Validation of Cleaning Processes

1. Validation of Cleaning Processes Part 2 ภก. ปราโมทย์ ชลยุทธ์ ภญ. ปิยาพร พิชัยคำ

2. Presentation Outline • Regulations, Regulatory Guidelines & Guidance • Reason, Definition and Concepts of Cleaning Validation • Cleaning Procedure • Cleaning agent • Microbiology/Sterilization • Practices and Procedures • Cleaning Validation Development • Protocol Development • Sampling • Analytical methods • Acceptable limits • Protocol Execution • Report Preparation (Summary and Conclusion)

3. Cleaning Validation Development

4. Steps to Proceed Process / Products / Equipments ……consideration Drawing diagram Develop test method. Surfacearea calc. Validate test method Schedule Plan Samplingsite set up Sampling method Recovery test Acceptancelimit set up Visual check

5. Steps to Proceed (cont.) CV Protocol RUN (Follow Protocol ) N Y Investigate & Correction Report Adopt CP( 3 runs ) Re-run & Evaluate ( until accomplish ) Maintain -Monitoring -Change control -Revalidation etc. Training

6. WHEN ARE CV SHOULD DONE ? ►INITIALLY ► PRODUCT CHANGE OVER ► CHANGE ( Formulation, Process, Equipment ) ► CHANGE ( Cleaning procedure ) ► AFTER SHUTDOWN ► AFTER MAINTENANCE ► PERIODICALLY

7. New Products During development : parameters are constantly being varied to optimize product quality CLEANING VERIFICATION Commercial production CLEANING VALIDATION

8. Documented evidence • CVMP • CV protocol • Cleaning process • CP development record • Analytical method validation • Method of analysis • Test result report • Sampling procedure • Recovery test • Summary report • Training record • Revalidation report • Surface area calculation record • Limits calculation record • Monitoring record • Deviation / Investigation record • Change control record • IQ , OQ ( Equipment ) • Maintenance & Calibration record

9. CV Protocol ☻Specific guide for validate CP of all equipment directly contact the represented product. ☻ Elements of the Protocol • acceptance criteria • - sampling plan / method • test method • procedure - purpose - scope - responsibility - equipment / materials - reference documents

10. Sampling Method • •Clean as soon as possible after use • –especially topical products, suspensions and bulk drug or • –where the drying of residues will directly affect the • efficiency of a cleaning procedure • •Two methods of sampling: • –direct surface sampling and • –rinse samples • •Combination of the two -most desirable

11. Direct surface sampling (direct method) • •Most commonly used method • •Use “swabs” (inert material) -type of sampling material should not interfere with the test • Factors to be considered include: • –supplier of the swab, • –area swabbed, number of swabs used, whether they are wet or dry swabs, • –swab handling and swabbing technique

12. Other factors include: –location from which the sample is taken (including worst case locations, identified in the protocol) –composition of the equipment (e.g. glass or steel) ** Critical areas (hardest to clean) –e.g. in semi-automatic/fully automatic clean-in-place systems ** Use appropriate sampling medium and solvent

13. Sampling Site Set-up for SWAB Concept : 1. hard to be cleaned 2. different material representatives 3. general area 4. slowest to dry 5. valve, orifice

14. Rinse samples (indirect method) •Allows sampling of: –a large surface –areas that are inaccessible or that cannot be routinely disassembled •Provides an "overall picture“ •Useful for checking for residues of cleaning agents •In combination with other sampling methods such as surface sampling

15. Visual inspection • should be performed as part of all CV studies because it is required by the guidelines. Thus, visual inspection is the minimum scope of sampling. • should cover all easy accessible surfaces of the equipment • also necessary to check critical spots which are not accessible for swabbing. • This may require dismantling of parts as e.g. valves (to check the inner surfaces of the valve) or the use of fiber optics (to check e.g. the inner surfaces of long pipes). Visual inspection Condition : •surface must be dry •consideration -viewer -angle -lighting -distance Typical visual limit is 1-4 mcg/cm2

17. Sampling Tools

19. Recovery Studies Recovery studies consist of using the selected sampling and detection methods on known levels of residues that have been “spiked” on the device surface above and below appropriate levels. For example, if 100 μg of residue was spiked on the surface and after swabbing or extracting, the detection analysis yielded 90 μg, the calculated percent recovery would be 90%. For cleaning validation, any analytical results would have to be adjusted by this recovery factor. Residue Detected / % Recovery = Adjusted Detected Residue

21. Swab Technique & Recovery Test - Trained & Verified Samplers - Spike target residue ( product // API ) - Surface type / Coupon - Uniformity of residue - Drying time ( min / max ) Using % Recovery to correct the result ?

22. Recovery Test ( cont.) ☻all trained ( samplers & analysts ) ☻ spike Product for specific test method spike Target residue for non specific test method ☻ spiked level : below the acceptance limit ☻ use the appropriate lowest recovery amount ( not the mean ) ☻ use recovery factor to correct the limit or test result

23. Recovery Test ( cont.) Each analyst Prepare solution of product/residue x6 Spike solvent Spike 50-100% residue limit Spread to uniform layer Let it dry x3 x3 test Max.DEHT

24. Recovery Test ( cont.) Swabrecovery Rinse samplingrecovery

25. Recovery Test % Recovery = amount detected x 100 amount spiked The recovery which is ≤ 50% improve Low recovery …. Residue adhesion to swab or surface …. Sampling technique …. Hold time consideration High recovery …. Interferences from swab or coupon

26. Test Method Specific method : HPLC, GC, IR, Spectro.( uv, visible ), TLC Non-specific method : TOC, Conductivity, pH, TDS, Titration • Should be validated before perform CV

27. Method Validation Parameters:USP and ICH Accuracy Precision Limit of Detection Method Validation Limit of Quantitation Specificity Linearity and Range Ruggedness/Robustness System Suitability

28. Method Validation( cont.) Specific method. Non-specific method Accuracy Precision Linearity Specificity Range LOD / LOQ

29. Method Validation Sensitivity of target residue LOD ( limit of detection ) : the assay value which show the existence of the residue but can not be quantified with exact value. LOQ ( limit of quantitation ) : the lowest precise assay value.

30. Test Method ( chemical residue ) • Swab & Rinse sample • HPLC • TOC • Spectrophotometer • Rinse sample • pH • Conductivity • Titration • Total Dissolve Solid new IMS ( Ion Mobility Spectrometer) : new developing equipment Photoemission ( direct surface monitoring ) : new developing equipment

31. Test Method( cont.) TOC: world-wide used to detect residue in Cleaning check

33. Establishing acceptable limits The limit-setting approach can: –be product-specific –group products into families and choose a worst case product –group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or difficult to detect products –use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials)

34. Limits may be expressed as: –a concentration in a subsequent product (ppm), –limit per surface area (mcg/cm2), or –in rinse water as ppm. •Limits for carry-over of product residues should meet defined criteria. •What are the three most commonly used criteria?

39. Factors to consider: -the nature of the primary product -the medical dosage of the primary product -the toxicity of the primary product -the solubility of the primary product -the difficult-to-reach locations of the equipment -route of administration -type of cleaning process ( manual / auto / semi ) -the medical dosage of the contaminated prod. -the batch size of other products made in the same equipment

41. Test Representatives ProductAหมายถึงผลิตภัณฑ์ที่จะใช้เป็นตัวแทนในการทาCleaning Validation ซึ่งอาจมีได้หลายผลิตภัณฑ์ในEquipment trainเดียวกันมีcriteriaในการเลือก คือ -ตัวยาสาคัญมีsolubilityต่ำ -เป็นผลิตภัณฑ์ที่ล้างทาความสะอาดยาก -เป็นpotentdrugs -lowest MACO (first choice) ** ProductB หมายถึงผลิตภัณฑ์สมมติเพื่อเป็นตัวแทนในการคานวณresidueของ ProductAมีcriteriaในการคัดเลือกคือ •smallest batch size •lowest# MDD (#MDD: จานวนวันที่จะได้รับยาทั้งbatch จนหมด)

42. Acceptance Daily Intake (ADI) Calculation by Toxicity -Based Limit คำนวณค่า ADI โดยใช้สูตร ADI = ((LD50x BW x 0.0005) x Safety Factor x Smallest Batch size B) * Max. Daily dose B

43. Note: กรณีที่คำนวณแล้วค่า ADI ของAPI Product A มีค่ามากกว่า 10 ppm. ให้ใช้ค่าdefault 10 ppm. ในการคำนวณacceptance limit

47. Establishing Toxicity-Based Acceptance Limits in Cleaning Validation

48. ‘Risk-Based Approach to CV’ Overview • Risk-based approach to cleaning validation • Risk-based approach to establishing cleaning validation (CV) acceptance limit (AL) • (Therapeutic or medical) dose-based approach • Toxicity-based approach • Risk-based approach to performing CV • Bracketing approach to performing CV (i.e. via grouping and selecting for the worst case using ‘worst case rating’ procedure – see CEFIC 2000 on CV in API plants) • Worst case approach to AL setting (lowest MACO) and sampling (product hardest to clean & area hardest to swab)

49. Relevant References • Therapeutic and toxicity-based approaches: • The two approaches have been referred by all guidelines including PIC/S and CEFIC (in 2000; The European Chemical Industry Council) • Recently ISPE issued Risk-Based Manufacture of Pharmaceutical Products Guide in Sept 2010 • PDA Technical Report # 29: Points to Consider for Cleaning Validation was revised in 2012 • ISPE paper was revised in Nov/Dec 2013 issue • CEFIC guide was revised in May 2014

50. Risk-Based Approach to Establishing Cleaning Validation Acceptance Limit (1) • Toxicity-Based App-roach (LD50 Approach) • MACO amount is NMT 0.1% of ‘no observed effect level’ (NOEL) amount carried over to maximum daily dose of smallest batch (wt. of MDD of product B) • Dose-Based App-roach • MACO amount is NMT 0.1% of single dose (active of prod. A) carried over to maximum daily dose of smallest batch (wt. of MDD of product B)