Process Validation FDA 工艺验证2011（英文原版）

Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 Guidance for Industry Process Validation: General Principles and Practices Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 10903 New Hampshire Ave. Silver Spring, MD 20993 Phone: 301-796-3400; Fax: 301-847-8714 druginfo@fda.hhs.gov http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 (Tel) 800-835-4709 or 301-827-1800 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 240-276-9300 http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm   U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 3 A. Process Validation and Drug Quality .......................................................................................... 3 B. Approach to Process Validation ................................................................................................... 4 III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION................................................................................................................... 5 IV. RECOMMENDATIONS.................................................................................................. 7 A. General Considerations for Process Validation .......................................................................... 7 B. Stage 1 ― Process Design.............................................................................................................. 8 1. Building and Capturing Process Knowledge and Understanding................................................... 8 2. Establishing a Strategy for Process Control.................................................................................... 9 C. Stage 2 ― Process Qualification................................................................................................. 10 1. Design of a Facility and Qualification of Utilities and Equipment ............................................... 10 2. Process Performance Qualification............................................................................................... 11 3. PPQ Protocol................................................................................................................................. 12 4. PPQ Protocol Execution and Report ............................................................................................. 13 D. Stage 3 ― Continued Process Verification ................................................................................ 14 V. CONCURRENT RELEASE OF PPQ BATCHES ...................................................... 16 VI. DOCUMENTATION...................................................................................................... 17 VII. ANALYTICAL METHODOLOGY.............................................................................. 17 GLOSSARY................................................................................................................................. 18 REFERENCES............................................................................................................................ 19 i Guidance for Industry1 Process Validation: General Principles and Practices 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 outlines the general principles and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle. 1 This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug Evaluation and Research (CDER), in cooperation with CDER’s Office of Pharmaceutical Sciences, the Center for Biologics Evaluation and Research (CBER), the Office of Regulatory Affairs (ORA) and the Center for Veterinary Medicine (CVM) at the Food and Drug Administration. 2 To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, the CBER guidance page at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or the CVM guidance page at http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm . Contains Nonbinding Recommendations The lifecycle concept links product and process development, qualification of the commercial manufacturing process,3 and maintenance of the process in a state of control during routine commercial production. This guidance supports process improvement and innovation through sound science. This guidance covers the following categories of drugs: • Human drugs • Veterinary drugs • Biological and biotechnology products • Finished products and active pharmaceutical ingredients (APIs or drug substances)4 • The drug constituent of a combination (drug and medical device) product This guidance does not cover the following types of products: • Type A medicated articles and medicated feed • Medical devices5 • Dietary supplements • Human tissues intended for transplantation regulated under section 361 of the Public Health Service Act6 This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining the type of information to include in a submission. This guidance also does not specifically discuss the validation of automated process control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing. 3 In this guidance, the term commercial manufacturing process refers to the manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material. 4 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7), available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Section XII of ICH Q7 describes in detail the principles for validating API processes. 5 Guidance on process validation for medical devices is provided in a separate document, Quality Management Systems – Process Validation, edition 2, available at http://www.ghtf.org/sg3/sg3-final.html. See infra note 6. 6 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 2 Contains Nonbinding Recommendations 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. II. BACKGROUND In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance).7 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDA’s current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. The revised guidance also provides recommendations that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical CGMPs for the 21st Century ― A Risk-Based Approach,” particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and concepts.8 This revised guidance replaces the 1987 guidance. FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)). A. Process Validation and Drug Quality Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist: • Quality, safety, and efficacy are designed or built into the product. • Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. 7 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to reference a process validation guidance prepared in cooperation with the Global Harmonization Task Force (GHTF). The principles and recommendations in that document, Quality Management Systems – Process Validation, edition 2 (available on the Internet at http://www.ghtf.org/sg3/sg3-final.html) are also useful to consider for drug manufacturing processes. 8 See “Pharmaceutical cGMPS for the 21st Century — A Risk-Based Approach: Second Progress Report and Implementation Plan,” available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm071836.htm. 3 Contains Nonbinding Recommendations • Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. B. Approach to Process Validation For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages. • Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. • Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. • Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. This guidance describes activities typical of each stage, but in practice, some activities might occur in multiple stages. Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial- scale studies. Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions. A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should: • Understand the sources of variation • Detect the presence and degree of variation • Understand the impact of variation on the process and ultimately on product attributes • Control the variation in a manner commensurate with the risk it represents to the process and product Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the 4 Contains Nonbinding Recommendations product. Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.9 Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify process or product problems or opportunities for process improvements that can be evaluated and implemented through some of the activities described in Stages 1 and 2. Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3. III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following: A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211. The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess...” (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes. 9 The statute and regulations described in section III of this guidance explain the requirement that the methods and facilities used for the manufacturing of drugs be operated and administered under control sufficient to assure that the identity, strength, purity, and quality of a drug are as they purport or are represented to possess. 5 Contains Nonbinding Recommendations Other CGMP regulations define the various aspects of validation. For example, § 211.110(a), Sampling and testing of in-process materials and drug products, requires that control procedures “. . . be estab