk, rather than using it to provide information to help make informed decisions and improve the process.

The objective of risk management should be to improve the process by reducing or mitigating risks. There needs to be a clear link between risk management principles as described in guidances such as ICH Q9 and other guidances and practical manufacturing activities. The book offers the reader multiple perspectives and approaches to risk management and assessments. The chapters in this b...