1、Designation: E3106 17Standard 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 l
2、ast revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide applies the life-cycle approach to cleaningprocess validation, which includes the development,qualification,
3、 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 to other health, cosmetics, and consumer products.1.2 This guide is
4、 focused only on the cleaning of equipmentproduct contact surfaces and does not cover disinfection ornon-product contact surfaces (which are covered under anotherexisting guide (1)2).1.3 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisst
5、andard.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, health, and environmental practices and deter-mine the applicability of regulatory limitations prior
6、 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 International Standards, Guides and Recom-mendations issued by the World Trade Organization TechnicalBar
7、riers 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, Development, and Operation of PATProcesses for Pharmaceutical Manufacture2.2 ICH Standards:4Q8 Pharma
8、ceutical DevelopmentQ9 Quality Risk ManagementQ10 Pharmaceutical Quality SystemQ11 Development and Manufacture of Drug Substances2.3 ISO Standards:5ISO 9000 Quality Management SystemsFundamentalsand Vocabulary2.4 Federal Standards:621 CFR 211.67 Equipment Cleaning and Maintenance3. Terminology3.1 De
9、finitions:3.1.1 acceptable daily exposure, 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 accept
10、able dailyintake (ADI) but is associated with 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 ingeste
11、d(orally) on a daily basis over a lifetime 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 clean-in-place, CIP, nmethod of cleaning withoutdismantling equipment.1This guide is under the jurisdicti
12、on of ASTM Committee E55 on Manufactureof Pharmaceutical and Biopharmaceutical Products and is the direct responsibility ofSubcommittee E55.03 on General Pharmaceutical Standards.Current edition approved Dec. 1, 2017. Published May 2018. DOI: 10.1520/E3106-17.2The boldface numbers in parentheses ref
13、er 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 information, refer to the standards Document Summary page onthe ASTM website.4Availa
14、ble 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.ich.org.5Available from American National Standards Institute (ANSI), 25 W. 43
15、rd 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.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19
16、428-2959. United StatesThis international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for theDevelopment of International Standards, Guides and Recommendations issued by the World Trade Organization Tech
17、nical Barriers to Trade (TBT) Committee.13.1.4 cleanability, nrelative difficulty for cleaning a pieceof equipment or product.3.1.5 cleaning control strategy, nplanned set of controlsderived from the risk assessment and current cleaning processunderstanding that ensures reliable and consistent clean
18、ingprocess performance. ICH Q103.1.5.1 DiscussionThe controls can include parametersand attributes related to materials and tools used for cleaning,cleaning procedure(s), equipment operating conditions, and theassociated sampling plans, methods for validation, and routinemonitoring.3.1.6 cleaning de
19、sign space, nmultidimensional combina-tion and interaction of cleaning input variables (for example,product cleanability, equipment design, and so forth) andcleaning process parameters (for example, solvent/cleaningagent concentration, temperature, time, and so forth) that havebeen demonstrated to p
20、rovide assurance of achieving accept-able cleaning outputs (for example, active pharmaceuticalingredients (API) residues, cleaning agent residues). ICH Q83.1.7 cleaning input variables (parameters), nthose fac-tors or settings whose values constitute the cleaning processand affect the cleaning outpu
21、t variables.3.1.7.1 DiscussionThese independent variables includeproduct cleanability, equipment size/groups, process residueload, holding times, cleaning agent concentration, cleaningagent type, rinse volume, pH, time, temperature, velocity,pressure, surface coverage, location and cleaning cycle, a
22、nd soforth.3.1.8 cleaning output attributes, nthese attributes includeproduct and cleaning agent residues remaining on the equip-ment surfaces after cleaning.3.1.8.1 DiscussionBioburden/endotoxin levels and opera-tional considerations such as total cleaning time, holding timesand costs may also be c
23、leaning output attributes.3.1.9 cleaning process, nany process designed to removeprocess residues from product contact surfaces of manufactur-ing equipment to levels that ensure patient safety and productquality.3.1.10 cleaning process parameters, ncleaning agentconcentration, temperature, time, and
24、 so forth.3.1.11 cleaning validation, ncollection and evaluation ofdata, from the cleaning process design stage through cleaningat commercial scale, which establishes scientific evidence thata cleaning process is capable of consistently delivering cleanequipment. Ref (3)3.1.12 cleaning verification,
25、 nconfirmation, through theprovision of objective evidence, that specified cleaning re-quirements have been fulfilled. ISO 900003.1.13 clean-out-of-place (COP) system, nautomated sys-tem usually used to clean large pieces of equipment or parts ofequipment that are disassembled, but too large to clea
26、nmanually.3.1.13.1 DiscussionCOP systems can range from elabo-rate washing cabinets with automatic control systems to simpledishwasher type units.3.1.14 coupon, nrepresentative surface that is typically arectangular piece of a material of construction in which aknown amount of a compound is deposite
27、d to simulate aprocess residue.3.1.15 design space, nmultidimensional combination andinteraction of input variables (for example, material attributes)and process parameters that have been demonstrated to provideassurance of quality. ICH Q83.1.16 exposure, nprocess by which a human or animalcan come
28、into contact with a hazard.3.1.16.1 DiscussionExposure may occur through anyroute (oral, inhalational, dermal, and so forth). Exposure maybe short-term (acute exposure), of intermediate duration, orlong-term (chronic exposure).3.1.17 grouping strategy, nstrategy of using groups ofproducts or equipme
29、nt to simplify cleaning validation.3.1.17.1 DiscussionProducts or equipment or both areplaced into groups and one or more representatives from thegroup are chosen for cleaning process performance studies. Agrouping strategy shall be scientifically justified.3.1.18 manual cleaning, vcleaning of equip
30、ment, either inplace or out of place, by hand and with the aid of brushes,cloths, detergents, and so forth.3.1.19 margin of safety, ndifference between the cleaningacceptance limit (based on ADE) and the process residue data.3.1.19.1 DiscussionThis value can be used as a measureof the overall risk t
31、o 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 (Ppk).3.1.20 maximum allowable carryover, MAC or MACO,nmaximum amount of carryover from one product to thenext.3.1.20.
32、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).3.1.21 maximum safe carryover, MSC, nmaximumamount of carryover of a residual process residue (API,cleaning agent, degradant, and
33、so forth) into the next productmanufactured without presenting an appreciable health risk topatients.3.1.21.1 DiscussionThe MSC is calculated from the ADEand the total number of doses in a subsequent batch.3.1.22 permitted daily exposure, PDE, nrepresents asubstance-specific dose that is unlikely to
34、 cause an adverseeffect if an individual is exposed at or below this dose everyday for a lifetime.3.1.22.1 DiscussionThis is the term used by the EuropeanMedicines Agency (EMA) and is equivalent to both the ADEand ADI.3.1.23 probability, nlikelihood of occurrence of harm.3.1.24 cleaning process resi
35、due, nany residue, including,but not limited to,APIs, cleaning agents, degradation products,intermediates, excipients, and microbes remaining after acleaning process.E3106 1723.1.25 qualified statistician, nindividual with a workingknowledge and education, training, or background in statisticswho ca
36、n apply statistical analysis to data from cleaning andcleaning validation studies.3.1.26 qualified toxicologist/pharmacologist, nindividualwith specific education and training in toxicology/pharmacology that can apply the principles of toxicology toderiving an ADE or PDE value for required process r
37、esidues.3.1.27 quality by design, nsystematic approach to devel-opment that begins with predefined objectives and emphasizesproduct and process understanding and process control basedon sound science and quality risk management. ICH Q83.1.28 representative surface, nsurrogate surface that maybe actu
38、al processing equipment or has characteristics similar tothat of processing equipment and is used for spiking studies.3.1.29 visual inspection, nprocess of using the humaneye, alone or in conjunction with various aids, as the sensingmechanism from which judgments may be made about thecondition of th
39、e surface to be inspected.3.1.30 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 viewing conditions.3.2 Definitions of Terms Specific to This Standard:3.2.1 CIP system, nin this standard, CIP systems
40、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 cleaning failure modes and effects analysis, FMEA,na procedure to identify all possible failures of a cleaningproces
41、s or procedure, their effects on cleaning, the likelihoodof occurrence, and the probability that the failure will goundetected.3.2.2.1 DiscussionThe cleaning FMEA can also identifyways to minimize the failures, decrease their likelihood, andimprove their detectability.4. Significance and Use4.1 Appl
42、ication 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 anddocumentation for cleaning should also be commensurate withthe level of risk.4.2 Application of the approach described within this
43、 guideapplies many of the science-based, risk-based, and statisticalconcepts and principles introduced in the FDAs Guidance forIndustry Process Validation: General Principles 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 C
44、onceptsThis guide applies the following keyconcepts: (1) quality risk management, (2) science-basedapproach, (3) statistics-based approach, (4) processunderstanding, and (5) continued improvement as described inthe ICH Q series.5. Science-Based, Risk-Based, and Statistics-BasedCleaning Process Devel
45、opment and Validation5.1 Science-based approaches should be applied throughoutthe cleaning process development and validation process.5.2 Quality risk management should be applied throughoutthe cleaning process development and validation process.5.3 Appropriate statistical analysis should be applied
46、throughout 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
47、harm).6.3 For the purposes of cleaning, risk can be further definedas a function of the severity of the hazards of process residues,likelihood and level of process residues, and detectability ofprocess residues.6.4 For a reliable assessment of risk, scientific means (forexample, risk management tool
48、s) should be used to identify thehazard presented by a process residue (for example, API,degradation products, intermediates, cleaning agent,bioburden/endotoxin, and so forth), the ability of a cleaningprocess to remove process residues to levels that areacceptable, and the ability to detect and qua
49、ntify the presenceof process residues after cleaning.6.5 Risk IdentificationRisk identification should encom-pass the identification of process residue hazards, equipmentdesign hazards, and procedural hazards.6.5.1 Process Residue Hazard Identification:6.5.1.1 The hazard presented by a potential process residuemay be determined from a toxicological review performed bya qualified toxicologist or qualified pharmacologist. For anAPI, this involves a thorough review of all relevant toxicologi-cal data available for the process residue
