1、Designation: E3106 181Standard Guide forScience-Based and Risk-Based Cleaning ProcessDevelopment and Validation1This standard is issued under the fixed designation E3106; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of
2、last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1NOTECorrections were made editorially to 3.1.13 in October 2018.1. Scope1.1 This guide applies the life-cycle approach to cleanin
3、gprocess validation, which includes the development,qualification, and verification of cleaning processes. It isapplicable to pharmaceuticals (including active pharmaceuticalingredients (APIs); dosage forms; and over-the-counter,veterinary, biologics, and clinical supplies) and is also appli-cable t
4、o other health, cosmetics, and consumer products.1.2 This guide is focused only on the cleaning of equipmentproduct contact surfaces and does not cover disinfection ornon-product contact surfaces (which are covered under otherexisting guides: Ref (1),2USP , Guide E2614, and ISO14698).1.3 The values
5、stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety
6、, health, and environmental practices and deter-mine the applicability of regulatory limitations prior to use.1.5 This international standard was developed in accor-dance with internationally recognized principles on standard-ization established in the Decision on Principles for theDevelopment of In
7、ternational Standards, Guides and Recom-mendations issued by the World Trade Organization TechnicalBarriers to Trade (TBT) Committee.2. Referenced Documents2.1 ASTM Standards:3E1325 Terminology Relating to Design of ExperimentsE2476 Guide for Risk Assessment and Risk Control as itImpacts the Design,
8、 Development, and Operation of PATProcesses for Pharmaceutical ManufactureE2614 Guide for Evaluation of Cleanroom Disinfectants2.2 ICH Standards:4Q8 Pharmaceutical DevelopmentQ9 Quality Risk ManagementQ10 Pharmaceutical Quality SystemQ11 Development and Manufacture of Drug Substances2.3 ISO Standard
9、s:5ISO 9000 Quality Management SystemsFundamentalsand VocabularyISO 14698 Guide for Evaluation of CleanroomDisinfectants, Parts 13.2.4 Federal Standards:621 CFR 211.67 Equipment Cleaning and Maintenance2.5 USP Standards:7USP Disinfectants and Antiseptics1This guide is under the jurisdiction of ASTM
10、Committee E55 on Manufactureof Pharmaceutical and Biopharmaceutical Products and is the direct responsibility ofSubcommittee E55.03 on General Pharmaceutical Standards.Current edition approved Sept. 1, 2018. Published September 2018. Originallyapproved in 2017. Last previous edition approved in 2017
11、 as E3106 17. DOI:10.1520/E3106-18E01.2The boldface numbers in parentheses refer to a list of references at the end ofthis standard.3For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume inform
12、ation, refer to the standards Document Summary page onthe ASTM website.4Available from International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH), ICHSecretariat, 9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland,http:/www.
13、ich.org.5Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.6Available from U.S. Government Printing Office, Superintendent ofDocuments, 732 N. Capitol St., NW, Washington, DC 20401-0001, http:/www.access.gpo.gov.7Available f
14、rom U.S. Pharmacopeial Convention (USP), 12601 TwinbrookPkwy., Rockville, MD 20852-1790, http:/www.usp.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United StatesThis international standard was developed in accordance with internationally rec
15、ognized principles on standardization established in the Decision on Principles for theDevelopment of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.13. Terminology3.1 Definitions:3.1.1 acceptable daily exposure,
16、 ADE, nrepresents a dosethat is unlikely to cause an adverse effect if an individual isexposed, by any route, at or below this dose every day for alifetime.3.1.1.1 DiscussionThis is the term used in the ISPERisk-MaPP Guide (1) and is equivalent to the acceptable dailyintake (ADI) but is associated w
17、ith any route of administration.3.1.2 acceptable daily intake, ADI, nmeasure of theamount of a specific substance (originally applied for a foodadditive, later also for a residue of a veterinary drug orpesticide) in food or drinking water that can be ingested(orally) on a daily basis over a lifetime
18、 without an appreciablehealth risk. Ref (2)3.1.2.1 DiscussionThis term is more commonly associ-ated with food and the oral route of administration.3.1.3 cleaning agent, na chemical or mixture of chemicalsfor the removal of residual material (for example, drugsubstance, drug product, machining oil, e
19、tc.) from equipmentsurfaces or other critical objects (such as a medical device).3.1.4 clean-in-place, CIP, nmethod of cleaning withoutdismantling equipment.3.1.5 cleanability, nrelative difficulty for cleaning a pieceof equipment or product.3.1.6 cleaning control strategy, nplanned set of controlsd
20、erived from the risk assessment and current cleaning processunderstanding that ensures reliable and consistent cleaningprocess performance. ICH Q103.1.6.1 DiscussionThe controls can include parametersand attributes related to materials and tools used for cleaning,cleaning procedure(s), equipment ope
21、rating conditions, and theassociated sampling plans, methods for validation, and routinemonitoring.3.1.7 cleaning design space, nmultidimensional combina-tion and interaction of cleaning input variables (for example,product cleanability, equipment design, and so forth) andcleaning process parameters
22、 (for example, solvent/cleaningagent concentration, temperature, time, and so forth) that havebeen demonstrated to provide assurance of achieving accept-able cleaning outputs (for example, active pharmaceuticalingredients (API) residues, cleaning agent residues). ICH Q83.1.8 cleaning input variables
23、 (parameters), nthose fac-tors or settings whose values constitute the cleaning processand affect the cleaning output variables.3.1.8.1 DiscussionThese independent variables includeproduct cleanability, equipment size/groups, process residueload, holding times, cleaning agent concentration, cleaning
24、agent type, rinse volume, pH, time, temperature, velocity,pressure, surface coverage, location and cleaning cycle, and soforth.3.1.9 cleaning output attributes, nthese attributes includeproduct and cleaning agent residues remaining on the equip-ment surfaces after cleaning.3.1.9.1 DiscussionBioburde
25、n/endotoxin levels and opera-tional considerations such as total cleaning time, holding timesand costs may also be cleaning output attributes.3.1.10 cleaning process, nany process designed to removeprocess residues from product contact surfaces of manufactur-ing equipment to levels that ensure patie
26、nt safety and productquality.3.1.11 cleaning process parameters, ncleaning agentconcentration, temperature, time, and so forth.3.1.12 cleaning validation, ncollection and evaluation ofdata, from the cleaning process design stage through cleaningat commercial scale, which establishes scientific evide
27、nce thata cleaning process is capable of consistently delivering cleanequipment. Ref (3)3.1.13 cleaning verification, nconfirmation, through theprovision of objective evidence, that specified cleaning re-quirements have been fulfilled. ISO 90003.1.14 clean-out-of-place (COP) system, nautomated sys-t
28、em usually used to clean large pieces of equipment or parts ofequipment that are disassembled, but too large to cleanmanually.3.1.14.1 DiscussionCOP systems can range from elabo-rate washing cabinets with automatic control systems to simpledishwasher type units.3.1.15 coupon, nrepresentative surface
29、 that is typically arectangular piece of a material of construction in which aknown amount of a compound is deposited to simulate aprocess residue.3.1.16 design space, nmultidimensional combination andinteraction of input variables (for example, material attributes)and process parameters that have b
30、een demonstrated to provideassurance of quality. ICH Q83.1.17 exposure, nprocess by which a human or animalcan come into contact with a hazard.3.1.17.1 DiscussionExposure may occur through anyroute (oral, inhalational, dermal, and so forth). Exposure maybe short-term (acute exposure), of intermediat
31、e duration, orlong-term (chronic exposure).3.1.18 grouping strategy, nstrategy of using groups ofproducts or equipment to simplify cleaning validation.3.1.18.1 DiscussionProducts or equipment or both areplaced into groups and one or more representatives from thegroup are chosen for cleaning process
32、performance studies. Agrouping strategy shall be scientifically justified.3.1.19 manual cleaning, vcleaning of equipment, either inplace or out of place, by hand and with the aid of brushes,cloths, detergents, and so forth.3.1.20 margin of safety, ndifference between the cleaningacceptance limit (ba
33、sed on ADE) and the process residue data.3.1.20.1 DiscussionThis value can be used as a measureof the overall risk to patient safety presented by the cleaningprocess. The margin of safety can be measured a number ofways including the process capability index (Cpk) and theprocess performance index (P
34、pk).3.1.21 maximum allowable carryover, MAC or MACO,nmaximum amount of carryover from one product to thenext.E3106 18123.1.21.1 DiscussionThe MAC is calculated as a fractionof the lowest therapeutic dose (usually 1/1000) or as a fractionof a lethal dose (LD50) (usually 1/100 000 or 1/1 000 000).3.1.
35、22 maximum safe carryover, MSC, nmaximumamount of carryover of a residual process residue (API,cleaning agent, degradant, and so forth) into the next productmanufactured without presenting an appreciable health risk topatients.3.1.22.1 DiscussionThe MSC is calculated from the ADEand the total number
36、 of doses in a subsequent batch.3.1.23 permitted daily exposure, PDE, nrepresents asubstance-specific dose that is unlikely to cause an adverseeffect if an individual is exposed at or below this dose everyday for a lifetime.3.1.23.1 DiscussionThis is the term used by the EuropeanMedicines Agency (EM
37、A) and is equivalent to both the ADEand ADI.3.1.24 probability, nlikelihood of occurrence of harm.3.1.25 cleaning process residue, nany residue, including,but not limited to,APIs, cleaning agents, degradation products,intermediates, excipients, and microbes remaining after acleaning process.3.1.26 q
38、ualified statistician, nindividual with a workingknowledge and education, training, or background in statisticswho can apply statistical analysis to data from cleaning andcleaning validation studies.3.1.27 qualified toxicologist/pharmacologist, nindividualwith specific education and training in toxi
39、cology/pharmacology that can apply the principles of toxicology toderiving an ADE or PDE value for required process residues.3.1.28 quality by design, nsystematic approach to devel-opment that begins with predefined objectives and emphasizesproduct and process understanding and process control based
40、on sound science and quality risk management. ICH Q83.1.29 representative surface, nsurrogate surface that maybe actual processing equipment or has characteristics similar tothat of processing equipment and is used for spiking studies.3.1.30 visual inspection, nprocess of using the humaneye, alone o
41、r in conjunction with various aids, as the sensingmechanism from which judgments may be made about thecondition of the surface to be inspected.3.1.31 visual limit of detection, nlowest level of a processresidue on a surface (in g/cm2or g/in.2) that is visible to aqualified inspector under defined vi
42、ewing conditions.3.2 Definitions of Terms Specific to This Standard:3.2.1 CIP system, nin this standard, CIP systems includethe 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).3.2.2
43、 cleaning failure modes and effects analysis, FMEA,na procedure to identify all possible failures of a cleaningprocess or procedure that could result in process residue levelsthat could put a patient at risk, the toxicity of those cleaningprocess failures, the likelihood of those cleaning processfai
44、lures leaving significant levels of process residue, and theprobability that the failure or process residues will go unde-tected.3.2.2.1 DiscussionThe cleaning FMEA can also identifyways to minimize the failures, decrease their likelihood, andimprove their detectability. Scales have been developed t
45、hatcan be specifically used for cleaning FMEAs and to measurethe risk of cleaning failures (4-8).4. Significance and Use4.1 Application of the approach described within this guideapplies risk-based concepts and principles introduced in ICHQ9. As stated in ICH Q9, the level of effort, formality anddo
46、cumentation for cleaning should also be commensurate withthe level of risk.4.2 Application of the approach described within this guideapplies many of the science-based, risk-based, and statisticalconcepts and principles introduced in the FDAs Guidance forIndustry Process Validation: General Principl
47、es and Practices(3).4.3 This guide supports, and is consistent with, elementsfrom ICH Q8, ICH Q9, ICH Q10, and ICH Q11.4.4 Key ConceptsThis guide applies the following keyconcepts: (1) quality risk management, (2) science-basedapproach, (3) statistics-based approach, (4) processunderstanding, and (5
48、) continued improvement as described inthe ICH Q series.5. Science-Based, Risk-Based, and Statistics-BasedCleaning Process Development and Validation5.1 Science-based approaches should be applied throughoutthe cleaning process development and validation process.5.2 Quality risk management should be
49、applied throughoutthe cleaning process development and validation process.5.3 Appropriate statistical analysis should be appliedthroughout the cleaning process development and validationprocess.6. Risk Assessment6.1 Under ICH Q9, risk assessment is broken into threestages: risk identification, risk analysis, and risk evaluation.6.2 Risk can be defined as: risk = f (probability of occur-rence of harm and the severity of that harm).6.3 For the purposes of cleaning, risk can be further definedas a function of the severity of t
