ICH Q9-Quality Risk Management(英文)

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE DRAFT CONSENSUS GUIDELINE QUALITY RISK MANAGEMENT Q9 Released for Consultation at Step 2 of the ICH Process on 22 March 2005 by the ICH Steering Committee At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Steering Committee to the regulatory authorities of the three ICH regions (the European Union, Japan and the USA) for internal and external consultation, according to national or regional procedures. QUALITY RISK MANAGEMENT Draft ICH Consensus Guideline Released for Consultation on 22 March 2005, at Step 2 of the ICH Process TABLE OF CONTENTS 1. INTRODUCTION .................................................................................................1 2. SCOPE....................................................................................................................2 3. PRINCIPLES OF QUALITY RISK MANAGEMENT.....................................2 4. GENERAL QUALITY RISK MANAGEMENT PROCESS .............................2 4.1 Responsibilities.......................................................................................................3 4.2 Initiating a Quality Risk Management Process....................................................3 4.3 Risk Assessment .....................................................................................................3 4.4 Risk Control ............................................................................................................4 4.5 Risk Communication ..............................................................................................5 4.6 Risk Review.............................................................................................................5 5. RISK MANAGEMENT TOOLS ..........................................................................6 5.1 Basic Risk Management Facilitation Methods .....................................................6 5.2 Informal Risk Management ...................................................................................6 5.3 Hazard Analysis and Critical Control Points (HACCP) .......................................6 5.4 Hazard Operability Analysis (HAZOP) .................................................................7 5.5 Failure Mode Effects Analysis (FMEA).................................................................7 5.6 Failure Mode, Effects and Criticality Analysis (FMECA)....................................8 5.7 Fault Tree Analysis (FTA) .....................................................................................8 5.8 Preliminary Hazard Analysis (PHA) .....................................................................9 5.9 Risk Ranking and Filtering ...................................................................................9 5.10 Supporting Statistical Tools...................................................................................9 6. INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND REGULATORY OPERATIONS........................................10 7. DEFINITIONS ....................................................................................................11 8. REFERENCES....................................................................................................13 i Quality Risk Management Annex I: Potential Opportunities for Conducting Quality Risk Management............... 14 I.1 Quality Risk Management as Part of Integrated Quality Management........... 14 I.2 Quality Risk Management as Part of Regulatory Operations ........................... 15 I.3 Quality Risk Management as Part of Development........................................... 15 I.4 Quality Risk Management for Facilities, Equipment and Utilities .................. 16 I.5 Quality Risk Management as Part of Materials Management.......................... 17 I.6 Quality Risk Management as Part of Production............................................... 18 I.7 Quality Risk Management as Part of Laboratory Control and Stability Studies............................................................................................ 18 I.8 Quality Risk Management as Part of Packaging and Labelling ....................... 18 I.9 Quality Risk Management as Part of Continuous Improvement ...................... 18 ii QUALITY RISK MANAGEMENT 1. INTRODUCTION Risk management principles are effectively utilized in many areas of business and government including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies regulating these industries. Although there are some examples of the use of quality risk management in the pharmaceutical industry today, they are limited and do not represent the full contributions that risk management has to offer. In addition, the importance of quality systems has been recognized in the pharmaceutical industry and it is becoming evident that quality risk management is a valuable component of an effective quality system. It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place different probability on each harm’s occurring and attribute different severities of the harm. In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, the protection of the patient by managing the risk to quality should be considered of prime importance. The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail some degree of risk. The risk to its quality is just one component of the overall risk. It is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of the drug (medicinal) product remain consistent with those used in the clinical studies. An effective quality risk management approach can further ensure the high quality of the drug (medicinal) product to the patient in providing a proactive means to identify and control potential quality issues during development and manufacturing. Additionally, use of quality risk management can improve the decision making if a quality problem arises. Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight. The purpose of this document is to serve as a foundational or resource document that is independent yet supports other ICH Quality documents and complements existing quality practices, requirements, standards, and guidelines within the pharmaceutical industry and regulatory environment. It will specifically provide guidance on the principles and some of the tools of quality risk management that can enable more effective and consistent risk based decisions, both by regulators and industry, regarding the quality of drug substances and drug (medicinal) products across the product lifecycle. It is not intended to create any new expectations beyond the current regulatory requirements. Although a systematic approach to quality risk management is generally preferred, it is neither always appropriate nor necessary to use a formal risk management process. The use of informal risk management processes can also be acceptable. Appropriate use of quality risk management can facilitate but does not obviate industry’s obligation to comply with regulatory requirements and does not replace appropriate communications between industry and regulators. 1 Quality Risk Management 2. SCOPE This guideline provides principles and examples of tools of quality risk management that can be applied to all aspects of pharmaceutical quality including development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances and drug (medicinal) products, biological and biotechnological products, including the use of raw materials, solvents, excipients, packaging and labeling materials. 3. PRINCIPLES OF QUALITY RISK MANAGEMENT Two primary principles of quality risk management are: • • The evaluation of the risk to quality should ultimately link back to the protection of the patient; The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk and be based on scientific knowledge. 4. GENERAL QUALITY RISK MANAGEMENT PROCESS Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. A model for quality risk management is outlined in the diagram (Figure 1). The emphasis on each component of the framework might differ from case to case but a robust process will incorporate consideration of all the elements at an appropriate level of detail. Figure 1: Overview of quality risk management process Risk ReviewRisk Communication Risk Assessment Risk Evaluation Initiate Risk Management Process unacceptable Risk Control Ri sk M an ag em en t t oo ls Output / Results of the Risk Management Process Risk Analysis Risk Reduction acceptable Risk Identification Risk Communication Review Events Risk Acceptance Risk Acceptance 2 Quality Risk Management Decision nodes are not shown in the diagram above because decisions can occur at any point in the process. These decisions might be to return to the previous step and seek further information, to adjust the risk models or even to terminate the risk management process based upon information that supports such a decision. 4.1 Responsibilities Decision makers should take responsibility for coordinating quality risk management across various functions and departments of their organization. The decision makers should ensure that a quality risk management process is defined, appropriate resources are involved and the quality risk management process is reviewed. Risk management activities are usually, but not always, undertaken by interdisciplinary teams dedicated to the task. Teams formed for quality risk management activities should include experts from the appropriate areas involved in addition to individuals who are knowledgeable of the quality risk management process. 4.2 Initiating a Quality Risk Management Process Quality risk management includes systematic processes designed to coordinate, facilitate and improve science-based decision making with respect to risk. Possible steps used to initiate and plan a quality risk management process might include the following: • • • • • Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk; Assemble background information and data on the potential hazard, harm or human health impact relevant to the risk assessment; Define how decision makers will use the information, assessment and conclusions; Identify a leader and necessary resources; Specify a timeline and deliverables for the risk management process. 4.3 Risk Assessment Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. The steps include risk identification, risk analysis and risk evaluation. Quality risk assessments begin with a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool (See Examples in Section 5) and the types of information needed to address the risk question will be more readily identifiable. As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often helpful: 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)? Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, 3 Quality Risk Management theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the “What might go wrong?” question, including identifying the possible consequences. This provides the basis for further steps in the quality risk management process. Risk analysis is the estimation of the risk associated with the identified hazards. It is the process that focuses on the second and third questions, seeking the likelihood that risks identified in risk identification might occur and an ability to detect them. Risk evaluation compares the identified and analyzed risk against given risk criteria. A qualitative or quantitative process might be used to assign the probability and severity of a risk. Risk evaluations consider the strength of evidence for all three of the fundamental questions. In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. Revealing assumptions and reasonable sources of uncertainty will enhance confidence in this output and/or help identify its limitations. Typical sources of uncertainty include gaps in knowledge (e.g., gaps in pharmaceutical science and process understanding), sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of problems. The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a numerical probability scale from 0 to 1 (0% to 100%) is used. Alternatively, risk can be expressed using qualitative descriptors, such as “high”, “medium”, or “low”, and they should be defined in as much detail as possible. In quantitative risk assessments, a risk estimate provides the likelihood of a specific consequence, given a set of risk- generating circumstances. Thus, quantitative risk estimation is useful for one particular consequence at a time. Alternatively, some risk management tools use a relative risk measure to combine multiple levels of severity and probability into an overall estimate of relative risk. The intermediate steps within a scoring process can sometimes employ quantitative risk estimation. 4.4 Risk Control Risk control includes decision making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional to the significance of the risk. Decision makers might use different processes for understanding the optimal level of risk control including benefit-cost analysis. Risk control might focus on the following questions: • • • • Is the risk above an acceptable level? What can be done to reduce, control or eliminate risks? What is the appropriate balance among benefits, risks and resources? Are new risks introduced as a result of the identified risks being controlled? Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds an acceptable level. Risk reduction might include actions taken to mitigate the severity and probability of harm. Processes that improve the detectability of 4 Quality Risk Management hazards and quality risks might also be used as part of a risk control strategy. By the implementation of risk reduction measures, new risks may be introduced into the system or the significance of other existing risks might be increased. Hence, it might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk. Risk acceptance is a decision to accept risk. Risk acceptance can be a formal decision to accept the residual risk or it can be a passive decision in which residual risks are not specified. For some types of harms, even the best quality risk management practices might not entirely eliminate risk. In these circumstances, it might be agreed that the optimal quality risk management strategy has been applied and that quality risk is reduced to an acceptable level. This acceptable level will depend on many parameters and should be decided on a case-by-case basis. 4.5 Risk Communication Risk communication is the exchange or sharing of information about risk and its management between the decision makers and others. Parties can communicate at any stage of the risk management process. Sometimes, a formal risk communication process is developed as a part of risk management. This might include communication among many interested parties; e.g., regulators and industry, industry and the patient, within a company, industry or regulatory authority, etc. The included information might relate to the existence, nature, form, probability, severity, acceptability, treatment, detectability or other aspects of risks to quality. This exchange need not be carried out for each and every risk acceptance. In the event that the communication is between the industry and regulatory authorities concerning quality risk management decisions, these might be made through existing channels as specified in regulations and guidances. The output of the quality risk management process should be documented when a formal process has been utilized. 4.6 Risk Review The output/results of the risk management process should be reviewed to take into account new knowledge and experience. Once a quality risk management process has been initiated, that process should continue to be utilized for events that might impact the original quality risk management decision whether these are planned (e.g., results of product review, inspections, audits, change control) or unplanned (e.g., root cause from failure investigations, recall). Risk management should be an ongoing quality management process and a mechanism to perform periodic review of events should be implemented. The frequency of the review should be based upon the level of risk. Risk review might include reconsideration of risk acceptance decisions (section 4.4). 5 Quality Risk Management 5. RISK MANAGEMENT TOOLS Quality risk management tools support a scientific and practical approach to decision- making by providing documented, transparent and reproducible methods to accomplish steps of the quality risk management process (Chapter 4). The purpose of this section is to provide a general overview and references of some of the primary tools that might be used in quality risk management. The references are included as an aid to gain more knowledge and detail on the particular tool. This is not an exhaustive list. Failure Mode Effects Analysis (FMEA); • • • • • • • • • • • • Failure Mode, Effects and Criticality Analysis (FMECA); Fault Tree Analysis (FTA); Hazard Analysis and Critical Control Points (HACCP); Hazard Operability Analysis (HAZOP); Preliminary Hazard Analysis (PHA); Risk ranking and filtering; Supporting statistical tools. It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and drug (medi