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 Schedule Plan
Process / Products / Equipments ……consideration
Drawing diagram
Develop test method.
Surface area calc.
Validate test method
Schedule Plan
Sampling site set up
Sampling method
Recovery test
Acceptance limit 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
กรณีเหล่านี้เป็นเพียงแนวทางที่เราจะเลือกนำไปกำหนด policy ของบริษัทในการดำเนินการ cv ใน CVMP
INITIALLY : ครอบคลุมยาใหม่ และเครื่องใหม่
เครื่องมือใหม่ นอกจากควรทำ cv แล้ว ก่อนใช้งานครั้งแรกควรทำการตรวจสอบ verify ว่าล้างสะอาด อย่าคิดว่าเครื่องใหม่ไม่เปื้อนยาเก่าหรือ detergent ไม่ต้องล้าง สิ่งที่เราต้องคำนึงคือ เราไม่ทราบว่าอาจมี lubricant, acid passivation, dyes used in testing equipment.

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
- purpose
- scope
- responsibility
- equipment / materials
- reference documents
acceptance criteria
- sampling plan / method
test method
procedure

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 Typical visual limit is 1-4 mcg/cm2
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. Residue Detected / % Recovery = Adjusted Detected Residue
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.) Prepare solution of product/residue test
Each analyst
Prepare solution of product/residue x6
Spike solvent
Spike % residue limit
Spread to uniform layer
Let it dry x3 x3
test
Max.DEHT

24. Recovery Test ( cont.)
Swab recovery
Rinse sampling recovery

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
Specific method: บอกปริมาณที่แน่นอนของ residue ทีต้องการหา
Non specific method : ไม่เจาะจงสิ่งที่ตรวจพบ
TOC - detect any residue containing carbon
Conductivity – detect any ionic material
pH – detect any residue having acidic / basic character

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
Advantages
disadvantages
low LOD / LOQ
easy method development
high recovery of samples
cost effective
minimal interferences
automated / on-line sampling application
sample must be water soluble
sample can not be prepared in organic solvents.

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
ProductA หมายถึงผลิตภัณฑ์ที่จะใช้เป็นตัวแทนในการทาCleaning Validation
ซึ่งอาจมีได้หลายผลิตภัณฑ์ใน Equipment trainเดียวกันมี criteria ในการเลือก
คือ
-ตัวยาสาคัญมี solubility ต่ำ
-เป็นผลิตภัณฑ์ที่ล้างทาความสะอาดยาก
-เป็น potentdrugs
-lowest MACO (first choice) **
ProductB หมายถึงผลิตภัณฑ์สมมติเพื่อเป็นตัวแทนในการคานวณ residueของ
ProductA มี criteriaในการคัดเลือกคือ
•smallest batch size
•lowest# MDD
(#MDD: จานวนวันที่จะได้รับยาทั้งbatch จนหมด)

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

43. ให้ใช้ค่า default 10 ppm. ในการคำนวณacceptance limit
Note: กรณีที่คำนวณแล้วค่า ADI ของAPI Product A มีค่ามากกว่า 10 ppm.
ให้ใช้ค่า default 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 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)

51. Risk-Based Approach to Establishing Cleaning Validation Acceptance Limit (2)
Select the worst case by determining the min.:
Therapeutic dose-based limit (surface limit),
Toxicity-based limit (surface limit),
Health-based limit (surface limit), and
The concentration limit linked to NMT 10 ppm i.e.
Not more than 10 mg of active in ‘product A’ (i.e. with minimum MACO) carried over to 1,000,000 mg (1 kg) of the smallest- batch-size product (i.e. with minimum number of MDD or minimum number of days used up) which is called ‘product B’

52. Single Dose-Based Approach (PIC/S, WHO)
MACO: Maximum allowable carryover for SB (mg/batch)
LTD: Lowest therapeutic dose (mg/dose)
SB: Smallest batch size (g/batch)
MDD: Maximum daily dose for SB (g/dose)
SF: Safety factor (oral) = 1000

53. Daily Dose-Based Approach by CEFIC 2000 & 2014
MACO: Maximum allowable carryover for SB (mg/batch)
SDDA: Minimum daily dose (mg/day)
SB: Smallest batch size (g/batch)
SDDB: Standard therapeutic daily dose for SB (g/day)
SF: Safety factor (oral) = 1000

54. LD50 NOEL/ADI Approach by Hall (Cleaning Agent)
NOEL: No observed effect level (mg/person)
LD50: Lethal dose 50 in animal (mg/kg)
BW: Body weight (kg/person), normally use 70 kg
EF: Empirical factor = 2000 or 1/2000 =
ADI: Acceptable daily intake (mg/person/day)
SF: Safety factor (oral) = 1000
MACO: Maximum allowable carryover for SB (mg/batch)
SB: Smallest batch size (g/batch)
MDD: Maximum daily dose for SB (g/person/day)

55. LD50 NOEL Approach by CEFIC 2000 (Toxic-Based)
NOEL: No observed effect level (mg)
LD50: Lethal dose 50 in animal (mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000 or 1/2000 =
MACO: Maximum allowable carryover for SB (mg/batch)
SB: Smallest batch size (g/batch)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (g)

56. LD50 NOEL Approach by CEFIC 2014 (Toxic-Based)
NOEL: No observed effect level (mg/person)
LD50: Lethal dose 50 in animal (mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000 or 1/2000 =
MACO: Maximum allowable carryover for SB (mg/batch)
SB: Smallest batch size (g/batch)
SF: Safety factor (oral) = 1000
SDD: Standard daily dose for SB (g/person)
Note: MDD in 2000 version changes to SDD in 2014 ver.

57. NOAEL/ADE Approach by CEFIC 2014 (Health-Based)
ADE: Acceptable daily exposure (mg/day/person)
NOAEL: No observed adverse effect level (mg/kg/day)
BW: Body weight (kg/person), normally use 70 kg
CF: Combination factor, MF: Modifying factor
PK: Pharmacokinetic adjustments
EF: Empirical factor = 2000 or 1/2000 =
MACO: Maximum allowable carryover for SB (mg/batch)
SB: Smallest batch size (g/batch)
SF: Safety factor (oral) = 1000
SDD: Standard daily dose for SB (g/day/person)

58. Daily Dose-Based Approach – GPO
MACO: Maximum allowable carryover for SB (mg/batch)
mDD: Minimum daily dose (mg/day)
#MDD: Number of maximum daily dose (day/batch)
SF: Safety factor (oral) = 1000

59. LD50 NOEL Approach – GPO (Toxic-Based)
NOEL: No observed effect level (mg/person)
LD50: Lethal dose 50 in animal (mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000 or 1/2000 =
MACO: Maximum allowable carryover for SB (mg/batch)
SB: Smallest batch size (g/batch)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (g/day)

60. MACO for API1 in Oral Paste (Toxicity-Based)
NOEL: No observed effect level (1.82 mg)
LD50: Lethal dose 50 in animal (52 mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000
MACO: Maximum allowable carryover for SB (386.75mg)
SB: Smallest batch size (850x1000 g)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (4 g)
MACO (single dose-based) = g (g/batch of prod. B)

61. MACO for API2 in Oral Gel (Toxicity-Based)
NOEL: No observed effect level (78.75 mg)
LD50: Lethal dose 50 in animal (2250 mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000
MACO: Maximum allowable carryover for SB (16, mg)
SB: Smallest batch size (850x1000 g)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (4 g)
MACO (single dose-based) = g (g/batch of product B)

62. MACO for API3 in Oral Drop (Toxicity-Based)
NOEL: No observed effect level (117.6 mg)
LD50: Lethal dose 50 in animal (3360 mg/kg)
BW: Body weight (kg), normally use 70 kg
EF: Empirical factor = 2000
MACO: Maximum allowable carryover for SB (24,990mg)
SB: Smallest batch size (850x1000 mL)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (4 mL)
MACO (single dose-based) = g (g/batch of prod. B)

63. Universal Approach MACO: Maximum allowable carryover to SB (mg/batch)
ADX: ADI, ADE or mDD (mg/day)
#MDD: Number of maximum daily dose MDD in SB i.e. number of days for use-up of SB (day/batch), SB means the batch with minimum number of days for use up
SB: Smallest batch size (g/batch)
SF: Safety factor (oral) = 1000
MDD: Maximum daily dose for SB (g/day)

64. Calculation of Acceptance Limit (AL)
AL: Acceptance limit (mg/cm2)
MACO: Maximum allowable carryover (mg/batch), selected from the minimum of the limits from potency (dose), LD50 and 10 ppm approaches
SA: Surface area (cm2/batch)

65. LD50 vs. ADE Approaches (Provisional vs. Holistic Approaches)

66. LD50 vs. ADE Approaches (Provisional vs. Holistic Approaches)
LD50 Approach
ADE Approach
Use LD50 values alone as indicator – provisional first-line approach for limits estimation
Holistic approach: Use all the toxicological and pharmacological data involved
LD50 determinations have been discontinued
ADE or permitted daily exposure is the current approach
Limit calculations (LD50) can be performed by unqualified personnel
ADEs are determined by qualified pharmacologists / toxicologists
Derived limits are conservative, impractical, and unverifiable
Derived limits are realistic, practical, and verifiable
Limits are based on assumption that product residue is completely excreted on daily basis
Limits are based on the fact that product residue is not excreted compl-etely, or accumulated over time

67. References http://apic.cefic.org/pub/pub-cleaning- validation.pdf
dmin/documents/pdf/Cleaning_Validation_f or_the_21st_Century- Acceptance_Limits_for_Cleaning_Agents.pdf
cument_library/Scientific_guideline/2014/11/ WC pdf

68. Execution of the CV Study
The CV study must be executed according to the approved CV protocol.
Execution of the CV study includes all work defined in the CV protocol, including the analytical work, etc.
Records have to be generated and collected for all executed activities.
Soiling
Cleaning
Sampling
Analytical work
All records have to be reviewed and approved before the CV study can be evaluated and a final conclusion can be drawn.

70. Choose : hardest to clean & highest risk
Product Grouping
Conditions :
-Similar product type
-Similar excipientformulations
-Similar level of risk/toxicity
-Same equipment train
-Same cleaning process
Choose : hardest to clean & highest risk

71. Sampling method and sites set up
Equipment Grouping
Condition :
-Same type / model
-May be different size ( 2x200L, 4x500L, 3x1000L)
-Same cleaning process
-Different types of parts in same washer
-Exclude dedicated equipment
Sampling method and sites set up
3PQ(biggest)+3PQ(smallest) or 1PQ (biggest)+1PQ(smallest)+1PQ(any size)

72. Cleaning Process Grouping
Group A, B, C, D, E together and clean 25min.
RT. 4x50L Separate F to be individually validated

74. CV Summary report Elements of the Summary report - purpose - scope
- reference documents
- sampling record
- testing result
- deviation & discussion
- overall conclusion

75. Once the CV has been validated
Monitoring
Once the CV has been validated
Not necessary for every batch of each product
Monitoring schedule with certain frequency
Using non-specific method as screening
Sampling only worst site / Rinse overall area
Misconception
-Test until clean is good enough or better
-Using water specification to check final rinse for CV
-Use only rinse sampling for CV
Revalidation
When CHANGE is significantly affect the validity of Cleaning
When monitoring results : show a trend toward higher and higher residues.
Fix revalidation program
Review processes every 1-2 years and revalidate only those that need to be revalidated.

76. Question and Answer