FDA guidance for PAT

Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) Pharmaceutical CGMPs September 2004 Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm and/or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 301-827-3800 http://www.fda.gov/cvm/guidance/published.html U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) September 2004 Pharmaceutical CGMPs Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION................................................................................................................. 1 II. GUIDANCE DEVELOPMENT PROCESS AND SCOPE ............................................... 2 III. BACKGROUND ................................................................................................................... 2 IV. PAT FRAMEWORK............................................................................................................ 4 A. Process Understanding .................................................................................................................. 6 B. Principles and Tools....................................................................................................................... 6 1. PAT Tools ........................................................................................................................................ 7 3. Risk-Based Approach..................................................................................................................... 11 4. Integrated Systems Approach ........................................................................................................ 12 5. Real Time Release.......................................................................................................................... 12 C. Strategy for Implementation....................................................................................................... 12 V. PAT REGULATORY APPROACH ................................................................................. 14 BIBLIOGRAPHY....................................................................................................................... 16 Contains Nonbinding Recommendations Guidance for Industry1 PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance is intended to describe a regulatory framework (Process Analytical Technology, PAT) that will encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance. Working with existing regulations, the Agency has developed an innovative approach for helping the pharmaceutical industry address anticipated technical and regulatory issues and questions. This guidance is written for a broad industry audience in different organizational units and scientific disciplines. To a large extent, the guidance discusses principles with the goal of highlighting opportunities and developing regulatory processes that encourage innovation. In this regard, it is not a typical Agency guidance. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. 1 This guidance was prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research (CDER) under the direction of Food and Drug Administration's Process Analytical Technology (PAT) Steering Committee with membership from CDER, Center for Veterinary Medicine (CVM), and Office of Regulatory Affairs (ORA). 1 Contains Nonbinding Recommendations II. SCOPE The scientific, risk-based framework outlined in this guidance, Process Analytical Technology or PAT, is intended to support innovation and efficiency in pharmaceutical development, manufacturing, and quality assurance. The framework is founded on process understanding to facilitate innovation and risk-based regulatory decisions by industry and the Agency. The framework has two components: (1) a set of scientific principles and tools supporting innovation and (2) a strategy for regulatory implementation that will accommodate innovation. The regulatory implementation strategy includes creation of a PAT Team approach to chemistry manufacturing and control (CMC) review and current good manufacturing practice (CGMP) inspections as well as joint training and certification of PAT review and inspection staff. Together with the recommendations in this guidance, our new strategy is intended to alleviate concern among manufacturers that innovation in manufacturing and quality assurance will result in regulatory impasse. The Agency is encouraging manufacturers to use the PAT framework described here to develop and implement effective and efficient innovative approaches in pharmaceutical development, manufacturing and quality assurance. This guidance addresses new and abbreviated new (human and veterinary) drug application products and specified biologics regulated by CDER and CVM as well as nonapplication drug products. Within this scope, the guidance is applicable to all manufacturers of drug substances, drug products, and specified biologics (including intermediate and drug product components) over the life cycle of the products (references to 21 CFR part 211 are merely examples of related regulation). Within the context of this guidance, the term manufacturers includes human drug, veterinary drug, and specified biologic sponsors and applicants (21 CFR 99.3(f)). We would like to emphasize that any decision on the part of a manufacturer to work with the Agency to develop and implement PAT is a voluntary one. In addition, developing and implementing an innovative PAT system for a particular product does not mean that a similar system must be developed and implemented for other products. III. BACKGROUND Conventional pharmaceutical manufacturing is generally accomplished using batch processing with laboratory testing conducted on collected samples to evaluate quality. This conventional approach has been successful in providing quality pharmaceuticals to the public. However, today significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, process analysis, and process control. Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which may result from the perception that our existing regulatory system is rigid and unfavorable to the introduction of innovative systems. For example, many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions. In addition, other scientific and technical issues have been 2 Contains Nonbinding Recommendations raised as possible reasons for this hesitancy. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines. Pharmaceuticals continue to have an increasingly prominent role in health care. Therefore pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along with the best principles of quality management to respond to the challenges of new discoveries (e.g., novel drugs and nanotechnology) and ways of doing business (e.g., individualized therapy, genetically tailored treatment). Regulatory policies must also rise to the challenge. In August 2002, recognizing the need to eliminate the hesitancy to innovate, the Food and Drug Administration (FDA) launched a new initiative entitled “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach.” This initiative has several important goals, which ultimately will help improve the American public's access to quality health care services. The goals are intended to ensure that: • The most up-to-date concepts of risk management and quality systems approaches are incorporated into the manufacture of pharmaceuticals while maintaining product quality • Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology • The Agency's submission review and inspection programs operate in a coordinated and synergistic manner • Regulations and manufacturing standards are applied consistently by the Agency and the manufacturer • Management of the Agency's Risk-Based Approach encourages innovation in the pharmaceutical manufacturing sector • Agency resources are used effectively and efficiently to address the most significant health risks Pharmaceutical manufacturing continues to evolve with increased emphasis on science and engineering principles. Effective use of the most current pharmaceutical science and engineering principles and knowledge — throughout the life cycle of a product — can improve the efficiencies of both the manufacturing and regulatory processes. This FDA initiative is designed to do just that by using an integrated systems approach to regulating pharmaceutical product quality. The approach is based on science and engineering principles for assessing and mitigating risks related to poor product and process quality. In this regard, the desired state of pharmaceutical manufacturing and regulation may be characterized as follows: • Product quality and performance are ensured through the design of effective and efficient manufacturing processes • Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance • Continuous real time quality assurance 3 Contains Nonbinding Recommendations • Relevant regulatory policies and procedures are tailored to accommodate the most current level of scientific knowledge • Risk-based regulatory approaches recognize – the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance – the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product This guidance, which is consistent with the Agency's August 2002 initiative, is intended to facilitate progress to this desired state. This guidance was developed through a collaborative effort involving CDER, the Center for Veterinary Medicine (CVM), and the Office of Regulatory Affairs (ORA).2 Collaborative activities included public discussions, PAT team building activities, joint training and certification, and research. An integral part of this process was the extensive public discussions at the FDA Science Board, the Advisory Committee for Pharmaceutical Science (ACPS), the PAT-Subcommittee of ACPS, and several scientific workshops. Discussions covered a wide range of topics including opportunities for improving pharmaceutical manufacturing, existing barriers to innovation, possible approaches for removing both real and perceived barriers, and many of the principles described in this guidance. IV. PAT FRAMEWORK The Agency considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The goal of PAT is to enhance understanding and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. Consequently, the tools and principles described in this guidance should be used for gaining process understanding and can also be used to meet the regulatory requirements for validating and controlling the manufacturing process. Quality is built into pharmaceutical products through a comprehensive understanding of: • The intended therapeutic objectives; patient population; route of administration; and pharmacological, toxicological, and pharmacokinetic characteristics of a drug • The chemical, physical, and biopharmaceutic characteristics of a drug 2 For products regulated by the Center for Biologics Evaluation and Research (CBER), manufacturers should contact CBER to discuss applicability of Process Analytical Technology. 4 Contains Nonbinding Recommendations • Design of a product and selection of product components and packaging based on drug attributes listed above • The design of manufacturing processes using principles of engineering, material science, and quality assurance to ensure acceptable and reproducible product quality and performance throughout a product's shelf life Using this approach of building quality into products, this guidance highlights the necessity for process understanding and opportunities for improving manufacturing efficiencies through innovation and enhanced scientific communication between manufacturers and the Agency. Increased emphasis on building quality into products allows more focus to be placed on relevant multi-factorial relationships among material, manufacturing process, environmental variables, and their effects on quality. This enhanced focus provides a basis for identifying and understanding relationships among various critical formulation and process factors and for developing effective risk mitigation strategies (e.g., product specifications, process controls, training). The data and information to help understand these relationships can be leveraged through preformulation programs, development and scale-up studies, as well as from improved analysis of manufacturing data collected over the life of a product. Effective innovation in development, manufacturing and quality assurance would be expected to better answer questions such as the following: • What are the mechanisms of degradation, drug release, and absorption? • What are the effects of product components on quality? • What sources of variability are critical? • How does the process manage variability? A desired goal of the PAT framework is to design and develop well understood processes that will consistently ensure a predefined quality at the end of the manufacturing process. Such procedures would be consistent with the basic tenet of quality by design and could reduce risks to quality and regulatory concerns while improving efficiency. Gains in quality, safety and/or efficiency will vary depending on the process and the product, and are likely to come from: Reducing production cycle times by using on-, in-, and/or at-line measurements and controls • • • • • • Preventing rejects, scrap, and re-processing Real time release Increasing automation to improve operator safety and reduce human errors Improving energy and material use and increasing capacity Facilitating continuous processing to improve efficiency and manage variability – For example, use of dedicated small-scale equipment (to eliminate certain scale- up issues) 5 Contains Nonbinding Recommendations This guidance facilitates innovation in development, manufacturing and quality assurance by focusing on process understanding. These concepts are applicable to all manufacturing situations. A. Process Understanding A process is generally considered well understood when (1) all critical sources of variability are identified and explained; (2) variability is managed by the process; and, (3) product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions. The ability to predict reflects a high degree of process understanding. Although retrospective process capability data are indicative of a state of control, these alone may be insufficient to gauge or communicate process understanding. A focus on process understanding can reduce the burden for validating systems by providing more options for justifying and qualifying systems intended to monitor and control biological, physical, and/or chemical attributes of materials and processes. In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an on- line process analyzer and a conventional test method on collected samples may be the only available validation option. In some cases, this approach may be too burdensome and may discourage the use of some new technologies. Transfer of laboratory methods to on-, in-, or at-line methods may not necessarily be PAT. Existing regulatory guidance documents and compendial approaches on analytical method validation should be considered. Structured product and process development on a small scale, using experimental design and on- or in-line process analyzers to collect data in real time, can provide increased insight and understanding for process development, optimization, scale-up, technology transfer, and control. Process understanding then continues in the production phase when other variables (e.g., environmental and supplier changes) may possibly be encountered. Therefore, continuous learning over the life cycle of a product is important. B. Principles