Cleaning validation presentation(1)
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This document discusses procedures for cleaning validation. It addresses: - Cleaning procedures need validation for product contact surfaces and consideration for non-contact parts with potential for product migration. - The objective is to provide evidence that cleaning procedures can effectively remove residues to a level that does not raise patient safety concerns. - It describes strategies for validating cleaning of product contact surfaces after product changes, between batches, and periodically. Validation protocols and reports are outlined. Standard operating procedures for cleaning procedures are also addressed.
Cleaning validation presentation(1)
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- 3. • Normally only cleaning procedures for product contact surfaceNormally only cleaning procedures for product contact surface need to be validated. Consideration shall be given to nonneed to be validated. Consideration shall be given to non contact parts where there are chances of product migration.contact parts where there are chances of product migration. • E. G. Mixing shafts, seals, flanges, fans and oven heatingE. G. Mixing shafts, seals, flanges, fans and oven heating elements.elements. 33
- 4. 44 Objective:Objective: To attain documentedTo attain documented evidence, which provides a highevidence, which provides a high degree ofdegree of assuranceassurance that thethat the Cleaning procedure canCleaning procedure can effectivelyeffectively remove residues of a product and aremove residues of a product and a cleaning agentcleaning agent from thefrom the manufacturing equipment, to a levelmanufacturing equipment, to a level that does not raisethat does not raise patient safetypatient safety concerns.concerns.
- 5. Possible contaminantsPossible contaminants • Product residuesProduct residues • Cleaning agent residues and breakdownCleaning agent residues and breakdown • Airborne matterAirborne matter • Lubricants, ancillary materialLubricants, ancillary material • Decomposition residuesDecomposition residues • Bacteria, mould and pyrogensBacteria, mould and pyrogens 55
- 6. Strategy on cleaning validationStrategy on cleaning validation • Product contact surfacesProduct contact surfaces • After product changeoverAfter product changeover • Between batches in campaignsBetween batches in campaigns • Periodic re-evaluation and revalidationPeriodic re-evaluation and revalidation 66
- 7. Cleaning validation protocolCleaning validation protocol Should include :Should include : • Objective and scopeObjective and scope • Responsibility for performing andResponsibility for performing and approving validation studyapproving validation study • Description of equipment to be usedDescription of equipment to be used • Time interval between production end,Time interval between production end, starting of cleaning.starting of cleaning. 77
- 8. • Details of cleaning procedureDetails of cleaning procedure • Sampling position and area and diagramSampling position and area and diagram with difficult to clean area.with difficult to clean area. • Sampling procedureSampling procedure • Acceptance criteriaAcceptance criteria • Analytical method including limit ofAnalytical method including limit of detection and limit of quantification ofdetection and limit of quantification of those method.those method. • Protocol should be formally approved byProtocol should be formally approved by the responsible and authorized person.the responsible and authorized person. 88
- 9. Cleaning validation reportCleaning validation report Should include :Should include : • Analytical methods including Limit ofAnalytical methods including Limit of Detection and Limit of QuantitationDetection and Limit of Quantitation • Acceptance criteria and rationaleAcceptance criteria and rationale • Results of validation of analyticalResults of validation of analytical methods.methods. • Any deviation of manufacturing orAny deviation of manufacturing or cleaning procedure.cleaning procedure. 99
- 10. • When revalidation will be requiredWhen revalidation will be required • Time period during which validation wasTime period during which validation was performed.performed. • Summary of the results.Summary of the results. • The report should be approved.The report should be approved. 1010
- 11. 1111 CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP) Standard Operating Procedure (SOP)Standard Operating Procedure (SOP) should be required duly approved byshould be required duly approved by approving authority and it shouldapproving authority and it should specify the following:specify the following: 1.1. PrecautionsPrecautions andand safety warningsafety warning.. 2.2. Cleaning tools and materialsCleaning tools and materials with theirwith their name, concentration, their dilutionname, concentration, their dilution instruction, volume requirement,instruction, volume requirement, storage period and requirements.storage period and requirements.
- 12. 1212 CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP) 3.3. Time limitationsTime limitations:: a. time between end of manufacturinga. time between end of manufacturing and start of cleaning.and start of cleaning. b. time between final rinse and drying.b. time between final rinse and drying. c. frequency of major cleaning for mfg.c. frequency of major cleaning for mfg. batches of the same product inbatches of the same product in campaign.campaign. d. time until additional cleaning isd. time until additional cleaning is performed for unused cleanperformed for unused clean equipment.equipment.
- 13. 1313 CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP) 44.. Cleaning levelCleaning level:: MINORMINOR between two batches of samebetween two batches of same product or between different strengths (interproduct or between different strengths (inter convertible formula) of the same product.convertible formula) of the same product. For minor cleaning, cleaning validation is notFor minor cleaning, cleaning validation is not required, since cross contamination is not anrequired, since cross contamination is not an issue.issue. MAJORMAJOR between two products.between two products. In this case, validation of the effectiveness ofIn this case, validation of the effectiveness of the cleaning procedure in removing residuesthe cleaning procedure in removing residues to the required level is mandatory.to the required level is mandatory.
- 14. 1414 CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP) 5.5. Cleaning procedureCleaning procedure covers followingcovers following steps…steps… Dismantling, Initial washing, FinalDismantling, Initial washing, Final washing & Parameters such aswashing & Parameters such as Time,Time, Temperature,Temperature, Volume,Volume, Flow rate etc. should beFlow rate etc. should be mentioned.mentioned.
- 15. 1515 CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP) 6.6. Drying :Drying : is very important to preventis very important to prevent microbiological proliferation. Sometimesmicrobiological proliferation. Sometimes the final rinse is conducted with hotthe final rinse is conducted with hot purified water to facilitate evaporation ofpurified water to facilitate evaporation of the water. Drying time and temperaturethe water. Drying time and temperature should defined.should defined. 7.7. Visual inspectionVisual inspection :: No traces or particles visible toNo traces or particles visible to thethe naked eye should benaked eye should be observed after the cleaning.observed after the cleaning.
- 16. 1616 CLEANING PROCEDURESCLEANING PROCEDURES 8.8. Cleaned statusCleaned status has to be indicated by puttinghas to be indicated by putting a label or a card on the clean equipmenta label or a card on the clean equipment.. 9.9. StorageStorage place of cleaned equipment /place of cleaned equipment / utensils withutensils with proper wrappingproper wrapping && instructions clearly mentionedinstructions clearly mentioned.. 10.10. Cleaning logCleaning log should be maintained.should be maintained.
- 17. 1717 THE CLEANING VALIDATIONTHE CLEANING VALIDATION PROGRAMMEPROGRAMME 1. Selection of cleaning method1. Selection of cleaning method 2. Selecting the Scientific basis for the2. Selecting the Scientific basis for the contamination limitcontamination limit 3. Selecting the Worst case related to the3. Selecting the Worst case related to the equipmentequipment 4. Selecting the Worst case related to the4. Selecting the Worst case related to the productproduct 5. Establishing the storage period after5. Establishing the storage period after cleaning.cleaning. 6. Selecting the sampling method6. Selecting the sampling method 7. Selecting the analytical method7. Selecting the analytical method 8. Documentation8. Documentation
- 18. 1818 1. SELECTION OF CLEANING METHOD1. SELECTION OF CLEANING METHOD • The equipment design and manual cleaning method areThe equipment design and manual cleaning method are taken into consideration for selection of equipment. Alltaken into consideration for selection of equipment. All equipments selected viewing following cleaningequipments selected viewing following cleaning considerations:considerations: Ease of disassembling of contact partsEase of disassembling of contact parts All contact surfaces are non-reactive to cleaning methodAll contact surfaces are non-reactive to cleaning method Dedicated disposable materials where difficult to cleanDedicated disposable materials where difficult to clean e.g. FBD bags, filters, Disposable bags in transite.g. FBD bags, filters, Disposable bags in transit containerscontainers Least chance of contamination from equipment non-Least chance of contamination from equipment non- contact parts e.g. lubricants, gaskets, drive system,contact parts e.g. lubricants, gaskets, drive system, mechanical seal etc.mechanical seal etc.
- 19. 1919 1. SELECTION OF CLEANING METHOD1. SELECTION OF CLEANING METHODThe risk involved in manual cleaningThe risk involved in manual cleaning processes is taken care of with following:processes is taken care of with following: Proper washroom design with drying,Proper washroom design with drying, protection and storage requirement.protection and storage requirement. Detailed cleaning SOPDetailed cleaning SOP Training of cleaning operatorsTraining of cleaning operators
- 20. 2020 2. SELECTING THE SCIENTIFIC BASIS FOR THE2. SELECTING THE SCIENTIFIC BASIS FOR THE CONTAMINATION LIMITCONTAMINATION LIMIT (Acceptance criteria.)(Acceptance criteria.) • The acceptance criteria:The acceptance criteria: The acceptance criteria for each piece ofThe acceptance criteria for each piece of equipment and for the complete manufacturingequipment and for the complete manufacturing process has to be determined. The carryover ofprocess has to be determined. The carryover of product residue should meet the most stringentproduct residue should meet the most stringent of the following criteria.of the following criteria. 1)1)Visibly clean criteria: No quantity of residue willVisibly clean criteria: No quantity of residue will be visible on the equipment after the cleaningbe visible on the equipment after the cleaning procedure are performed.procedure are performed.
- 21. 2)10 PPM criteria:2)10 PPM criteria: To have least MACO for A product, considerTo have least MACO for A product, consider the next API with smallest batch size.the next API with smallest batch size. In case of product A the MACO in mg isIn case of product A the MACO in mg is calculated using following abbreviatedcalculated using following abbreviated formula. MBS =35 Kgformula. MBS =35 Kg MACO= MAX CONC x MBS in mgMACO= MAX CONC x MBS in mg Where,Where, •MAX CONC= General limit for maximumMAX CONC= General limit for maximum allowed concentration of previous substanceallowed concentration of previous substance in next batch.in next batch. 2121
- 22. MBS = Minimum batch size for the next APIMBS = Minimum batch size for the next API MACO= 0.00001x 35000000MACO= 0.00001x 35000000 MACO= 350 mgMACO= 350 mg 3) 1/1000 Dose criteria:3) 1/1000 Dose criteria: MACO=MACO= TDDprevious x MBSTDDprevious x MBS SF x TDD nextSF x TDD next MACO= Maximum allowable carryoverMACO= Maximum allowable carryover acceptable transferred amount from theacceptable transferred amount from the investigated APIinvestigated API 2222
- 23. • TDD previous= Standard therapeutic doseTDD previous= Standard therapeutic dose of the investigated APIof the investigated API • TDD next= Standard therapeutic dose ofTDD next= Standard therapeutic dose of the next product.the next product. • MBS = Minimum batch size for the nextMBS = Minimum batch size for the next APIAPI • SF= safety factor (1000 is used inSF= safety factor (1000 is used in calculation based on TDD)calculation based on TDD) 2323
- 24. 2424 SAFETY FACTORSAFETY FACTOR Normally accepted Safety Factor for differentNormally accepted Safety Factor for different dosage forms are given in the followingdosage forms are given in the following table:table: Dosage FormDosage Form Safety FactorSafety Factor • Research compoundResearch compound 1/100000 – 1/100001/100000 – 1/10000 • Parentral productsParentral products 1/10000-1/50001/10000-1/5000 • Ophthalmic productsOphthalmic products 1/50001/5000 • Oral dosage formsOral dosage forms 1/10001/1000 • Topical productsTopical products 1/100-1/101/100-1/10
- 25. 2525 2. SELECTING THE SCIENTIFIC2. SELECTING THE SCIENTIFIC BASIS FOR THE CONTAMINATIONBASIS FOR THE CONTAMINATION LIMITLIMIT • Contamination Limit Based on OtherContamination Limit Based on Other Considerations:Considerations: •• Not DetectableNot Detectable This type of limit refers to aThis type of limit refers to a specific analytical method.specific analytical method. •• Absolute LimitAbsolute Limit An absolute limit also termedAn absolute limit also termed “single limit” or “blanket specification” means“single limit” or “blanket specification” means that the same limit is set for any product,that the same limit is set for any product, without consideration to toxicological data or towithout consideration to toxicological data or to the detection level of the analytical method, andthe detection level of the analytical method, and is usually expressed in parts per million (ppm)is usually expressed in parts per million (ppm)
- 26. 2626 3. SELECTING THE WORST CASE3. SELECTING THE WORST CASE RELATED TO THE EQUIPMENTRELATED TO THE EQUIPMENT • The worst case for a group ofThe worst case for a group of equipment is represented by theequipment is represented by the equipment with the larger productequipment with the larger product contact surface and the hardest-to-contact surface and the hardest-to- clean locations.clean locations.
- 27. 2727 4. SELECTING THE WORST CASE4. SELECTING THE WORST CASE RELATED TO THE PRODUCT:RELATED TO THE PRODUCT: Only one product out of a group ofOnly one product out of a group of product processed in a piece ofproduct processed in a piece of equipment is selected for the cleaningequipment is selected for the cleaning validation study, based on the lowestvalidation study, based on the lowest solubility of the active ingredient andsolubility of the active ingredient and its therapeutic dose.its therapeutic dose.
- 28. 2828 4. SELECTING THE WORST CASE4. SELECTING THE WORST CASE RELATED TO THE PRODUCT:RELATED TO THE PRODUCT: • To arrive at theTo arrive at the worst case equipmentworst case equipment andand worst case productworst case product we needwe need Equipment Database and ProductEquipment Database and Product Database.Database.
- 29. 2929 5. ESTABLISHING THE STORAGE5. ESTABLISHING THE STORAGE PERIOD AFTER CLEANINGPERIOD AFTER CLEANING The objective for establishing time The objective for establishing time limit between equipment cleaning and limit between equipment cleaning and reuse is to ensure that the equipment reuse is to ensure that the equipment remains clean till the next use. This remains clean till the next use. This needs demonstration that there is no needs demonstration that there is no microbial proliferation in cleaned microbial proliferation in cleaned equipments during storage.equipments during storage.
- 30. 3030 5. ESTABLISHING THE STORAGE5. ESTABLISHING THE STORAGE PERIOD AFTER CLEANINGPERIOD AFTER CLEANING For establishing the time limit, the For establishing the time limit, the equipment should be dried. Initial swab equipment should be dried. Initial swab samples for surface should be taken. samples for surface should be taken. Thereafter, the equipment should be Thereafter, the equipment should be protected as prescribed in the SOP and protected as prescribed in the SOP and stored in its designated area. Periodic stored in its designated area. Periodic samples of product contact surface for samples of product contact surface for microbiological contamination should be microbiological contamination should be taken. (1taken. (1stst day, 2 day, 2ndnd day, 3 day, 3rdrd day etc.) day etc.) Based on the data generated establish Based on the data generated establish the acceptable time limit. the acceptable time limit.
- 31. 3131 5. ESTABLISHING THE STORAGE5. ESTABLISHING THE STORAGE PERIOD AFTER CLEANINGPERIOD AFTER CLEANING • Cleaned equipment surface sample (contact Cleaned equipment surface sample (contact surface only) test results should demonstrate surface only) test results should demonstrate absence of specified micro organisms (E. absence of specified micro organisms (E. Coli, Salmonella etc.) Coli, Salmonella etc.) • The acceptance level for surface sampling is The acceptance level for surface sampling is 25CFU per 25 sq. cm. 25CFU per 25 sq. cm.
- 32. 3232 6. SELECTING THE SAMPLING METHOD6. SELECTING THE SAMPLING METHODThe two main sampling methods are:The two main sampling methods are: 1. Swab sampling.1. Swab sampling. 2. Rinse sampling.2. Rinse sampling.
- 33. 3333 6. SELECTING THE SAMPLING METHOD6. SELECTING THE SAMPLING METHOD 6.1 Swab sampling method6.1 Swab sampling method Selection of samling point are madeSelection of samling point are made based on multiple criteria asbased on multiple criteria as 1.1.Area exposed most to API contactArea exposed most to API contact 2.2.Area difficult to cleanArea difficult to clean Selection of sampling points based onSelection of sampling points based on Worst case identification.Worst case identification. Swab samling: Take reaymade swab forSwab samling: Take reaymade swab for samplingsampling
- 34. • Pipette out 5 mL solvent in test tubePipette out 5 mL solvent in test tube • Pour the swab in test tube & cover it.Pour the swab in test tube & cover it. • Swab the surface approximately 10 x 10 Swab the surface approximately 10 x 10 CM area (100sq. Cm)CM area (100sq. Cm) • After the swabbing, put the swab in test After the swabbing, put the swab in test tube.tube. • Identification as sampleIdentification as sample • Submit the sample in QC for analysis.Submit the sample in QC for analysis. 3434
- 35. • Rinse sampling: Rinse sampling: • Initially take appropriate quantity of solvent Initially take appropriate quantity of solvent in suitable containers as mentioned in in suitable containers as mentioned in respective SOP.respective SOP. • Rinse the equipmentRinse the equipment • Collect the rinse at the discharge port in Collect the rinse at the discharge port in suitable container.suitable container. • Discharge the rinse completely and Discharge the rinse completely and recycle the total content twice.recycle the total content twice. • Stir the content in container and sample Stir the content in container and sample the required quantitythe required quantity • Submit the sample to QC for analysis.Submit the sample to QC for analysis. 3535
- 36. 3636 SAMPLE SURFACE AREASAMPLE SURFACE AREA Sample surface areas usually vary from 25Sample surface areas usually vary from 25 sq.cm to 100 sq.cm. The swab area chosen issq.cm to 100 sq.cm. The swab area chosen is 100 sq.cm.100 sq.cm. SWAB RECOVERY STUDYSWAB RECOVERY STUDY A swab recovery study is performed toA swab recovery study is performed to determine the ability of the swab todetermine the ability of the swab to quantitatively remove the contaminant fromquantitatively remove the contaminant from the surface sampled.the surface sampled. The swab taken isThe swab taken is Whatman– Carbon freeWhatman– Carbon free paperpaper..
- 37. 3737 7. SELECTING THE ANALYTICAL7. SELECTING THE ANALYTICAL METHODMETHOD • The Basic Requirements for the AnalyticalThe Basic Requirements for the Analytical Method.Method. 1. The sensitivity of the method shall be appropriate to1. The sensitivity of the method shall be appropriate to the calculated contamination limit.the calculated contamination limit. 2. The method shall be practical and rapid, and, as2. The method shall be practical and rapid, and, as much as possible use instrumentation existing in themuch as possible use instrumentation existing in the company.company. 3. The method shall be validated in accordance with3. The method shall be validated in accordance with ICH, USP and EP requirements.ICH, USP and EP requirements. 4. The analytical development shall include a recovery4. The analytical development shall include a recovery study to challenge the sampling and testingstudy to challenge the sampling and testing methods.methods.
- 38. 3838 7. SELECTING THE ANALYTICAL7. SELECTING THE ANALYTICAL METHODMETHOD • SPECIFIC METHODSSPECIFIC METHODS Chromatographic methods such as GC andChromatographic methods such as GC and HPLCHPLC Thin layer chromatographyThin layer chromatography
- 39. 3939 7. SELECTING THE ANALYTICAL7. SELECTING THE ANALYTICAL METHODMETHOD The chromatography methodThe chromatography method (HPLC) was selected for cleaning(HPLC) was selected for cleaning validation studies because of theirvalidation studies because of their sensitivity, specificity, and abilitysensitivity, specificity, and ability to quantify. The method should beto quantify. The method should be validated.validated.
- 40. 4040 7. SELECTING THE ANALYTICAL7. SELECTING THE ANALYTICAL METHODMETHOD • NON-SPECIFIC METHODS.NON-SPECIFIC METHODS. Spectrophotometric methods in the visible,Spectrophotometric methods in the visible, infrared, or UV rangesinfrared, or UV ranges Total organic carbon (TOC)Total organic carbon (TOC) Other MethodsOther Methods For monitoring cleaning procedure TOCFor monitoring cleaning procedure TOC method is used. It offers at a moderatemethod is used. It offers at a moderate cost and in addition to its rapidity, acost and in addition to its rapidity, a detection capability down to thedetection capability down to the ppbppb range.range.
- 41. 4141 8. DOCUMENTATION8. DOCUMENTATION • Validation Master PlanValidation Master Plan • Technical Transfer InformationTechnical Transfer Information such as solubility of product ingredients, such as solubility of product ingredients, therapeutic dose, equipments to be used and therapeutic dose, equipments to be used and its contact surface area, batch size, minimum its contact surface area, batch size, minimum daily dose, maximum daily dose etc for the daily dose, maximum daily dose etc for the preparation of preparation of Equipment Matrix &Equipment Matrix & ProductProduct MatrixMatrix.. • Equipment Qualification ReportsEquipment Qualification Reports (DQ/IQ/OQ/PQ)(DQ/IQ/OQ/PQ)
- 42. 4242 8. DOCUMENTATION8. DOCUMENTATION • Equipment logsEquipment logs • Training recordsTraining records • Method validation of analytical testMethod validation of analytical test methodmethod.. • Cleaning Validation ProtocolCleaning Validation Protocol • Cleaning Validation ReportsCleaning Validation Reports
- 44. 4444 The validation of cleaning method isThe validation of cleaning method is only meaningful if the written cleaningonly meaningful if the written cleaning procedures (on which the validation isprocedures (on which the validation is based) are always meticulouslybased) are always meticulously followed.followed.