CONTAMINATION ACCEPTANCE LIMITHow to Choose the Limit?• Pharmaceutical products: • The minimum known pharmacological limit • Toxicological limit • <10 ppm• Detergent or some Pharmaceutical products • Toxicological limit • <10 ppm• Unknown sample: <10 ppm 52
CONTAMINATION ACCEPTANCE LIMIT• Microbial contamination • Rinsing sample: depend on rinsing solution • Purified water: 100 CFU / mL • Water for injection: 10 CFU / 100mL • Enterobacterial count, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella species are negative. 53
CONTAMINATION ACCEPTANCE LIMIT (Lucia Clontz, 2009)Based on bioburden specification for non-sterile pharmaceuticalproductsSwab limit (CFU/cm2) = BioS (CFU/g) x BSmin (g) x 1,000 Total surface area (cm2)BioS = Bioburden SpecificationBSmin = Smallest batch size of the next products1,000 = Conversion factorTotal surface area =Total surface area of equipment train 54
CONTAMINATION ACCEPTANCE LIMIT (Lucia Clontz, 2009)Based on bioburden specification for non-sterile pharmaceuticalproductsRinse limitswab (CFU/mL) = Swab limit (CFU/cm2) x Surface area (cm2) Rinse volume (mL)Swab limit = swab limit for surface samplingSurface area = sampled contact surface areaRinse volume = the used volume of rinse solutionCEHT: The bioload does not increase by more than 0.5 log (0.3 log harmonized) from the initialbioburden (baseline). 55
CLEANING VALIDATION PLANNING AND EXECUTIONORGANIZATION• Validation unit• Production• Production planning• Engineering• Quality assurance• R&D Analytical Development• Quality control 56
CLEANING VALIDATION PLANNING AND EXECUTIONORGANIZATIONResponsibility of Validation unitPrepare validation master plan, working plan and protocol including preparation ofdatabase, grouping, determination of worst case and identification of hard-to-cleanlocation.Responsibility of Production-Approve the validation master plan and the working plan-Verify accuracy of the cleaning procedure-Identify the equipment hard-to-clean location-Perform cleaning 57
CLEANING VALIDATION PLANNING AND EXECUTIONORGANIZATIONResponsibility of Production planning- Provide all information to build databaseResponsibility of Engineering- Verify accuracy of drawings and calculate product contact area- Assist in the identification of equipment hard-to-clean location 58
CLEANING VALIDATION PLANNING AND EXECUTIONORGANIZATIONResponsibility of Quality Assurance-Approve the validation master plan and the working plan-Approve validation protocol-Approve validation reportResponsibility of R&D Analytical development-Develop and validate the analytical method 59
CLEANING VALIDATION PLANNING AND EXECUTIONORGANIZATIONResponsibility of Quality Control- Perform the recovery study- Test samples and prepare analytical report 60
CLEANING VALIDATION PLANNING AND EXECUTIONDATABASE • The list of product, Cleaning agent and Equipment must be controlled, by date and edition, verified to be accurate at time the cleaning validation study starts and maintained up-to-date through the change control system. Product A Product B Product C Product D Product E Mixer #1 Mixer #2 Mixer #2 - Mixer #1 Dryer #1 Dryer #1 Dryer #1 - Dryer #2 Mill #1 Mill #2 Mill #1 Mill #3 Mill #2 Blender #1 Blender #2 Blender #3 Blender #1 Blender #2Tablet press #1 Tablet press #2 Tablet press #3 Tablet press #3 Tablet press #2 • List of equipment per product 61
CLEANING VALIDATION PLANNING AND EXECUTIONEQUIPMENT GROUPINGEquipment no. Equipment name Product 1 Mixer #1 A,E 2 Mixer #2 B,C 3 Dryer #1 A,B,E 4 Dryer #2 E 5 Mill #1 A,C 6 Mill #2 B,D 7 Mill #3 D 8 Blender #1 A,D 9 Blender #2 B,E 10 Blender #3 C 11 Tablet press #1 A 12 Tablet press #2 B,E 13 Tablet press #3 C,D 62
CLEANING VALIDATION PLANNING AND EXECUTIONEQUIPMENT GROUPING AND SELECT WORST CASEEquipment Equipment name Operating principle size Product Product contact 63 no. surface area 1 Mixer #1 High shear mixer X A,E Y bottom driven 2 Mixer #2 X B,C Y High shear mixer 3 Dryer #1 side driven X A,B,E Y 5 Mill #1 X A,C Y Fluid bed dryer 6 Mill #2 Screening mill with X B,D Y 8 Blender #1 oscillating bars X A,D 25000 cm3 9 Blender #2 Screening mill with 2X B,E 50000 cm3 12 Tablet press #2 X B,E 13 Tablet press #3 oscillating bars X C,D Y Twin shell blender Y Twin shell blender Force fed Gravity fed
CLEANING VALIDATION PLANNING AND EXECUTIONEQUIPMENT GROUPING AND SELECT WORST CASEGroup no. Equipment name Operating principle Product Product contact Hard-to-clean location surface area 1 Mixer #1 High shear mixer A,E 18000 cm3 XXX 2 bottom driven Mixer #2 B,C 20000 cm3 XXX 3 High shear mixer 4 Dryer #1 side driven A,B,E 12000 cm3 XXX Mill #1, 2 A,C,B,D 25000 cm3 XXX 5 Fluid bed dryer 6 Blender #1 Screening mill with A,D 25000 cm3 XXX 7 Blender #2 B,E 50000 cm3 XXX 8 Tablet press #2 oscillating bars B,E 9000 cm3 XXX Tablet press #3 Twin shell blender C,D 17000 cm3 XXX Twin shell blender Force fed Gravity fed 64
CLEANING VALIDATION PLANNING AND EXECUTION• PRODUCT GROUPING AND SELECT WORST CASEEquipment Product Active Solubility in LTD Daily dose Unit weight Batch sizeGroup no. name ingredient water 0.5 4 170 2381 A a Insoluble 10 8 245 245 E e Very slightly 100 8 245 2452 g Very soluble 2 6 123 247 B b Slightly soluble 125 3 1060 2653 C c Sparingly soluble 50 3 1060 265 f Freely soluble 0.5 4 170 2384 A a 2 6 123 247 B b Insoluble 125 3 1060 265 C c Slightly soluble 50 3 1060 265 f Sparingly soluble 0.5 4 170 238 A a Freely soluble 2 6 123 247 B b 125 3 1060 265 C c Insoluble 50 3 1060 265 f Slightly soluble 10 8 245 245 E e Sparingly soluble 100 8 245 245 g Freely soluble 65 Very slightly Very soluble
CLEANING VALIDATION PLANNING AND EXECUTION• PRODUCT GROUPING AND SELECT WORST CASEEquipment Product Active Solubility in LTD Daily dose Unit weight Batch sizeGroup no. name ingredient water 0.5 4 170 2385 A a Insoluble 1 8 530 493 D d Soluble 25 8 530 4936 h Soluble 2 6 123 247 B b Slightly soluble 10 8 245 2457 E e Very slightly 100 8 245 245 g Very soluble 2 6 123 2478 B b Slightly soluble 10 8 245 245 E e Very slightly 100 8 245 245 g Very soluble 125 3 1060 265 C c Sparingly soluble 50 3 1060 265 f Freely soluble 1 8 530 493 D d Soluble 25 8 530 493 h Soluble 66
CLEANING VALIDATION PLANNING AND EXECUTIONSolubility Term Approximate volume of solvent in ml. per g. of soluteVery solubleFreely soluble Less than 1Soluble From 1 to 10Sparingly soluble From 10 to 30Slightly soluble From 30 to 100Very slightly soluble From 100 to 1000Practically insoluble, Insoluble From 1000 to 10,000 More than 10,000 67
CLEANING VALIDATION PLANNING AND EXECUTIONCLEANING AGENTS• A similar approach is applied to the cleaning agents, using the LD50 of the most toxic component instead of LTD and most insoluble component to represent the visual worst case cleaning agent.Group no. Equipment Cleaning Active Solubility LTD Virtual Virtual Virtual X mg product product productname agent ingradient in water daily dose unit weight batch size5 Blender #1 Kleen k soluble 8 units/day 0.530 g 238*103 g 68
CLEANING VALIDATION PLANNING AND EXECUTIONCALCULATION OF THE CONTAMINATION ACCEPTANCE LIMIT• Active ingredient• Cleaning agent 69
CLEANING VALIDATION PLANNING AND EXECUTIONCALCULATION OF THE CONTAMINATION ACCEPTANCE LIMITSWABBING RINSINGSs = Swab area V = Volume of rinseSe = Product contact surface area R = Recovery factorR = Recovery factor 70
CLEANING VALIDATION PLANNING AND EXECUTIONCALCULATION OF THE CONTAMINATION ACCEPTANCE LIMIT For group no.5 Active ingredient 71
CLEANING VALIDATION PLANNING AND EXECUTIONCLEANING VALIDATION MASTER PLAN•A cleaning validation master plan is drawn up and serves as the basisfor the determination of all the activities to be performed to conductthe cleaning validation studies in cost-effective and timely manner.•Cleaning validation master plan is comprehensive and controldocument that include : • Cleaning validation policy • Product and equipment database • Product and equipment grouping • Product and equipment worst case • Calculation of the contamination limit 72
CLEANING VALIDATION PLANNING AND EXECUTIONCLEANING VALIDATION PROTOCOL • Protocol is written in a generic format. • Protocol should refer to the cleaning validation master plan, be concise and give clear instructions how to conduct the cleaning validation study. • Protocol should be reviewed and approved by the validation group, production and QA before execution. 73
CLEANING VALIDATION PLANNING AND EXECUTIONCLEANING VALIDATION PROTOCOL DEFINITIONS• Should contain REFERENCES ATTACHMENTS OBJECTIVE SCOPE Product, Cleaning agent database RATIONALE Equipment database ACCEPTANCE LIMITS Cleaning procedure RESPONSIBILITIES Sampling procedure EQUIPMENT TO BE CLEANED Drawing MATERIALS TO BE USED TEST PROCEDURES Equipment surface area VALIDATION REPORT Hard to clean locations 74
CLEANING VALIDATION PLANNING AND EXECUTIONSAMPLING AND TESTING • Sampling is performed, as a worst case, after cleaning at the end of the time limitation allowed. • Swab sampling is performed in accordance with an approved diagram of equipment, marked with location to be sampled. • Residue in the swabs are extracted into a measured volume of an appropriate extraction solvent. • After extraction, the solvent is tested according to the appropriate analytical method • The results are recorded in mg/ml, converted to mg/swab and compared to the calculated contamination limit. 75
CLEANING VALIDATION PLANNING AND EXECUTIONCLEANING VALIDATION REPORTThe report should include the following: • Record of cleaning, sample and test. • Physical and analytical test results. • Conclusions regarding the acceptability of the results. • Approval of conclusions • Review any deviations for the protocol. 76
References• PIC/S: PI006-3, Recommendations on VMP, IQ, OQ, PV and CV, 25 Sep. 2007• PIC/S: PE009-11 (Part II), GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS PART II, 1 March 2014• Cleaning and Cleaning Validation, Volume 2, Paul L. Pluta, PDA, USA, 2013• Cleaning Validation Manual: A Compehensive Guide fo the Pharmaceutical and Biochnology Industries, Syed Imtiaz Haider, Ph.D., Erfan Syed Asif, Ph.D., CRC Press, Taylor & Francis Group. 2010• Microbial Limit and Bioburden Tests: Validation Approaches and Global Requirements, 2nd edition, Lucia Clontz, 2009• Cleaning Validation, A Practical Approach, Gil Bismuth and Shosh Neumann, Interpharm Press, Denver, Colorado, 2000• Cleaning Validation for the Pharmaceutical Industry, Bill Hall, Ph.D. President, Hall and Associates, Technomics Publishing Pharmaceutical Division• Validated Cleaning Technologies for Pharmaceutical Manufacturing, Destin A. LeBlanc, Interpharm Press, Denver, Colorado, 2000• World Health Organization, WHO Technical Report Series, No. 961, 2011, Annex 6 77
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