Fundamental cleaning principles

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Fundamental cleaning principles

  1. 1. Cleaning Validation Principles: Developing, Deploying and Maintaining Your Cleaning Validation Program Cleaning Validation 1Cleaning Validation Principles• ISPE Welcome and Opening Remarks• Course Leader Introduction• Housekeeping • • • Breaks Lunch Emergency Egress ? • ISPE Membership • Evaluations• Rules of the Road• Overview of Notebooks • Glossary / Acronyms • Index to Materials Cleaning Validation 2 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 1
  2. 2. Cleaning Validation Principles Table of Contents Section Description 1 Regulatory Requirements for Cleaning Validation 2 Fundamentals of Cleaning Validation 3 Cleaning Validation Master Plans 4 Equipment Characterization 5 SOP Development for Cleaning 6 Selecting Residues, then Developing and Maintaining Limits 7 Methods Validation and Recovery Studies 8 Engineering Studies and Cycle Development 9 Cleaning Validation Protocols 10 Field Execution -- Collecting and Testing Samples 11 Cleaning Validation Reports and Beyond! Cleaning Validation 3Cleaning Validation Principles Learning Objectives • Creation of scientifically sound rationales validation protocols rationales, and reports • Identification and characterization of potential residues including product, processing aids, cleaning agents and adventitious agents • Selection of appropriate analytical methodology for your selected residues • Determination of suitable sampling techniques and the selection of sampling locations that represent challenging locations for your cleaning process • Calculation of residue limits that meet all necessary regulatory requirements Cleaning Validation 4 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 2
  3. 3. Cleaning Validation Principles Job-Focused Skills• Learning to manage the challenges of limits limits, validation strategies and maintaining the validated state in: • Multi-product facilities • Campaign-based production environments• Differentiating the requirements for cleaning validation f lid ti for: • Manual • Semi-automatic • Automatic cleaning Cleaning Validation 5Cleaning Validation Principles Job-Focused Skills, cont.• Determining scientific grouping or bracketing approaches• Comprehending common cleaning validation pitfalls• Accomplishing analytical method validation and recovery study requirements in cost-effective studies• Evaluating your cleaning practices through internal self- audits• Practicing what you have learned through hands-on exercises Cleaning Validation 6 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 3
  4. 4. Class Introductions• Name• Department• Company• Types of Products Your Company Produces• Status of Your Cleaning Validation Efforts• What Topics / Questions You Came to Learn About• This course is designed to address the concerns for all pharmaceutical dosage forms including the production of APIs forms,• The principles are broadly applicable to IVD and consumer products, as well• If you have a question for your industry, please ASK!! Cleaning Validation 7 Module 1 Regulatory Requirements for R i t f Cleaning Validation: “Limit”ing the Risk Cleaning Validation 8 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 4
  5. 5. FDA Regulatory Timeline (Relatively Speaking) 1997 – HACCP Adopted for Food Industry 1992/3 – Mid- 1997 – Quality System 2002 – 2004 Atlantic Cleaning Inspection Technique Techniq e Risk-Based Ri k B d1986 – Process Validation Inspection (QSIT) for Devices Inspection ApproachValidation Guidance Guide Finalized as Identified & National Document 1996 – 2001 Rolled Out SUPAC Drafted 1992 – First E-Rec 1996 – Quality 2001 – Drug1978 – Last significant Rule Draft – Not Inspection Program System RegulationUpdate to Finished Finalized Until (6 Subsystems of Issued for DevicesPharmaceutical CGMPs 1996 (P11) Quality) Piloted - Finalized in 2002 1991 – 1993 Inspection 1998 – API Draft Guides Issued Guidance Issued • Aseptic Processing 1996 – Proposed • Bulk Pharmaceutical Chemical Revision to GMPs • Solid Dosage Form • Semi-Solid Dosage Form • Biotechnology • Laboratories (QC and Micro) Cleaning Validation 9 Significant Sources of Regulation on Cleaning and Cleaning Validation • Worldwide GMPs, (Especially EU Annex 15 (¶ 36) (2006) & GMP Part II (formerly Appendix 18) (2005) • US FDA, Guide to Inspections of Validation of Cleaning Processes (1993) • Pharmaceutical Inspection Convention (PIC), Recommendations on…Cleaning Validation (2001) • Canadian HPFB, Cleaning Validation Guidelines , g (2001) • WHO Supplementary Guidelines on GMP: Validation (2005) Cleaning Validation 10 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 5
  6. 6. Worldwide cGMPs Design and construction features and 21 CFR 211.42 EU 3.1 – 3.25 Equipment design, size, and location 21 CFR 211.63 EU 3.34 – 3.44 Any building or equipment used in the manufacture, processing, packing, or holding of a drug product shall be of:• Suitable size • All surfaces can be readily contacted by cleaning process; accessed for inspection• Suitable construction • Coved corners, free-draining, non-reactive, non-additive, non-absorptive materials of construction• Suitable location • Location appropriate to cleaning utilities / supplies; away from walls or other interfering surfaces to facilitate cleaning, maintenance, and proper operations. Cleaning Validation 11Worldwide cGMPs (continued) Sanitation 21 CFR 211.56 EU 4.26 Equipment cleaning and maintenance 21 CFR 211.67 EU 4.28 • Written procedures for cleaning and for use of cleaning and sanitizing agents shall be followed and shall: • Assign responsibility for sanitation • Describe in sufficient detail: • Schedules Prevent malfunctions or contamination that would alter the • Methods safety, identity, strength, quality, or • Equipment purity of the drug product beyond • Materials to be Used the official or other established requirements. Cleaning Validation 12 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 6
  7. 7. Worldwide cGMPs (continued)Equipment cleaning and maintenance 21 CFR 211.56 EU 4.26 21 CFR 211.67 EU 4.28More specifics with regard to the procedures to be established: As before• Responsibilities, Schedules, Methods, Equipment, Materials• Methods of Disassembling and Reassembling to ensure proper cleaning and maintenance• Removal or obliteration of previous batch identification• Protection of clean equipment from contamination prior to use• Inspection of equipment for cleanliness immediately before use• Records shall be kept of maintenance, cleaning, sanitizing, and inspection Cleaning & Use Log Record retention Cleaning Validation 13Worldwide cGMPs (continued) Equipment cleaning and use log 21 CFR 211.182 EU 4.28 – 4.29 A written record of major equipment cleaning, maintenance and use showing, for each batch processed: • Date • Time • Product • Lot number • Signature and date of person(s) performing • Signature and date of person(s) double-checking For dedicated equipment, the records of cleaning, maintenance, and use shall be part of the sequentially numbered batch record (if no separate log is kept). Cleaning Validation 14 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 7
  8. 8. European Requirements – EC Guide to GMPOverall, wording and content nearly identical to variousUS requirements Pertinent Sections: Section 3: Premises and Equipment (3.34 – 3.44 equipment design for cleanability) Section 5: Production (5.19 cross-contamination; 5.21 – 5.24 Validat. & Change Ctrl) Annex 2: Manufacture of Biologicals (15, 17 – design to promote cleanability) Cleaning Validation 15European Requirements – EC Guide to GMPOverall, wording and content nearly identical to variousUS requirements Pertinent Sections: Annex 15: Qualification and Validation (36 – 42 – Cleaning Validation; 45 - Revalidation) – see next GMP Part II: GMP for APIs (5.2 – Equipment Maintenance and Cleaning; 6.2 6 2 – Equipment Cleaning and Use Record; 12.7 – Cleaning Validation) – aligns with ICH Q7A Cleaning Validation Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 8
  9. 9. Definition of Cleaning Validation • Documented evidence to ensure that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration batch size, dosing, toxicology, equipment size, etc. - World Health Organization • Note that this definition immediately employs “risk-based” language Cleaning Validation 17Cleaning Validation –Sections 36 – 42 of EU Annex 15 on Qualificationand Validation • Cleaning validation should confirm effectiveness g of cleaning procedures; rationales should be logical for: • Limits for carry-over of drug product residue, cleaning agents and microbial contamination • Should be based on material to be cleaned Cleaning Validation 18 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 9
  10. 10. Cleaning Validation –Sections 36 – 42 of EU Annex 15 on Qualificationand Validation • Sufficiently sensitive validated analytical methods should be employed • Product contact surfaces only for validation; although non-product contact parts should be considered • Intervals should be validated for: • Time between use and cleaning • Time between cleaning and reuse Cleaning Validation 19 Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation • Worst-case approaches for similar materials / processes may be employed • Typically three consecutive trials should be performed • “Test Until Clean” is not an appropriate substitute for validation Cleaning Validation 20 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 10
  11. 11. Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation • Products which simulate the physiochemical properties of the residues may be used where those materials are either toxic or hazardous Revalidation - Section 45 of EU Annex 15 • Facilities, systems, equipment and processes, including cleaning, should be p g g, periodically y evaluated to confirm that they remain valid; a review with evidence may suffice if no significant changes were made Cleaning Validation 21Guide to Inspections of Validation ofCleaning Processes (1993) SOP Requirements • F each major piece of equipment: For h j i f i • Between batches of same product Dedicate where equipment is difficult to clean or hazardous • Between batches of different products • For cleaning validation process, requiring: • Cleaning validation protocols • S Sampling procedures li d • Analytical methods • Limits (“acceptable level”) • Final Report • Approval by management Cleaning Validation 22 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 11
  12. 12. Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Evaluation of Cleaning Process • Examine objectives of the validation process, written procedure and documentation At what point does a piece of equipment or system become clean? • Examine training and level of Does it have to be scrubbed by experience of the cleaning operators hand? What is accomplished by hand • Examine allowed length of time scrubbing? between the end of processing and How variable are manual cleaning processes from batch to batch and each cleaning step and its potential product to product? effect on the cleaning process • Examine steps taken to p e e t microbiological contamination a e ta e prevent c ob o og ca co ta at o IQ / OQ Elements to Consider • Examine equipment design especially when using CIP • Assure proper identification of process equipment to ensure correct implementation of cleaning procedures Cleaning Validation 23Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Scientific Design of Analysis • D t Determine th specificity and sensitivity of th i the ifi it d iti it f the analytical method(s) used to detect residuals or contaminants • Testing of rinse solutions should include testing for residues or contaminants rather than for water quality Cleaning Validation 24 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 12
  13. 13. Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Scientific Design of Analysis • Challenge analytical methods in combination with the sampling method(s) to show recovery • Sampling techniques include direct surface sampling and sampling of rinse solutions. • “Test until clean” systems should not be used. The need f retesting may indicate th t the cleaning d for t ti i di t that th l i process is not validated. Cleaning Validation 25Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Scientific Limits Determination • FDA does not intend to set limits • Determine how the firm established their residue limits: • Sensitivity of analytical methods is critical to establish valid limits • Logical, practical, achievable and verifiable • Scientifically justifiable • Three examples given: 10ppm, biological activity levels as 1/1000 of normal therapeutic dose and organoleptic f l th ti d d l ti levels • Cleaning Agents - “...no or very low detergent levels remain after cleaning...” UhOh! Don’t use words such as “absence, no or none” when creating your procedures or rationales!! Cleaning Validation 26 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 13
  14. 14. Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Other Important Statements: • Microbiological aspects of equipment cleaning should be considered; there should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation; equipment should be dried before storage • “When variable residue levels are detected following cleaning, one must establish the effectiveness of the process and operator performance.” • “Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. … Any indirect test method must have been shown to correlate with the condition of the equipment.” Cleaning Validation 27Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Other Important Statements: • “There are two general types of sampling that have been There found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.” • “Rinse and/or swab samples should be used in conjunction with the placebo method” (when it is justified for use) • “The firm should challenge the analytical method in combination with th sampling method(s) used t show th t bi ti ith the li th d( ) d to h that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc.” Does not mean that these values presented here are “acceptance criteria” for recovery. Cleaning Validation 28 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 14
  15. 15. Guide to Inspections of Validation ofCleaning Processes (1993) (continued) Other Important Statements: • “In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove…. the issue of by- products needs to be considered if equipment is not dedicated.” • “When cleaning is between batches of the same product (or different lots of the same intermediate in a bulk process) the firm fi need only meet a criteria of, " i ibl clean" f the d l t it i f "visibly l " for th equipment. Such between batch cleaning processes do not require validation.” Not scientifically justifiable!! Does not consider by-products, cleaning agent, micro, the area in which the equipment is cleaned / stored, etc. Cleaning Validation 29 PIC/S, Canadian and WHO Guidance on Limits Limits shall be logical, practical, achievable, verifiable; for example, the most stringent of the following first three criteria: • No more than 0.1% (1/1000th) of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product • No more than 10 ppm of any product will appear in another product • No visible residue on the equipment after cleaning procedures are performed * * Based on spiking studies that show the visible level • Also, for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods (or may require dedication) Cleaning Validation 30 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 15
  16. 16. US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation • (a) The manufacturer shall validate all drug product manufacturing processes including, but not limited to, computerized systems that monitor and/or control the manufacturing process. • The manufacturing process includes all manufacturing steps in the creation of the finished product including, but not limited to, the following procedures: Cleaning to Cleaning, weighing, measuring, mixing, blending, compressing, filling, packaging, and labeling. Cleaning is not only considered a step in the manufacturing process, but it is the FIRST step in getting ready for the next process. Cleaning Validation 31US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • (b) Validation protocols that identify the product and product specifications and specify th procedures and acceptance criteria ifi ti d if the d d t it i for the tests to be conducted and the data to be collected during process validation shall be developed and approved. • The protocol shall specify a sufficient number of replicate process runs to demonstrate reproducibility of the process and provide an accurate measure of variability among successive runs Number of runs to be justified. Rule of three typically applies. Three may b th minimum!! Th be the i i !! • Validation documentation shall include evidence of the suitability of materials and the performance and reliability of equipment and systems. The manufacturer shall document execution of the protocol and test results. Cleaning Validation 32 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 16
  17. 17. US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • (c) The manufacturer shall design or select equipment and ( ) g q p processes to ensure that product specifications are consistently achieved. • The manufacturers determination of equipment suitability shall include testing to verify that the equipment is capable of operating satisfactorily within the operating limits required by the process. • Parts of the process that may cause variability or otherwise affect p product qquality shall be tested. y Considerations for worst-cases in cleaning validation include: • Maximum hold times • Maximum residue loads • Minimum process parameters during validation Cleaning Validation 33US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • (d) There shall be a quality assurance system in p ( ) q y y place which requires q revalidation whenever there are changes in packaging, component characteristics, formulation, equipment, or processes, including reprocessing, that could affect product effectiveness or product characteristics, and whenever changes are observed in product characteristics. Change control considerations include: • Cleaning agents • Cleaning process parameters • Cleaning procedures • Training procedures • Formulation • Equipment • Environments / storage locations for clean equipment • Introduction of a new product (as it might affect the limit for an existing product – see limits section) Cleaning Validation 34 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 17
  18. 18. Module 2: Fundamentals of Cleaning Validation: Emphasis on Fun! Cleaning Validation 35First, Some DefinitionsCleaning Validation• Documented evidence that provides a high degree ofassurance that a cleaning process can reproducibly producea clean piece of equipment in accordance with thedesignated specifications • Generally cleaning validation applies the “rule of three three” for the number of validation trials to be completed Cleaning Validation 36 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 18
  19. 19. First, Some DefinitionsVerification• documented evidence that provides a high degreeof assurance that a single cleaning event canproduce a clean piece of equipment in accordancewith the designated specifications, suitable for thenext use • Generally verification is used for development batches where three may not be made or for infrequently manufactured products; when three runs have been completed they may be summarized as a validation if all conditions used in the three studies were the same Cleaning Validation 37 First, Some Definitions • Certification – depending on the firm, certification often has the same meaning as verification; some companies differentiate certification as an expected process that will diff ti t tifi ti t d th t ill occur after each production event as a change over process, for example • Monitoring – a routine evaluation of cleaning to determine whether the original cleaning validation conditions are still being achieved; may involve fewer samples or less invasive sampling techniques p g q • Engineering Trials – experimental cleaning trials that help to evaluate whether a cleaning process for a new / revised product or process will be effective; still requires validated test methods and sampling procedures Cleaning Validation 38 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 19
  20. 20. Fundamentals of Cleaning Cleaning depends upon process control… T ime A ction C oncentration / Chemistry T emperature Cleaning also depends upon the conditions of cleaning cleaning… W ater I ndividual Performing Cleaning N ature of Soil S urface Being Cleaned T.A.C.T. W.I.N.S. Example Cleaning Validation 40 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 20
  21. 21. Influences on Cleaning Equipment Type – Major, Minor,Product Type Dedicated, Non-DedicatedManufacturing Process Role i th P R l in the Process – U t Upstream,Hold TimesCampaign Length Surface Downstream Materials of Construction Surface Finish Geometry / Complexity Soil Chemistry Water Quality Time Action / Type of Cleaning – Manual (Individual), CIP, COP Concentration Temperature Cleaning Validation 41 Equipment Categories Major Equipment - Attributes of Each Category equipment critical t th i t iti l to the • Generally large and manufacturing process significant contributor to overall contamination (usually has a unique identification number) • May be dedicated Minor Equipment - • Generally small but may be apparatus and utensils (such used for highly concentrated g y as scoops, hoses, beakers) materials which perform a support • May or may not be dedicated function Cleaning Validation 42 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 21
  22. 22. Equipment Categories Major Equipment - Consequences of Each Category equipment critical t th i t iti l to the • S Significant contamination f manufacturing process contributor; position / role in (usually has a unique process will be highly critical identification number) • Generally easy to track for cleaning status Minor Equipment - apparatus and utensils (such • Generally not a significant contributor, contributor but we can t leave can’t as scoops, hoses, beakers) them out of our program which perform a support • Difficulties arise in tracking of function small parts through the cleaning process Cleaning Validation 43 Equipment Categories Attributes of Each CategoryDedicated Equipment - q pequipment which is used for the • Lower risk of cross-manufacture of one product only contaminationNon-Dedicated Equipment - • Multi-use nature presents pequipment commonly used f i t l d for significant cross-several products or processes contamination concerns Cleaning Validation 44 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 22
  23. 23. Equipment Categories Consequences of EachDedicated Equipment - Categoryequipment which is used for themanufacture of one product only • Potentially higher risk of degradant and impurity build-up, especially if campaignedNon-Dedicated Equipment - • Validation will be requiredequipment commonly used for for f each product (or h d t(several products or processes representative from a grouping / bracketing) • May also be at risk for Remember the precautions stated degradants and earlier for the Guide to Inspection of Cleaning Validation Processes with impurities if campaigning regard to the pitfalls in not validating is observed the cleaning of dedicated equipment. Cleaning Validation 45Types of Cleaning Attributes of Each Type Manual Cleaning - scrub brushes and high pressure hoses used by • Adaptable to varying soil loads an operator to remove product t t d t residue • Highly dependent upon trainingAutomated Cleaning (e.g., CIP –(Clean-In-Place) - cleaning • Reproducible if equipment isperformed by a control system or qualified for usemicroprocessor whichautomatically controls functions of • Will not recognize variability in thewash, rinse and dry incoming soil condition Semi-Automated Cleaning (e g (e.g., COP – Clean-Out-of-Place) - • Often combines strengths and cleaning performed in a parts weakness of the above washer or sink; often requires manual intervention or • May depend upon accurate load disassembly; may be automated placement / disassembly for proper cleaning Cleaning Validation 46 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 23
  24. 24. Types of Cleaning Consequences of Each TypeManual Cleaning - scrub brushesand high pressure hoses used by • Lack of inherent reproducibility mayan operator to remove product require extensive monitoring overresidue time • Detailed procedures a must!Automated Cleaning (e.g., CIP –(Clean-In-Place) - cleaningperformed by a control system or • Need to ensure that cleaningmicroprocessor which validation considers the worst-automatically controls functions of case soil loads or that productionwash, rinse and dry can adequately identify outliers for study in the futureSemi-AutomatedSemi Automated Cleaning (e g (e.g.,COP – Clean-Out-of-Place) - • Detailed procedures and loadcleaning performed in a parts maps are typically requiredwasher or sink; often requiresmanual intervention or • May require monitoring asdisassembly; may be automated with manual above Cleaning Validation 47Position / Role in Process Attributes of Each PositionUpstream – equipment early in the i t l i th • May have nreacted Ma ha e unreacted startingmanufacturing process, for example materials present on equipmentprimary reactors, initial culture,initial blending • In-process materials may still be “crude” in that they have not yet undergone purificationDownstream – equipment usedlater in the manufacturing or • Residues are less likely to befinishing process including such homogeneously distributedprocess steps as final throughout the batch as oftencrystallization, purification or viral there is limited mixing after thereduction, filling equipment or upstream processestableting equipment • Product is often purified Cleaning Validation 48 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 24
  25. 25. Position / Role in Process Consequences of Each PositionUpstream – equipment early in the • Additional residues may need to bemanufacturing process, for example f t i f l considered for cleaning validationprimary reactors, initial culture,initial blending • Sampling sites will have to be selected Downstream – equipment used highly critically to ensure that non- later in the manufacturing or homogeneous distribution of residues finishing process including such does not adversely affect portions of process steps as final batch crystallization, purification or viral reduction, filling equipment or • Limits may need to be more tableting equipment conservative to accommodate the critical nature of many sampling sites • Be careful that purification processes don’t concentrate contaminants Cleaning Validation 49Precautions withPurification Processes• Purification processes are generally intended to remove process-related impurities only• Don’t falsely assume that residues from prior cleaning operations will be successfully removed by purification without validation Cleaning Validation 50 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 25
  26. 26. Precautions withPurification Processes• Remember that cleaning validation affects the next product to be produced – don’t assume that don t the residues from a prior process will be compatible with the next product or purification process If part of your rationale intends to use the purification process as part of your basis for residue or limits selection, remember that FDA stated in Human CGMP Notes that impurities are intended to come from the starting materials or the manufacturing process itself and not from elements left over from the cleaning process Cleaning Validation 51 Module 3: Cleaning Validation Master Plans: It is Always Pl i Al Good to Have a Plan Cleaning Validation 52 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 26
  27. 27. Transformation of Data – Knowledge ManagementSource: The Certified Quality Manager Handbook, 2nd Ed., ASQ Wisdom is derived from the collective database of knowledge, built from experience and values, by being able to see the connectivity among seemingly disparate Wisdom knowledge sets enabling deductive solutions. solutions Knowledge is built through the correlation and integration of information with policies, Knowledge procedures and regulations. Information has meaning, but the meaning is based on the interpretation of the user of the information. Information Data is meaningless unless something is done with it. Data Cleaning Validation 53Transformation of Data –For Cleaning ValidationYou will achieve wisdom when you understand whetheror not your policies, procedures and master plansadequately support the complexity of your plant! Oftenin depthin-depth analysis such as risk and impact assessments Wisdomare necessary to become truly enlightened!Establish policies, procedures and master plansthat integrate the information collected about Knowledgeyour plant.Relate the various forms of data tounderstand the equipment, cleaningprocess and product residue Informationinteractions.Collect information aboutyour equipment, products Dataand processes. Cleaning Validation 54 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 27
  28. 28. So What Data Need to Be Collected? Data Required Required For …Formulation Attributes • Analytical method selection y(i.e., dosage, toxicity, • Sampling method selectionconcentration, • Limits determinationexcipients, degradants, • Worst-case determination (if grouping / bracketing)impurities) • Segregation requirements (if hazardous)Equipment • Materials of Construction for Recovery StudiesCharacteristics • Surface Area for Limits Determination(i.e., materials of • Hard to clean sampling locations or “hot spots”construction, geometry, • Sampling locations where non-homogeneous contamination issurface area, cleaning likely or “critical sites”procedure, cleaning • Worst-case determination (if grouping / bracketing)agent, disassembly • Segregation requirements (if highly difficult to clean effectively)requirements) So What Data Need to Be Collected? Data Required Required For … Process Attributes • Residue selection (i.e., batch size, upstream / • Limits determination downstream, extreme • Sampling location selection temperatures / holds, etc.) • Worst-case determination (if grouping / bracketing) • Segregation requirements (if hazardous) Standard Operating • Process parameters for validation Procedures • Witnessing requirements • Sampling locations • Grouping / Bracketing (if applicable) So what activities convert these Data into Information? . . . Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 28
  29. 29. Engineering Operations Validation and Technical Operations Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation Equipment Cleaning SOP Critical Process Characterization Defintion Parameters Product Grouping / Product Attributes Bracketing Equipment Train Definition Cleaning Agent Residue Selection Quality Control Usage MatrixEquipment Grouping Hard to Clean Sampling Sites Sampling Method / Bracketing Locations And MOC Selection Limits Definition Methods Validation Recovery Studies Hold Time Definition Worst-Case W tC DefinitionsEngineering Runs / Campaign DefinitionCycle Development Protocol Definition Protocol Execution and Summary Report PreparationNow We Have Data and Information, WhereDoes the Knowledge Come From?… • Knowledge is the integration of Information with policies policies, Wisdom procedures and regulations Knowledge • We must first start by creating our policies or Information master plan for cleaning as well as the SOPs that will govern our Cleaning Data Validation Program Cleaning Validation 58 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 29
  30. 30. What is a Master Plan*?Our Needs for an Effective Roles of the Master Plan:Program: • Single source for information • High Level Philosophy • Consistent understanding by • Framework for consistent risk- all team members based decision-making • Assessment of what needs to • Inventory of actions and be done and by whom projects, resource planning, • Effective control of strategies scheduling to ensure that they are • Location to consolidate our consistent scientific rationales • Less time spent by regulators • Single source for regulatory in our facility review * Frequently Master Plans are called Project Plans, Validation Plans or Policies, depending on the site’s document hierarchy Cleaning Validation 59What are TypicalMaster Plan Sections? 1. Introduction Objective and Scope 2. Description and Background 3. References 4. Responsibilities 5. Validation Approach • Strategy and organization • Inventory of qualification activities to be accomplished 6. Acceptance Criteria (as appropriate) 7. 7 Procedures & Format (as appropriate) 8. Risk / Hazard / Failure Analysis (or may be in separate document) 9. Planning & Scheduling (as appropriate, high level, typically) 10. Appendices Cleaning Validation 60 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 30
  31. 31. Master Plan Contents• Introduction Objective and Scope - Goals of the Master Plan and brief content insight as well as boundaries of the Validation Project and of the j Master Plan Typical scope boundary elements: • Production areas included: marketed production, clinical trial materials, R&D, laboratories, contract manufacturer / packagers • Types of Residues / Analysis included: chemical, microbiological Cleaning Validation 61Master Plan Contents• Description and Background - overview and orientation to the facility, process, technology or project; may include product overviews as overviews, appropriate Typical elements: • Program progress to date or significant iterations • Dosage forms, primary manufacturing processes forms processes, significant attributes of products (e.g., toxic, potent), production characteristics (e.g., batch, campaign) Cleaning Validation 62 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 31
  32. 32. Master Plan Contents References - pertinent internal and external documents Examples include: • Scientific rationales, SOPs, risk analyses, literature supporting key rationales or strategies Avoid excessive generic references (e.g., GMPs) Responsibilities – high level overview of key project participants – sufficient detail here may supercede the need to continue to reiterate responsibilities in protocols Department Responsibilities QC Methods Validation Recovery Studies Analysis of Samples Engineering Surface Area Calculations Materials of Construction ID Validation Protocol and Report Preparation Operations Cleaning in accordance with SOPs Collecting samples Cleaning Validation 63 Master Plan Contents (continued)Validation Approach – highlight the key elements of thevalidation program • Scientific rationales (see next slide) – the basis for the selection of the validation testing and trade-offs • Basis for the selection of validation priorities (e.g., New product introductions, worst-case products, multi-purpose equipment, etc.) • Project management overview of the responsibilities for the oversight of the cleaning validation program • Inventory of validations to be accomplished or already accomplished i support of the plan li h d in f h l Cleaning Validation is as much about what you choose not to do as it is about what you choose to do. Ensure your scientific rationales defend both! Cleaning Validation 64 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 32
  33. 33. Scientific Rationales Will be Needed for … • Product grouping / bracketing rationale • Equipment grouping / bracketing rationale • Residue selection criteria • Limit selection and calculation rationale • Analytical approach (specific / direct vs. non-specific/ indirect / screening) • Sampling method selection • Sampling site selection criteria • Others? (e.g., disassembly philosophy, campaign or minor clean strategies, etc.) Document these well as these will serve as the guideposts for future personnel or auditors navigating your cleaning validation program. Cleaning Validation 65Master Plan Contents (continued) Acceptance Criteria For cleaning validation, the acceptance criteria section typically refers to the way in which the acceptance criteria will be calculated; if more than one criterion applies, the acceptance criteria section will need to define how the terms will be applied Visually Clean and 1/1000th of a Therapeutic Dose or 10 ppm in the next batch, whichever is lower Cleaning Validation 66 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 33
  34. 34. Master Plan Contents (continued) Procedures & Format Refers to Reference section for the procedures and formats to be followed; in some cases samples of specific documentation samples or outlines of document headings may be included Scope – Products and Procedures Equipment Boundaries / Train Definition Pre-Requisites (e.g., methods validation, recovery studies, IQ, OQ of equipment, training, etc.) Validation Study Design Sampling Plan Acceptance Criteria Cleaning Validation 67 Master Plan Contents (continued)• Risk / Hazard / Failure / Criticality / Impact Analysis – may be provided here or in a separate document to substantiate scientific rationales priorities trade-offs overall approach rationales, priorities, trade offs, approach, CTQs or critical parameters• Planning & Scheduling – include or reference a project schedule for major milestones; if referenced, ensure that it exists; if included, remember the audience and keep it high level• Appendices – sample flow diagrams for key processes, specimen documentation formats, supporting documentation for the approach, data tables of key product attributes, tables including product-specific limits, etc. Cleaning Validation 68 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 34
  35. 35. Other Possible Master Plan Contents• Master Plans may also capture compliance and regulatory requirements beyond validation in order g y q y to ensure that the project correctly integrates these activities with the completion of validation• This is especially valid if the program is undergoing any significant changes in strategy or if corrective actions have b ti ti h been id tifi d identified Cleaning Validation 69Other Possible Master Plan Contents• For example: • SOP development • Training package preparation and training of operators / technicians • Development of test methods or in-process controls • Vendor audits / surveillance / visits • Factory / Site Acceptance Tests ( y (FAT / SAT) / ) Commissioning and/or Qualification Activities for new CIP or COP systems Cleaning Validation 70 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 35
  36. 36. Master Plan Maintenance • Maintain a Revision History • Circulate approved copies of the Validation Project Plan to all involved departments • Keep the Master Plan up to date with regard to changes in priorities and schedule • Place the Master Plan on a periodic review cycle to ensure that there is frequent challenge to scientific rationales and current approaches to validation Cleaning Validation 71Summary Reports for Master Plans• In some cases, where a plan is developed for a specific project such as a new product introduction, a summary report t th plan can i t d ti t to the l provide project closure• In other cases, an annual summary can provide updates on critical activities / accomplishments from prior year while providing hi hli ht of goals f i hil idi highlights f l for next year Cleaning Validation 72 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 36
  37. 37. Summary Reports for Master Plans• Summary report to a Master Plan can provide: • Closure to validation activities for regulators or change control purposes • Mechanism to describe and defend deviations from the original plan • Location to tie together disparate validation protocols and reports and their conclusions in a high level overview Cleaning Validation 73Standard Operating Proceduresfor Cleaning Validation• Develop an infrastructure of procedures that define the validation program responsibilities and activities.• Possible topics to include (in a single or in several SOPs): • Equipment Characterization (New and Existing) • Standard Operating Procedure Development for Cleaning • Developing and Maintaining Limits Calculations • Cleaning Validation Methods Validation and Recovery Studies • Engineering Studies / Cycle Development g g y p • Developing Cleaning Validation Protocols and Reports • Collecting and Testing Cleaning Validation Samples• These topics will form the outline of the remaining sections of the presentation Cleaning Validation 74 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 37
  38. 38. Module 4: Equipment Characterization: Do not L t Lose “Site” of “Sit ” f What you Are Cleaning! Cleaning Validation 75Equipment Characterization• We’ve already examined that the surface is a critical to the success of the cleaning f• So let’s examine what we can do about it: • Equipment Design / Construction • Equipment Characterization • Sampling Site Selection • Documentation of Equipment Characterization Cleaning Validation 76 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 38
  39. 39. Equipment Design and ConstructionProduction equipment and facilities should be designed to be cleanableand maintainable in accordance with CGMPs – other critical attributesmay apply depending on the nature of your production process • Coved corners • Welded seams • Sealed joints or crevices, when necessary (with temperature / chemical resistant caulk or sealant) • Sanitary clamp type connections • Minimize dead leg opportunities (not only length of T but also orientation of lines) • Positive slope (typically minimum for long runs of 1/8th in/ft or 10.4mm/m) • Free-draining • Non-additive, non-reactive, non-absorptive materials of construction • Smooth, polished finishes (ex: 20 – 25 µin or 0.5 – 0.625 µm Ra on 316L SS) Cleaning Validation 77Existing Equipment Design Survey• Survey the equipment (see example of potential tool on the next slide)• Identify weaknesses in the design• Identify risks associated with the weaknesses Product Contact ?• Mitigate as possible Yes No When ranking, it may also be helpful to rank each Critical Site Non-Critical or section of the (i.e., location likely to be Incidental equ p e t equipment by t e the non homogeneously non-homogeneously Contact nature of its distributed in next batch or product contact: location which is likely to be in contact with highly concentrated active) High Risk Low Risk Cleaning Validation 78 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 39
  40. 40. Example of DesignSurvey Risk Assessment Characteristic High Rating Low Equip. Possible Mitigations / Rating Section Actions for High Ratings Surveyed Positive Slope / Non-free Free draining Reengineering Free Draining draining Forced flow and forced drying Non-additive / MOC not MOC Reengineering Non-reactive / appropriate appropriate Special considerations for Non-absorptive for easy cleaning action / MOC cleaning chemistry Enhanced inspection / testing to confirm cleanliness Smooth, Finish was Finish is Refinishing surfaces polished not designed smooth, Enhanced cleaning action finishes to be smooth polished and / chemistry or finish has in tact Enhanced inspection / significant testing to confirm damage cleanliness 79Example of DesignSurvey Risk Assessment Characteristic High Rating Low Equip. Possible Mitigations / Rating Section Actions for High Ratings Surveyed Coved Not coved and Coved or Tool selection for Corners critical product non-critical cleaning contact surface Special instructions during cleaning Joints Not sealed or Sealed with Replace sealant sealant inapprop- the correct Use different chemistry riate to rigors of material or or tool for that location cleaning not critical More frequent PM and to product / p replacement cleaning contact Dead leg Dead legs are No dead Reengineering survey present or legs or Disassembly for cleaning orientations that poor or disassembly after CIP would hold up orientations for inspection and product and fluids additional off-line cleaning 80 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 40
  41. 41. Equipment DesignRisk Assessment Results Product Risk  High Low Equipment Design Risk High Reengineering to Reengineering is still mitigate is your best best, but procedural course of action improvements may suffice Low Equipment is not q p No worries! likely to be a problem, but take care in your cleaning program design Equipment Characterization Goals of Equipment Characterization are to: Gather Develop • Equipment design data: • MOC list for recovery studies • MOC / finish / geometry • Sampling site identification • Difficult to clean locations • Sampling method determination • Cleaning SOP #s and • Cleaning procedure and Cleaning Agent types cleaning agent correlation to equipment for grouping / • E i Equipment surface area data t f d t bracketing • Equipment train data • Equivalency rationales for grouping / bracketing • Limit determination Cleaning Validation 82 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 41
  42. 42. Equipment CharacterizationField Assessments• Set Priorities for Equipment – (new, non-dedicated major, downstream, non- dedicated minor, upstream, etc.)• Identify potential equivalent equipment Cleaning Validation 83Equipment CharacterizationField Assessments• Initiate the Assessment: • Identify product contact materials of construction for processing equipment and their locations • Use drawings, vendor certifications, field inspections • Identify the approximate percentage of surface area that each MOC comprises (may be approximate) • Calculate or contact vendor for the product contact surface area calculations for the total piece of equipment • List the cleaning SOPs and cleaning agents in use for the equipment • Interview operations personnel for hard to clean locations Cleaning Validation 84 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 42
  43. 43. Equipment Characterization FieldAssessments (cont’d) Grouping or Bracketing Repeat the review for any potential equivalent members Review for equivalency should include: R i f i l h ld i l d • Make / Model / Geometry / Features • Scale / Size / Capacity • Materials of Construction / Surface Finish • Installation and Operational Qualification Equivalence • Same Position / Role in the Process Equivalency will also be determined based on: • Cleaned with same procedure • Cleaned with identical cleaning agent • Overlap in products produced on those pieces Grouping / bracketing equipment will then drive: Number / organization of cleaning validation trials Cleaning Validation 85Equipment Characterization FieldAssessments (cont’d) Identify sampling locations and sampling techniques Sampling locations should be selected based on: p g • Hard to clean locations or complex geometries – hot spots • Locations that might disproportionately contribute residue to the next process (e.g., filling needles, discharge valves, punch and dies, chromatography skid fraction collection valves and piping, etc.) – critical sites • Materials of construction or surface finishes with an affinity for the residue • Role in process that is likely to lead to build up or difficult to build-up clean residue Number of sampling locations should be based on the: • Number of locations that fit the descriptions above • Overall size of the equipment Cleaning Validation 86 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 43
  44. 44. Documenting Sampling Site SelectionRationales Through Risk Assessment Role in Process Likely Sampling S li Critical C iti l Affinity t Affi it to MOC to L d to t Lead t Location Site Hot Spot or surface finish Residue Ranking Risk assessment technique aids in ensuring that sampling sites are effectively rationalized and eliminates some of the subjectivity • Rankings can be scaled as H, M, L or given a number scale Methods for identifying sampling locations include: • Interviewing operators for difficult to clean locations • Witnessing cleaning procedures to identify weaknesses in cleaning • Conducting screening studies such as Riboflavin testingModule 4 – Equipment CharacterizationSlide 88 Baby in the Bathwater Sampling Methods - Survey * May get a different rating depending upon technique Sampling Method  Rinse Direct Surface Swab Placebo Coupon (see Baby) AnalysisPhysical Removal Good Poor * Moderate* Good * N/ATechnique Yes No No No No *DependentHard to Reach Poor Good Good Poor PoorLocationsAdaptable to Somewhat Yes Somewhat No No *Irregular SurfacesControlled Area Yes No * No Yes YesSamplingNon-Invasive No Can Be Yes Yes * NoAdaptable to On-Line No Yes No * No NoMonitoringCan Use Solvents Yes Yes No Yes N/A Solubility of Ability of Placebo to Ability to Defend Residue Remove Residue that Soiling and Surface Site Selection (e.g., solubility) Cleaning of Coupon Character-izationHighly Dependent Contact Time Training Homogeneity of is Equivalent to the Qualification ofOn…: Homogeneity of Production Recovery Residue in Placebo Method Rinse Solution for Detection Equipment Limit of Detection Recovery Recovery Recovery Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 44
  45. 45. Example of Equipment Characterization Documentation 1. Equipment Name 5. Sampling Site Selection 2. Equivalent Equipment IDs Rationale and Sampling 3. Equipment Description & Role Method in th P i the Process 6. Digital Photographs of • Key Design Features Sampling Sites • Key Performance • Highlighted sampling Attributes (esp. those that area affect cleaning) • Text description of • Critical Sites or Hot Spots sampling location • Rationales for Equivalency (as required) 7. Calculation of Sampling Site Surface Area 4. Materials of Construction 8. 8 Calculation of Equipment • Material Surface Area • Location Appendix – Sampling Data Sheet* • % of Total Surface Area * To be discussed in Limits section Cleaning Validation 89Establish an Equipment Use MatrixEquipment Cleaning SOP Cleaning Agent Product A Product BNameTank 11 SOP 1234 CleanAll 345 X(600 L)Tank 12 SOP 1234 CleanAll 345 X X(500 L)Transfer Line SOP 6789 SonicCare 657 X X101 (2”)Pump 602 SOP 4567 CleanAll 345 X X(diaphragm) • Matrix helps to establish which products share equipment in order to determine the maximum shared equipment train between products (esp. if you use equipment surface area instead of X’s) • Can assist in seeing logical relationships for equipment groupings / bracketing • Records similarities and differences between pieces based on cleaning SOPs and cleaning agents Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 45
  46. 46. Ensure That Your CharacterizationWork Also Assesses The Following • Identify materials that should be reviewed against cleaning agent and cleaning tools to look for compatibility issues • Develop rationales for those materials that will not need to be included in sampling and recovery studies based on elements such as: • Position in the P iti i th process • Overall percentage of surface area • Similarity to other locations or materials of construction Cleaning Validation 91Ensure That Your CharacterizationWork Also Assesses The Following • Materials that are candidates for dedication or for making them disposable, such as those g p that are: • Likely to have a high affinity to product • Likely to be extremely difficult to clean • In contact with highly concentrated residues • Used as ancillary components Cleaning Validation 92 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 46
  47. 47. Discuss the Following:Can sampling size legitimately be based on thefollowing? (Why or why not?) • Easy to discern part of the equipment (i.e., specific fixture, or identifiable part such as 1 agitator blade) • Convenient number (e.g., 100 cm2) • Different sizes for each sample collected Cleaning Validation 93Discuss the Following:Do you think there will be a maximum and aminimum surface area that is legitimate tocollect?(Don’t give a specific numeric value, just think about whythis might be the case) Cleaning Validation 94 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 47
  48. 48. Module 5: SOP Development for Cleaning - Cl i Reproducibility is No Accident Cleaning Validation 95FDA Perspectives on Manual Cleaning Pre-1993 – Manual Cleaning Can’t Be Validated • Industry Concern • Manual Cleaning Impossible to Eliminate 1993 – Manual Cleaning Can Be Validated • Requires Detailed Procedures • Requires Effective Training • Requires Periodic Monitoring So what are the elements that we need to control in order to ensure that we meet FDA’s expectations? Cleaning Validation 96 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 48
  49. 49. Manual Procedures v. Automated ProcessesManual Procedures Automated Processes• Rely on trained staff • Less reliance on people• Rely on detail in • Rely on cycle parameters, parameters procedures for instrumentation and reproducibility; controls for reproducibility compliance with • Validation of instruments procedure is paramount and controls in IQ / OQ is• Few requirements for IQ key / OQ of the cleaning g • Monitoring is chiefly process performed through• Few effective means of instrumentation and monitoring unless documentation such as sampled periodically alarm and cycle records Both require T.A.C.T. ! Cleaning Validation 97 Fishbone Diagram Also called an Ishikawa Diagram or Cause and Effect diagram is used to show (and group) the contributors to a problem through brainstorming or the review of a process flow. Controlling the elements on the “ribs” of the fishbone (or at least the most critical elements along the ribs) will help to ensure that the problem is corrected or controlled. The groups that are present on the ribs of the fishbone may vary; below are some of the more common categories. “Mother Nature” Methods Manpower (or environment) Preventing Unsuccessful Cleaning Validation Materials Measurement Machinery Cleaning Validation 98 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 49
  50. 50. Fishbone Diagram forCleaning Validation “Mother Nature” Methods Manpower (or environment) Analytical Training HVAC method Classification Experience Sampling Temperature method Attention Rel. Humidity to detail Cleaning Procedure Other Clean equip. T.A.C.T. distractors Preventing storage conditions Unsuccessful Cleaning Analysis y Cleaning Cleaning Residues agent Recovery equipment i t Materials of Validation V lid ti Water Sampling construction Tools for Quality Manufacturing cleaning Calibration of equipment Geometry Instruments Materials Measurement Machinery Cleaning Validation 99 Q Question: How do we ensure control over these key elements? Cleaning Validation 100 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 50
  51. 51. A: Detailed SOPs • Materials List with part numbers and descriptions • Responsibilities List • Preparation • Cleaning • Inspection • Procedures • Specific to categories of equipment • Step-wise and sequenced • Concise, clearly written in simple language, yet detailed • Include T A C T Incl de T.A.C.T. • Reference distinct measures or metrics to determine achievement of T.A.C.T. parameters • Include documentation requirements • Include diagrams for clarity Cleaning Validation 101 SOP Contents• Preparation Procedures • Preparation of area, tools & cleaning agent• Documentation Procedures • Status Tags, Checklists, Cleaning & Use Log• Disassembly Procedures • Exploded diagrams or digital photos• Cleaning Procedures • Step-Wise, Tools, TACT, Measures• Completion Procedures • Cleaning of Tools, Baskets, Carts• Inspection Procedures • Methods & Tools, Locations for Inspection• Drying Procedures • Environment / Controls• Wrapping / Covering / Storage • Materials, Handling, Location Procedures• Post-Cleaning Documentation • Re-Tagging, Cleaning & Use Log Procedures• Equipment Expiration • Dating Requirements, Re-Cleaning Requirements Procedures • Verification of Expiration, Integrity of Wraps /• Pre-Use Inspection Procedures Covers Cleaning Validation 102 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 51
  52. 52. SOP Contents Peculiar to CleaningValidation• Time after use before cleaning• Maximum interruption within a cleaning p p g process (such as hold times after a pre-rinse or time before a final rinse)• Time after cleaning before use• Cleaning Frequency (if tied to levels of cleaning such as major clean and minor clean) Elements Affecting Cleaning That Would Be Included in Batch Records or Master Cleaning Policy• Maximum number of batches and/or days in a campaign Cleaning Validation 103Batch Record-Like Format • Enables formal review of cleaning procedures • Enforces consistency between operators • Enforces sequence of activities q • Captures accomplishment of T.A.C.T. through documented completion of key steps, including: • Preparation of cleaning agent • Disassembly checklist • Pre-rinse, Wash, Final Rinse • Drying • Inspection • Covering and Storage • Cleaning and Storage of Tools • Captures start / stop times and critical process parameter achievement Cleaning Validation 104 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 52
  53. 53. Special Considerations for Sanitizationor Disinfection Procedures • Cleaning steps must be specified prior to the application of the sanitant • Contact time with chemical sanitant is critical • Method of application may need to be demonstrated to reliably leave sufficient “liquid” on the surface to effect the sanitization • Expiration dates for formulated sanitizers are p particularly important • Aseptic techniques should be taught and practiced Cleaning Validation 105Special Considerations for Sanitizationor Disinfection Procedures • Other validation considerations: • Sanitant efficacy must be demonstrated in the presence of known residues from processing or cleaning at the levels that are typically present after an effective cleaning procedure; ensure the cleaning agent residues don’t inactivate the sanitant • Re-use of a sanitizing solution must be validated as they often lose efficacy quickly when contaminated with residues / debris Cleaning Validation 106 Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 53

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