Cleaning Validation.pptx

Cleaning validation

1. Cleaning Validation Presented By: Owais Ahmed Manager QA (Validation) Dated : Jul 01 , 2022

2. What is cleaning validation? Cleaning validation is documented evidence that the cleaning process can effectively and reproducibility clean equipment to a pre-defined acceptable level. Pre defined Acceptable level ? MACO : Maximum Allowable Carry Over Microbial Limit Cleaning Attributes: pH, TOC, Conductivity

3. RATIONALE Effective cleaning prevents unacceptable levels of contamination from products, cleaning agents A systematic, standardised approach to cleaning validation and verification is required in order to provide assurance that cleaning is effective.

4. Objective : The objective of cleaning validation is: To verify the effectiveness of the cleaning procedure that the equipment is consistently cleaned of product, detergent and microbial residues to an acceptable level, to prevent possible contamination and cross-contamination. To provide documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use.

5. Cleaning Validation Approach: The approach for conducting cleaning validation studies is “Risk based” approach i.e. to select “worst case” on the basis of following criteria: Solubility. Ease of Cleaning. Toxicity. Potency.

6. CALCULATION OF ACCEPTANCE CRITERIA There are different methods for calculation of Acceptance criteria for cleaning validation study which are as follows: Based on Therapeutic Daily Dose Based on 10 ppm General Limit Note: Both methods are used for calculation and most stringiest limit calculated from two methods will be used for cleaning validation study.

7. FORMULA USED FOR CALCULATION 1/1000 of Therapeutic daily dose: MACO = TDD previous (mg) x BS (mg) 1000 x TDD next (mg) Where: MACO = Maximum Allowable Carryover TDD previous = Minimum TDD of the contaminating substance (mg) TDD next = Maximum TDD of the contaminated substance (mg) BS = Batch size of the contaminated substance (mg) 1000 = Safety factor 10 ppm general limit: MACOppm = MAXCONC x MBS MACOppm Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous"). Calculated from general ppm limit. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm ) of "previous" substance in the next batch. MBS Minimum batch size for the next product

8. Question

9. CALCULATION TABLE

10. Answer

11. Question Product D is considered as investigated Product whose therapeutic daily dose is 5 mg/day. The next Product which will be manufactured is Product B which have a batch size of 417.749 kg i.e. 417749000 mg and its therapeutic daily dose in 25 mg/day. Calculate the MACO based on both methods i.e. therapeutic approach and 10 ppm (0.00001 mg) general limit. Which limit will be used as MACO.

12. Answer Based on therapeutic approach MACO = TDD previous (mg) x BS (mg) 1000 (safety factor) x TDD next (mg) = 5x417749000 1000x25 = 83549.8 mg

13. Answer Based on 10 ppm general limit 10 ppm general limit: MACO = MAXCONC x MBS = 0.00001x417749000 = 4177.49 mg

14. ANSWER 10 ppm general limit will be considered MACO due to most stringent limit calculated.

15. RECOVERY STUDY Recovery factors for cleaning validation residue testing are an essential element of any cleaning validation program. The FDA Guide to Inspection of Validation of Cleaning Processes states that firms need to “show that contaminants can be recovered from the equipment surface and at what level”. The Health Canada and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) cleaning validation guidances also require that recovery experiments be completed. Recoveries are necessary for direct surface sampling using a swab.

16. RECOVERY STUDY To determine the recovery factor through experiments in which sample equipment materials of construction (MOC) spiked with known amounts of the substance of interest are recovered and tested. The recovery must be capable of capturing a sufficient amount of material to allow an accurate and precise measurement of the spiked component.

17. Recovery studies Usually carried out in the laboratory using coupons to simulate the product contact surface. •Generally 80% recovery required/ considered good •Less than 50% recovery needs a justification / not acceptable

18. Recovery Factor:- % Recovery =   Area of Sample × Concentration of Standard ×100                          Area of Standard × Concentration of Sample Acceptance Criteria for recovery >80% Considered good >50% Reasonable <50% Questionable

19. Sampling Method: Two methods of sampling considered to be acceptable. These are direct surface sampling and rinse sample. A combination of the two methods is generally the most desirable and best suited. Selection of method shall be identified and justified in the protocol. a) Surface Sampling (Direct Method): This method is designed for sampling of hard to clean area i.e. surface of Equipment, Machine area etc. Swab of hard to clean areas shall be taken by dragging it on the surface of the equipment horizontally and vertically. Press down the swab handle firmly to ensure proper surface contact Swab Samples will be taken & should be covered 10cm x 10cm for QC testing & 5cm x 5cm area for Microbial tests. Swab will be taken in right to left and top to bottom & vice versa directions,

20. Continue…. b ) Rinse Sample (Indirect Method): This method allows sampling of a large surface area that are inaccessible or that cannot be routinely disassembled and provides an overall picture. Rinse samples may give sufficient evidence of adequate cleaning where accessibility of equipment parts can preclude direct surface sampling, and be useful for checking of the residues for cleaning agent e.g. detergents.

21. SAMPLING METHODOLOGY The recommended strategy is to wet a swab with solvent. Remove any excess solvent from the swab as described previously. Swab an area of 100 cm 2 (10 cm x 10 cm).

22. EQUIPMENT HOLD TIME Dirty Hold Time Definition: The interval allowed between the completion of production activities and the start of cleaning Purpose: The dirty hold time validation demonstrates the capability of the cleaning cycle to reduce bioburden and endotoxin to the acceptance criteria.

23. EQUIPMENT HOLD TIME Clean Hold Time Definition: The interval that equipment may be held between the completion of cleaning and the initiation of the subsequent manufacturing operation without requiring further cleaning Purpose: The purpose of validating a clean hold time is to confirm that the equipment remains clean following cleaning and before use when stored under normal storage conditions.

24. CLEANING PROCESS PARAMETERS Cleaning process parameters typically used during cleaning validation mentioned below: Cleaning time Cleaning technique (Automatic/Manual Cleaning) Quantity of Water used Quantity of cleaning agent used Temperature of Water Clean Hold time Dirty Hold time

25. ROUTINE MONITORING To ensure the continued effectiveness of the cleaning cycle, routine monitoring/trending is required for validated cleaning processes. Depending upon the facility and products, this includes testing and monitoring of critical cleaning attributes ( TOC,pH , conductivity, Bioburden , endotoxin )

26. REFERENCES WHO Guideline (Appendix -3 Cleaning Validation)-TRS 937, 2006 (APIC). Sep-2016 Section 211.67 of part 21 of the Code of Federal Regulations (CFR) Section 211.182 of part 21 of the CFR Health Canada Cleaning Validation Guidelines (GUIDE-0028) PIC/S Annex15 Qualification and validation PE 009-14 July 2018

27. THANKS