doc_project_part2 (1).ppt

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

 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)
Presentation Outline
2

3
Cleaning Validation Development

4
Steps to Proceed
Process / Products / Equipments ……consideration
Drawing diagram
Sampling site set up
Surface area calc.
Acceptance limit set up
Develop test method.
Validate test method
Recovery test
Sampling method
Visual check

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

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
- 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
• should be performed as part of all
CV studies because it is required
the guidelines. Thus, visual
inspection is the minimum scope
sampling.
• should cover all easy accessible
surfaces of the equipment
• also necessary to check critical
which are not accessible for
swabbing.
• This may require dismantling of
parts as e.g. valves (to check the
Visual
inspection
Condition :
•surface must
be dry
•consideration
-viewer
-angle
-lighting
-distance
Typical visual limit is 1-

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

24
Rinse sampling recovery Swab 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

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

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

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.

Test Method ( chemical residue )
Swab & Rinse sample
HPLC
TOC
Spectrophotometer
Rinse sample
pH
Conductivity
Titration
Total Dissolve Solid
30
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
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)
Establishing acceptable limits

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
ProductA หมายถึงผลิตภัณฑ์ที่จะใช้เป็ นตัวแทนในการทาCleaning
Validation
ซึ่งอาจมีได้หลายผลิตภัณฑ์ใน Equipment trainเดียวกันมี criteria ใน
การเลือก
คือ
-ตัวยาสาคัญมี solubility ต่า
-เป็ นผลิตภัณฑ์ที่ล้างทาความสะอาดยาก
-เป็ น potentdrugs
-lowest MACO (first choice) **
ProductB หมายถึงผลิตภัณฑ์สมมติเพื่อเป็ นตัวแทนในการคานวณ
residueของ
ProductA มี criteriaในการคัดเลือกคือ
•smallest batch size
Test Representatives

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

43
Note: กรณีที่คานวณแล้วค่า ADI ของAPI Product A มีค่า
มากกว่า 10 ppm.
ให้ใช้ค่า default 10 ppm. ในการคานวณacceptance limit

Establishing Toxicity-Based
Acceptance Limits in Cleaning
Validation

‘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)

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
Relevant References

Risk-Based Approach to Establishing
Cleaning Validation Acceptance
Limit (1)
 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)
 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)

 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’
Risk-Based Approach to Establishing
Cleaning Validation Acceptance
Limit (2)

 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
Single Dose-Based Approach (PIC/S, WHO)
MACO =
LTD(mg/ dose)xSB(g/ batch)
MDD(g/ dose)xSF
...(mg/ batch)

(mg/batch)
 SDDA: Minimum daily dose (mg/day)
 SDDB: Standard therapeutic daily dose for SB
(g/day)
Daily Dose-Based Approach by CEFIC 2000 & 2014
MACO =
SDDA
(mg/ day)xSB(g/ batch)
SDDB
(g/ day)xSF
...(mg/ batch)

 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 = 0.0005
 ADI: Acceptable daily intake (mg/person/day)
 MACO: Maximum allowable carryover for SB (mg/batch)
 MDD: Maximum daily dose for SB (g/person/day)
LD50 NOEL/ADI Approach by Hall (Cleaning Agent)
NOEL =LD50
(mg/ kg)xBW(kg/ person) /EF...(mg/ person)
MACO =
ADI(mg / person / day)xSB(g/ batch)
MDD(g/ person / day)
...(mg / batch)
ADI=NOEL(mg/ person) / SF...(mg/ person) / day

 NOEL: No observed effect level (mg)
 BW: Body weight (kg), normally use 70 kg
 MDD: Maximum daily dose for SB (g)
LD50 NOEL Approach by CEFIC 2000 (Toxic-Based)
NOEL =LD50
(mg/ kg)xBW(kg) /EF...(mg)
MACO =
NOEL(mg)xSB(g / batch)
MDD(g)xSF
...(mg/ batch)

 SDD: Standard daily dose for SB (g/person)
 Note: MDD in 2000 version changes to SDD in 2014 ver.
LD50 NOEL Approach by CEFIC 2014 (Toxic-Based)
NOEL =LD50
MACO =
NOEL(mg / person)xSB(g/ batch)
SDD(g/ person)xSF
...(mg/ batch)

 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
 SDD: Standard daily dose for SB (g/day/person)
NOAEL/ADE Approach by CEFIC 2014 (Health-Based)
ADE =
NOAEL(mg/ kg/ day)xBW(kg/ person)
CFxMFxPK
...(mg/ day / person)
MACO =
ADE(mg / day / person)xSB(g/ batch)
SDD(g / day / person)xSF
...(mg / batch)

(mg/batch)
 mDD: Minimum daily dose (mg/day)
 #MDD: Number of maximum daily dose
(day/batch)
Daily Dose-Based Approach – GPO
MACO =
mDD(mg/ day)x #MDD(day / batch)
SF
...(mg/ batch)
#MDD =
SB(g / batch)
MDD(g / day)
...(day / batch)

 MDD: Maximum daily dose for SB (g/day)
LD50 NOEL Approach – GPO (Toxic-Based)
NOEL =LD50
MACO =
NOEL(mg/ day)x #MDD(day / batch)
SF
...(mg/ batch)
#MDD =
SB(g / batch)
MDD(g / day)
...(day / batch)

 NOEL: No observed effect level (1.82 mg)
 LD50: Lethal dose 50 in animal (52 mg/kg)
 EF: Empirical factor = 2000
 MACO: Maximum allowable carryover for SB (386.75mg)
 SB: Smallest batch size (850x1000 g)
 MDD: Maximum daily dose for SB (4 g)
 MACO (single dose-based) = 0.425 g (g/batch of prod. B)
MACO for API1 in Oral Paste (Toxicity-Based)
NOEL =LD50
(mg/ kg)xBW(kg) /EF = 52(mg/ kg)x70(kg) / 2000 =1.82mg
MACO =
NOEL(mg)xSB(g)
MDD(g)xSF
=
1.82(mg)x850x1000(g)
4(g)x1000
= 386.75mg
= 0.387g= 0.455ppm

 MACO: Maximum allowable carryover for SB (16,734.375mg)
 SB: Smallest batch size (850x1000 g)
 MDD: Maximum daily dose for SB (4 g)
 MACO (single dose-based) = 42.500 g (g/batch of product B)
NOEL =LD50
(mg/ kg)xBW(kg) /EF = 2250(mg/ kg)x70(kg) / 2000 = 78.75mg
MACO =
NOEL(mg)xSB(g)
MDD(g)xSF
=
78.75(mg)x850x1000(g)
4(g)x1000
=16,734.375mg
=16.734g=19.688ppm
MACO for API2 in Oral Gel (Toxicity-Based)

 MACO: Maximum allowable carryover for SB (24,990mg)
 SB: Smallest batch size (850x1000 mL)
 MDD: Maximum daily dose for SB (4 mL)
 MACO (single dose-based) = 285.855 g (g/batch of prod. B)
NOEL =LD50
(mg/ kg)xBW(kg) /EF = 3360(mg/ kg)x70(kg) / 2000 =117.6mg
MACO =
NOEL(mg)xSB(mL)
MDD(mL)xSF
=
117.6(mg)x850x1000(mL)
4(mL)x1000
= 24,990mg
= 24.99g= 29.4ppm
MACO for API3 in Oral Drop (Toxicity-Based)

 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
 MDD: Maximum daily dose for SB (g/day)
Universal Approach
MACO =
ADX(mg/ day)x #MDD(day / batch)
SF
...(mg/ batch)
#MDD =
SB(g / batch)
MDD(g / day)
...(day / batch)

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)
Calculation of Acceptance Limit (AL)
AL =
MACO(mg / batch)
SA(cm2
/ batch)
=
MACO(mg)
SA(cm2
)
...(mg/ cm2
)

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

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

References
 http://apic.cefic.org/pub/pub-cleaning-
validation.pdf
 http://web.stevens.edu/ses/documents/fileadmin/
documents/pdf/Cleaning_Validation_for_the_21st_
Century-
Acceptance_Limits_for_Cleaning_Agents.pdf
 http://apic.cefic.org/pub/APIC_Cleaning_Validation_2014.pdf
 http://www.ema.europa.eu/docs/en_GB/document
_library/Scientific_guideline/2014/11/WC5001777
35.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

70
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
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
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
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.
-Test until clean is
good enough or
better
-Using water
specification to
check final rinse
for CV
-Use only rinse
sampling for CV
Misconception

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