Designation:E3106−18
Standard Guide for
Science-Based and Risk-Based Cleaning
Process Development and Validation1
基于科学和风险的清洁工艺开发和验证的标准指
南
This standard is issued under the fixed designation E3106;the number immediately following
the designation indicates the year of original adoption or,in the case of revision,the year of last
revision.A number in parentheses indicates the year of last reapproval.A superscript epsilon(´)
indicates an editorial change since the last revision or reapproval.
1.Scope范围
1.1This guide applies the life-cycle approach to cleaning process validation,which includes the development,qualification,and verification of cleaning processes.It is applicable to pharmaceuticals (including active pharmaceutical ingredients(APIs);dosage forms;and over-the-counter,veterinary, biologics,and clinical supplies)and is also appli-cable to other health,cosmetics,and consumer products.
此指南将生命周期方法应用于清洁工艺验证（包括清洁工艺方法开发、确认、验证）。它将适用于多种类型药物（包括API、剂型、OTC、兽用药、生物药、临床用药），并且适用于其他保健品、化妆品和消费品。
1.2This guide is focused only on the cleaning of equipment product contact surfaces and does not cover disinfection or non-product contact surfaces(which are covered under other existing guides: Ref(
1),2USP<1072>,Guide E2614,and ISO14698).
此指南仅关注设备与产品接触面的清洁，不包括设备消毒或不与产品接触的表面（此部分指导见其他指南：USP<1072>，指南E2614,ISO14698）。
1.3The values stated in SI units are to be regarded as standard.No other units of measurement are included in this standard.
本指南使用SI单位作为标准单位。除此之外指南内未使用其他计量单位。
1.4This standard does not purport to address all of the safety concerns,if any,associated with its use.It is the responsibility of the user of this standard to establish appro-priate safety,health,and environmental practices and deter-mine the applicability of regulatory limitations prior to use.
本标准指南的目的并不是解决与使用相关的所有安全问题(如果有的话)。本标准的使用者有责任在使用前建立适当的安全、健康和环境规范，并确定法规限制的适用性。
1.5This international standard was developed in accor-dance with internationally recognized principles on standard-ization established in the Decision on Principles for the Development of
International Standards,Guides and Recom-mendations issued by the World Trade Organization Technical Barriers to Trade(TBT)Committee.
2.Referenced Documents参考文献
2.1ASTM Standards:3ASTM标准
E1325Terminology Relating to Design of Experiments
E2476Guide for Risk Assessment and Risk Control as it Impacts the Design,Development,and Operation of PAT Processes for Pharmaceutical Manufacture
E2614Guide for Evaluation of Cleanroom Disinfectants
2.2ICH Standards:4
Q8Pharmaceutical Development Q9Quality Risk Management
Q10Pharmaceutical Quality System
Q11Development and Manufacture of Drug Substances
2.3ISO Standards:5
ISO9000Quality Management Systems—Fundamentals and Vocabulary
ISO14698Guide for Evaluation of Cleanroom Disinfectants,Parts1–3.
2.4Federal Standards:6
21CFR211.67Equipment Cleaning and Maintenance
2.5USP Standards:7
USP<1072>Disinfectants and Antiseptics
3.Terminology术语
3.1Definitions定义:
3.1.1acceptable daily exposure,ADE,n—represents a dose that is unlikely to cause an adverse effect if an individual is exposed,by any route,at or below this dose every day for a lifetime.
可接受的日暴露量，ADE，n—在个体一生中的每天通过各种途径暴露于低于或等于某毒物一个剂量下，不太可能引起个体副作用的剂量。
3.1.1.1Discussion—This is the term used in the ISPE Risk-MaPP Guide(1)and is equivalent to the acceptable daily intake(ADI)but is associated with any route of administration.
讨论—此术语在ISPE基于风险的药品生产指南中也被使用，并且相当于指南中的可接受每日摄入量（ADI）。但是此术语的任何途径包括任何给药方式。
3.1.2acceptable daily intake,ADI,n—measure of the amount of a specific substance(originally applied for a food additive,later also for a residue of a veterinary drug or pesticide)in food or drinking water that can be ingested(orally)on a daily basis over a lifetime without an appreciable health risk.
可接受的每日摄入量，ADI—指食物或饮用水中某一特定物质（最初仅指食物添加剂，后来范围扩至兽药或杀虫剂残留）的量，该物质（口服）在人的一生中每天都能被消化，不会对健康造成明显的危害。
Ref(2)
3.1.2.1Discussion—This term is more commonly associated with food and the oral route of administration.
讨论—此术语常指的是食物和口服途径。
3.1.3cleaning agent,n—a chemical or mixture of chemicals for the removal of residual material (for example,drug substance,drug product,machining oil,etc.)from equipment surfaces or other critical objects(such as a medical device).
清洁剂—清除设备表面或其他必须被清洁的物体（例如医学设备）残留的化学物质
或化学混合物（例如，原料药，药物，机油等）。
3.1.4clean-in-place,CIP,n—method of cleaning without dismantling equipment.
原地清洗，CIP，n—不拆除设备的清洁方式
3.1.5cleanability,n—relative difficulty for cleaning a piece of equipment or product.
洁净度，n—清洁设备或产品的相对困难度
3.1.6cleaning control strategy,n—planned set of controls derived from the risk assessment and current cleaning process understanding that ensures reliable and consistent cleaning process performance.ICH Q10
清洁控制措施，n—根据风险评估和当前清洁工艺理解制定的控制计划，确保清洁工艺的可靠和性能一致
3.1.6.1Discussion—The controls can include parameters and attributes related to materials and tools used for cleaning,cleaning procedure(s),equipment operating conditions,and the associated sampling plans,methods for validation,and routine monitoring.
讨论—控制措施可以包括关于清洁、清洁程序、设备操作情况、相关取样计划、验证方法、监控路线的参数和特性。
3.1.7cleaning design space,n—multidimensional combina-tion and interaction of cleaning input variables(for example,product cleanability,equipment design,and so forth)and cleaning process parameters(for example,solvent/cleaning agent concentration,temperature,time,and so forth)that have been demonstrated to provide assurance of achieving accept-able cleaning outputs(for example, active pharmaceutical ingredients(API)residues,cleaning agent residues).ICH Q8
清洁设计空间，n—多维组合和相互作用的清洁变量（例如，清洁剂浓度，温度，时间，等等）已被证明可以保证达到可接受的清洁结果（例如，API残留、清洁剂残留）。
cleaning input variables(parameters),n—those factors or settings whose values constitute the cleaning process and affect the cleaning output variables.
3.1.7.1Discussion—These independent variables include product cleanability,equipment size/groups,process residue load,holding times,cleaning agent concentration,cleaning agent type, rinse volume,pH,time,temperature,velocity,pressure,surface coverage,location and cleaning cycle, and so forth.
3.1.8cleaning output attributes,n—these attributes include product and cleaning agent residues remaining on the equip-ment surfaces after cleaning.
3.1.8.1Discussion—Bioburden/endotoxin levels and opera-tional considerations such as total cleaning time,holding times and costs may also be cleaning output attributes.
3.1.9cleaning process,n—any process designed to remove process residues from product contact surfaces of manufactur-ing equipment to levels that ensure patient safety and product quality.
3.1.10cleaning process parameters,n—cleaning agent concentration,temperature,time,and so forth.
3.1.11cleaning validation,n—collection and evaluation of data,from the cleaning process design stage t
hrough cleaning at commercial scale,which establishes scientific evidence that a cleaning process is capable of consistently delivering clean equipment.Ref(3)
3.1.12cleaning verification,n—confirmation,through the provision of objective evidence,that specified cleaning re-quirements have been fulfilled.ISO90000
3.1.13clean-out-of-place(COP)system,n—automated system usually used to clean large pieces of equipment or parts of equipment that are disassembled,but too large to clean manually.
3.1.13.1Discussion—COP systems can range from elabo-rate washing cabinets with automatic control systems to simple dishwasher type units.
3.1.14coupon,n—representative surface that is typically a rectangular piece of a material of construction in which a known amount of a compound is deposited to simulate aprocess residue.
3.1.15design space,n—multidimensional combination and interaction of input variables(for example,material attributes)and process parameters that have been demonstrated to provide assurance of quality.ICH Q8
3.1.16exposure,n—process by which a human or animal can come into contact with a hazard.
3.1.16.1Discussion—Exposure may occur through any route(oral,inhalational,dermal,and so forth).Exposure may be short-term(acute exposure),of intermediate duration,or long-term(chronic exposure).
3.1.17grouping strategy,n—strategy of using groups of products or equipment to simplify cleaning validation.
3.1.17.1Discussion—Products or equipment or both are placed into groups and one or more representatives from the group are chosen for cleaning process performance studies.A grouping strategy shall be scientifically justified.
3.1.18manual cleaning,v—cleaning of equipment,either in place or out of place,by hand and with the aid of brushes,cloths,detergents,and so forth.
3.1.19margin of safety,n—difference between the cleaning acceptance limit(based on ADE)and the process residue data.
3.1.19.1Discussion—This value can be used as a measure of the overall risk to patient safety presented by the cleaning process.The margin of safety can be measured a number of ways including the process capability index(Cpk)and the process performance index(Ppk).
3.1.20maximum allowable carryover,MAC or MACO,n—maximum amount of carryover from one product to the next.
3.1.20.1Discussion—The MAC is calculated as a fraction of the lowest therapeutic dose(usually 1/1000)or as a fraction of a lethal dose(LD50)(usually1/100000or1/1000000).
3.1.21maximum safe carryover,MSC,n—maximum amount of carryover of a residual process residue(API,cleaning agent,degradant,and so forth)into the next product manufactured without presenting an appreciable health risk to patients.
Discussion—The MSC is calculated from the ADE and the total number of doses in a subsequent batch.
3.1.22permitted daily exposure,PDE,n—represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.
3.1.22.1Discussion—This is the term used by the European Medicines Agency(EMA)and is equivalent to both the ADE and ADI.
3.1.23probability,n—likelihood of occurrence of harm.
3.1.24cleaning process residue,n—any residue,including,but not limited to,APIs,cleaning agents,degradation products,intermediates,excipients,and microbes remaining after a cleaning process.
3.1.25qualified statistician,n—individual with a working knowledge and education,training,or background in statistics who can apply statistical analysis to data from cleaning and cleaning validation studies.
3.1.26qualified toxicologist/pharmacologist,n—individual with specific education and training in toxicology/pharmacology that can apply the principles of toxicology to deriving an ADE or PDE value for required process residues.
validation verification3.1.27quality by design,n—systematic approach to devel-opment that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management.ICH Q8
3.1.28representative surface,n—surrogate surface thatmay be actual processing equipment or has characteristics similar to that of processing equipment and is used for spiking studies.
3.1.29visual inspection,n—process of using the human eye,alone or in conjunction with various aids,as the sensing mechanism from which judgments may be made about the condition of the surface to be inspected.
3.1.30visual limit of detection,n—lowest level of a process residue on a surface(inµg/cm2or µg/in.2)that is visible to aqualified inspector under defined viewing conditions.
3.2Definitions of Terms Specific to This Standard:
3.2.1CIP system,n—in this standard,CIP systems include the manufacturing equipment itself (mix tanks,transfer piping,and so forth)as well as the equipment used for cleaning(detergent tanks, rinse tanks,pumps,and so forth).
3.2.2cleaning failure modes and effects analysis,FMEA,n—a procedure to identify all possible failures of a cleaning process or procedure that could result in process residue levels that could put a patient at risk,the toxicity of those cleaning process failures,the likelihood of those cleaning process failures leaving significant levels of process residue,and the probability that the failure or process residues will go unde-tected.
3.2.2.1Discussion—The cleaning FMEA can also identify ways to minimize the failures,decrease their likelihood,and improve their detectability.Scales have been developed that can be specifically used for cleaning FMEAs and to measure the risk of cleaning failures(4-8).
4.Significance and Use意义和用途
Application of the approach described within this guide applies risk-based concepts and principles introduced in ICH Q9.As stated in ICH Q9,the level of effort,formality and documentation for cleaning should also be commensurate with the level of risk.
本指南所述方法的应用适用于ICH Q9中引入的基于风险的概念和原则。如ICH Q9所述，清洁程度、形式和文件应与风险程度相称。
4.1Application of the approach described within this guide applies many of the science-based, risk-based,and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation:General Principles and Practices(3).
本指南中描述的方法的应用了许多FDA行业指南：工艺验证：通则及实践中的基于科学、
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