上海CMC培训 GMP and Quality System in the US.pptx

GMP and Quality System in the US,Jim Li, Ph.D. MBA June 29, 2010,2,Presentation Overview,21 CFR Part 210 and 211 美国药品GMP法规 ICH Q7A ICH的原料药指南 CGMP principles CGMP 基本原则 Quality systems based GMP approach 基于系统的GMP方法 FDA current concepts on process validation 目前FDA对工艺验证方面的观点,美国药品GMP法规,21 CFR Part 210 and 211,3,21 CFR Parts 210 and 211,21 CFR Parts 210 and 211 GMP Regulations for finished pharmaceuticals: 美国药品生产的GMP法规 Establish “what to” do, not “how to” 法规建立了药品生产规范的基本要求, 但未阐明如何做 Minimal standards Maximum flexibility Specific enough to address problems Technology neutral Scalable,History of CGMP Regulation CGMP法规的历史和发展,5,History of CGMP Regulation CGMP法规的历史和发展,6,Part 210: CGMP, General 通则,210.1 Status of current good manufacturing practice regulations Minimum CGMP requirements for methods, facilities or controls, manufacture, processing, packing, or holding of a drug Failure renders drug adulterated 伪劣 HCT/Ps subject to 1271 in addition to Part 211 210.2 Applicability of CGMP regulations. Parts 211-226, 600-680 and 1271 considered to supplement, Applicable to the operations in which he or she is engaged Phase 1 drug exempt from part 211 but subject to U.S.C. 351(a)(2)(B). 210.3 Definitions,7,Content of Part 211 内容,Subpart A General Provision 211.1 Scope 211.3 Definitions Subpart B Organization and Personnel 211.22 Responsibilities of quality control unit 211.25 Personnel qualifications 211.28 Personnel responsibilities 211.34 Consultants Subpart C Building and Facilities 211.42 Design and construction features 211.44 Lighting 211.46 Ventilation, air filtration, air heating and cooling 211.48 Plumbing 211.50 Sewage and refuse 211.52 Washing and toilet facilities 211.56 Sanitation 211.58 Maintenance,8,Subpart D Equipment 211.63 Equipment design, size, and location 211.65 Equipment construction 211.67 Equipment cleaning and maintenance 211.68 Automatic, mechanical, and electronic equipment 211.72 Filters Subpart E Control of Components and Drug Product Containers and Closures 211.80 General requirements 211.82 Receipt and storage of untested components, drug product containers, and closures 211.84 Testing and approval or rejection of components, drug product containers, and closures 211.86 Use of approved components, drug product containers, and closures,Content of Part 211 内容,Subpart E Control of Components and Drug Product Containers and Closures (cont.) 211.87 Retesting of approved components, drug product containers, and closures 211.89 Rejected components, drug product containers, and closures 211.94 Drug product containers and closures Subpart F Production and Process Controls 211.100 Written procedures; deviations 211.101 Charge-in of components 211.103 Calculation of yield 211.105 Equipment identification 211.110 Sampling and testing of in-process materials and drug products,9,211.111 Time limitations on production 211.113 Control of microbiological contamination 211.115 Reprocessing Subpart G Packaging and Labeling Controls 211.122 Materials examination and usage criteria 211.125 Labeling issuance 211.130 Packaging and labeling operations 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products 211.134 Drug product inspection 211.137 Expiration dating,Content of Part 211 内容,Subpart H Holding and Distribution 211.142 Warehousing procedures 211.150 Distribution procedures Subpart I Laboratory Controls 211.160 General requirements 211.165 Testing and release for distribution 211.167 Special testing requirements 211.170 Reserve samples 211.173 Laboratory animals 211.176 Penicillin contamination Subpart J Records and Reports 211.180 General requirements,10,211.182 Equipment cleaning and use log 211.184 Component, drug product container, closure, and labeling records 211.186 Master production and control records 211.188 Batch production and control records 211.192 Production record review 211.194 Laboratory records 211.196 Distribution records 211.198 Complaint files Subpart K Returned and Salvaged Drug Product 211.204 Returned drug products 211.208 Drug product salvaging,ICH的原料药指南,ICH Q7A: Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,11,ICH Q7A: GMP Guidance for APIs,GMP guidance for API manufacturing 有效成份生产的GMP指南 Scope chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination. Excludes Vaccines and whole cells whole blood and plasma blood and plasma derivatives gene therapy APIs,12,Application of GMP to API Manufacturing,13,Content of ICH Q7A 内容,Quality Management Personnel Building and Facilities Process Equipment Documentation and Records Materials Management Production and In-Process Controls Packaging and Identification Labeling of APIs and Intermediates Storage and Distribution Laboratory Controls Validation,14,Change Control Rejection and Re-Use of Materials Complaints and Recalls Contract Manufacturers (Including Laboratories) Agents, Brokers, Traders, Distributors , Repackers , and Relabelers Specific Guidance for APIs Manufactured by Cell Culture/Fermentation APIs for Use in Clinical Trials,15,ICH Q7A and System based CGMP Q7A与系统GMP的联系,CGMP 基本原则,CGMP Basic Principles,16,GMP Principles 基本原则,Quality built into product By “taking care” in making medicine Cant test quality into product Without/inadequate CGMP Product adulterated (defects need not be shown) Firm is responsible Non-compliance = eventual problems Superpotency/subpotency Contamination Misbranding Bioavailability Safety and efficacy,17,GMP Principles 基本原则,Scope Ingredients Finished dosage forms administered to humans/animals OTC, Rx products Biologicals, veterinary drugs Drugs undergoing study Manufacturers, test laboratories, packagers (including pharmacies) Excluded from CGMP Positron emission tomography Drug products compounded per section 503 Pharmacy Compounding,18,GMP Principles 基本原则,Current = dynamic Standards evolve over time Good practices Minimal standards Not best practices Unless “best” is, in fact current minimal Feasible and valuable No “percentage” in practice threshold Doesnt have to be “predominant” Enforceable even nobody is doing it Stronger case if someone is doing it,19,基于质量系统的GMP,Quality Systems Based GMP Approach,20,Quality Systems Based CGMP系统GMP的概念,Activities in drug firms can be organized into systems that are sets of operations and related activities Control of all systems helps to ensure the firm will produce drugs that are safe, have the identity and strength, and meet the quality and purity characteristics as intended Assure efficiency and consistency in inspection,21,Six Systems 六大系统,22,System Based Inspection 系统GMP检查,Inspection of Systems An inspection covers 2 or more systems with QS as mandatory Different numbers of systems may be covered depending on the purpose of the inspection Inspection of the systems as the basis for an overall CGMP decision Coverage of a system should be sufficiently detailed so that outcome reflects the state of control in that system for every profile class If a particular system is adequate, it should be adequate for all profile classes manufactured by the firm Complete inspection of one system may necessitate further follow-up of some items within another system,23,Common to All Systems 共同要求,Witten procedures Adherence to procedures Personnel qualification and training Investigation into any unexpected discrepancies Records for production, control and distribution Change control Computer qualification, validation, and security,24,Quality System 质量系统,Assures overall compliance with CGMP, internal procedures and specifications Quality control unit and all of its review & approval duties (e.g. change control, reprocessing, batch release, annual record review, validation protocols & reports, etc.) All product defect evaluations and evaluation of returned and savaged drug products See 21 CFR 211 Subparts B, E, F, G, I, J and K.,25,Quality System Assessment by FDA FDA对质量系统的评定,Evaluate whether the Quality Control Unit has fulfilled the responsibility review & approve all procedures related to production, quality control, and quality assurance assure the procedures are adequate for their intended use, including the associated recordkeeping systems Assess the data to identify quality problems and may link to other major systems for inspectional coverage.,26,Quality System Inspection Coverage质量系统检查内容,Product reviews Complaint reviews Discrepancy & failure investigations Change control Reprocess & rework,Returns & salvage Rejects Stability failures Quarantine Validation status Training/qualification,27,GMP,Pharmaceutical Quality System Model 质量系统模式,28,Facilities and Equipment System 生产设施和设备系统,Provide an appropriate physical environment and resources used to produce drugs of drug products Buildings and facilities along with maintenance Equipment qualifications Equipment calibration & preventative maintenance Cleaning & validation of cleaning procedures Utilities that are not intended to be incorporated into the product such as HAVC, compressed gases, steam and water systems See 21 CFR Subparts B, C, D and J,29,Facilities and Equipment System 生产设施检查内容,Facilities 生产设施 Cleaning & maintenance 清洗与维护 HAVC to prevent cross contamination 用高效过滤预防交叉污染 Layout to prevent mix-ups and contamination 合理布局预防 Lighting, sewage & refuse disposal, potable water, washing & toilet facilities 照明, 排污, 供应水, 清洗和厕所设施 Sanitation of the building 生产设施的消毒,30,Facilities and Equipment System 设备检查内容,Equipment 设备 IQ/OQ 安装与运行 Design, size, location 设计, 容量, 位置 Surface not reactive, additive, or absorptive 设备表面 Cleaning procedures and validation 清洗步骤和验证 Calibration and maintenance 校验与维护 Identification 鉴别 Controls to prevent contamination 防止污染的控制,31,Materials System 物料系统,Control finished products, components, including water or gases, that are incorporated into the product, containers and closures Validation of computerized inventory control processes Drug storage Distribution controls Records See 21 CFR 211 Subparts B, E, H and J,32,Materials System Coverage 物料系统检查内容,Identification & inventory Storage conditions Quarantine Sampling Testing,Retesting FIFO Water & process gas Distribution records Rejection,33,Production System 生产系统,Control the manufacture of drugs and drug products Batch compounding Dosage form production In-process sampling and testing Process validation Establishing, following, and documenting performance of approved manufacturing procedures See 21 CFR Subparts B, F, and J,34,Production System Coverage 生产系统检查内容,Charge-in of components Identification of equipment status Formulation Master & batch records Yields In-process controls,35,Time limits Process validation Other validation Cleaning, sterilization, & depyrogenation Environmental control & monitoring,Packaging and Labeling System 包装标签系统,Control the packaging and labeling of drugs and drug products Written procedures Label examination and usage Label storage and issuance Packaging and labeling operations controls Validation of these operations See 21 CFR Subparts B, G and J,36,Packaging and Labeling System Coverage 包装标签系统检查内容,Acceptance of materials Storage Control of different labeling Visual identification Control of filled unlabeled containers Packaging records Specimens of label Issuance of labeling Examination of finished labeled product,37,Packaging and Labeling System Coverage 包装标签系统检查内容,Lot numbers Separation between packaging and labeling lines Monitoring of printing devices Line clearance Expiration dates Temper-evident packaging requirements Validation,38,Laboratory Control System 实验室控制系统,Measures & activities related to: Laboratory procedures Testing Analytical methods development and validation or verification Stability program See 21 CFR 211 Subparts B, I, J and K,39,Laboratory Control System Coverage实验室控制系统检查内容,Staff Equipment & facility Calibration & maintenance Reference standards System suitability Samples Raw data,40,Methods validation & verification Procedures OOS Records Stability Reserve samples,State of Control 控制状况,If a system cannot be adequately assured quality, identity, strength and purity of the products from the system，the system is out of control. If any one system is out of control, the firm is out of control If one or more systems is/are out of control The outcome will be classified OAI Findings of deficiency may be used as evidence for taking appropriate advisory, administrative and/or judicial actions Type of action is based on the seriousness and/or the frequency of the problem Significant and/or a trend of deficiencies may result in the issuance of a Warning Letter or other regulatory actions,41,目前FDA对工艺验证方面的观点,FDA Current Concepts on Process Validation,42,Concepts on Process Validation 关于工艺验证的几个重要概念,43,Definition of Process Validation工艺验证的定义,The collection and evaluation of data, from the process design stage throughout 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.,44,Stages of Process Validation 工艺验证的步骤,45,Role of Process Understanding 工艺理解的作用,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,46,Stage1：Process Design 第一步：工艺设计,47,Stage 2: Process Qualification 第二步：工艺验证,48,Stage 2: PQ Protocol 验证方案的内容和要求,Manufacturing conditions including operating parameters, processing limits, and component inputs Data to be collected, when and how it will be evaluated Tests to be performed and AC for each significant processing step Sampling plan: sampling points, # of samples and frequency Criteria to draw conclusion if the process consistently produces quality products How to address deviations and handle nonconforming data No data excluded without a documented, science-based justification Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources Status of the validation of analytical methods Review and approval by appropriate departments and the quality unit,49,Stage 2: Protocol Execution and Report 验证方案的执行,Execution after the protocol reviewed and approved Departure must follow established procedure, justified and approved Follow CGMP requirements Commercial process and routine procedures Manufactured by personnel expected to routinely perform operation Should also cover utilities, material, and environment,50,Stage 2: Protocol Execution and Report 验证方案报告,Report should Discuss and cross-reference all aspects of the protocol Summarize and analyze data Evaluate any unexpected observations and data Discuss all nonconformances that has bearing on the validity of process Describe any corrective actions or changes to existing procedures and controls Conclusion on process: met the conditions, in a state of control If not, what should be accomplished before such a conclusion can be reached. Include review and approvals.,51,Stage 3: Continued Process Verification 第三步：连续工艺确认,Continually assure that the process remain