CLEANING VALIDATION PROTOCOL

FOR KIMSY IBUPROFEN ORAL

SUSPENSION

PROTOCOL NUMBER :

EFFECTIVE DATE :

SUPERSEDES NUMBER : NA

REASON FOR VALIDATION : New Protocol Prepared /Revalidation/ Periodic

re-validation / worst case change

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Table of content
Sr. Page
Topics
No. No.
1. Protocol pre-approval 3
2. Objective 4
3. Scope 4
4. Validation team & their responsibilities 5
5. Prerequisites for cleaning validation 6
6. Cleaning validation strategy 6
Total contact surface area of equipment’s used for the
7. 11
manufacturing
8. Product profile 12
9. Required materials 14
10. Elements of cleaning validation 15
11. Validation methodology 16
12. Sampling procedure 22
13. Calculation for maximum allowable carry over (MACO) 24
14. Analytical test methods 28
15. Determination of final acceptance criteria 29
16. Revalidation criteria 32
17. Variance sheet 32
18. Abbreviation 32
19. List of attachments 34
20. Revision history 34
Appendix 1: validation variance report form 35

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1.0 Protocol Pre-Approval:

The Cleaning Validation protocol has been prepared, reviewed and approved for
execution by authorized personnel from the following functional departments.

Prepared By:

Functional
Name Designation Signature Date
Area
Quality
Assurance

Reviewed By:

Functional
Name Designation Signature Date
Area

Production

Quality
Control/ADL

Engineering

Approved By:

Functional
Name Designation Signature Date
Area
Quality
Assurance

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2.0 Objective:
 The objective of this protocol is to establish and assure with the
documented evidence that the cleaning procedures used after
manufacturing of Kimsy Ibuprofen Oral Suspension 100 mg/ 5ml is
effective and consistently performs as expected and produce a result that
meets predetermined acceptance criteria when manufactured.
 To provide documented evidence through the scientific data to show that
the cleaning procedures used after manufacturing of Kimsy Ibuprofen
Oral Suspension 100 mg/ 5ml is effective and consistently performs as
expected and produce a result that meets predetermined acceptance
criteria when manufactured.
 To establish that the cleaning process shall provide a high degree of
assurance for removal of residue for last manufactured product, so that the
residues are not transferred to the subsequently manufactured product.
 To prove that the equipment is consistently cleaned of product to an
acceptable level to prevent contamination and cross-contamination.
3.0 Scope :

 This protocol is applicable for cleaning validation of Kimsy Ibuprofen

Oral Suspension 100 mg/ 5ml manufactured area. This protocol will
evaluate the acceptability of cleaning procedures used in cleaning of
equipments and utensils, established analytical method to determine the
content of product residues in equipments and areas after cleaning.
 Cleaning validation efforts shall be directed to the critical processing steps,
where contamination or incidental carryover of previous product residue
poses the great risk to the quality and safety of subsequent product to be
manufactured.
 Minimum three consecutive successful cleaning procedures after the usage
of high risk product shall be performed to satisfy the cleaning validation
approach.
 This protocol is applicable to manufacturing facility located at Kimsy
Pharmaceutical Industries Limited.

4.0 Validation team & their Responsibilities :

 The validation team comprising of a representative from each of the following
departments shall be responsible for the overall compliance with this protocol.
4.1 Quality Assurance:
4.1.1 To prepare cleaning validation protocol and to ensure the correctness to the
cGMP requirements.
4.1.2 To coordinate the planning and scheduling of the cleaning validation activities.

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4.1.3 To coordinate for the development, analytical studies and sampling as required in
cleaning validation.
4.1.4 To execute cleaning validation study.
4.1.5 To collect the swab and rinse samples as per identified location.
4.1.6 To review cleaning validation protocol.
4.1.7 Approval of cleaning validation protocol and to authorize the cleaning procedure
for equipments.
4.2 Production:
4.2.1 To review the document from the process/system owner perspective.
4.2.2 Ensure appropriate resources are available to execute the cleaning validation
activities.
4.2.3 To participate in the planning and scheduling of cleaning validation activities.
4.2.4 Making available equipments/areas/containers/man power as per the test
requirements.
4.2.5 To support the timely execution of validation activities.
4.2.6 Checking that all the required equipments are operating as per the respective
SOP and that measuring components on the equipment are in calibration status.
4.2.7 Ensuring availability of equipments/ areas/ containers/ man power as per
requirements.
4.2.8 To report deviations from the protocol, if any
4.2.9 To review cleaning validation protocol.
4.3 Engineering :
4.3.1 To support the surface area calculation of equipment train.
4.3.2 To schedule the utility and area requirements in line with the production
departments.
4.3.3 Ensure correct functioning of the utilities and to make sure that required utilities
are available in the operating range.
4.3.4 To participate in planning and scheduling of cleaning validation activities
4.3.5 To review cleaning validation protocol.
4.4 Quality Control:
4.4.1 Swab preparation for cleaning validation activities.
4.4.2 To provide the swab wetting agent for swab sampling.
4.4.3 To analyze the swab samples and rinse samples and then provide results to QA.
4.4.4 To review cleaning validation protocol.

5.0 PREREQUISITES FOR CLEANING VALIDATION

5.1 Pre-requisites for cleaning validation activities are approved SOPs of cleaning
procedure for equipment’s, validated analytical methods for estimation of active
residues, as well as the training for the operators on the specific SOPs of
equipment cleaning.

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5.2 All equipment and processes must be designed to ensure that equipment is
cleanable.
5.3 All process and cleaning equipment and clean utilities have been qualified.
5.4 Information on Materials of Construction (MOC's) and their associated surface
areas are available for all surfaces being cleaned, and these are documented.
5.5 SOP for the equipment’s are available and Operators have been trained on
approved cleaning procedures.
5.6 PDEs for all products are documented.
5.7 Analytical and sampling methods are validated.

6.0 CLEANING VALIDATION STRATEGY:

6.1 For Selection of Worst-Case Molecule, consider of below criteria:
6.1.1 Solubility – Practically insoluble in water.
6.1.2 Toxicity- Health based exposure limits (ADE Value)
6.1.1 Solubility (S): Solubility is identified based on the parts of water required for 1
part of solute (API), as presented in the table below.
Active Pharmaceutical
Brand Name Solubility in Water
Ingredient
Magnesium Trisilicate,
Maaga Suspension Light Magnesium Carbonate Practically Insoluble
Sodium Bicarbonate
Kimsy Metronidazole Metronidazole Benzoate
Practically Insoluble
Oral Suspension
Kimsy Paracetamol Oral Paracetamol
Sparingly Soluble
Suspension
Kimsy Ibuprofen Oral Ibuprofen
Practically Insoluble
Suspension
Note: Refer Attachment 01.
Remarks: Based on above criteria, if two or more API are having the same solubility
then API with the highest toxicity (lowest PDE value) shall be considered as worst case.
2. Toxicity (Health based exposure limits (ADE) approach):
The PDE value shall be calculated on the basis of the LD50 which is outsourced from the
Google.
 Determination of PDE:
LD50 x BW (Weight adjustment)

NOAEL =
2000

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Where,
NOAEL = No Observable Adverse Effect Level (mg/kg/day)
LD50 = Lethal Dose
BW = Body Weight (70 kg constant)
2000 = Empirical Constant
NOAEL x BW (Weight adjustment)
PDE =
Fl x F2 x F3 x F4.x F5
Where,
PDE = Permitted Daily Exposure (mg/day)
BW = Body weight of patient taking next product (e.g., 50 kg)
UFC = Composite Uncertainty Factor: combination of factors from F1 to F5.
Fl = A factor (2 to 12) to account for extrapolation between species.
F2 = A factor of 10 to account for variability between individuals.
F3 = A factor 10 to account for repeat dose toxicity studies of short duration
F4 = A factor (1 to 10) that may be applied in cases of severe toxicity,
e.g., non-genotoxic carcinogenicity, neurotoxicity or teratogenicity.
F5 = A variable factor that may be applied if the no-effect level (NOAEL) was not
established. When only an LOAEL is available, a factor of up to 10 could be used
depending on the severity of the toxicity.
Active Pharmaceutical Permitted Daily
Brand Name
Ingredient Exposure (mg/day)
Magnesium Trisilicate,
Light Magnesium
Maaga Suspension 12.25
Carbonate
Sodium Bicarbonate
Kimsy Metronidazole Oral Metronidazole Benzoate
7.35
Suspension
Kimsy Paracetamol Oral Paracetamol
4.76
Suspension
Kimsy Ibuprofen Oral Ibuprofen
1.56
Suspension
Note: Refer Attachment 02.
Remarks: Based on the PDE calculation, Kimsy Ibuprofen Oral Suspension have
been identified as worst-case product.
7.0 PRODUCT DETAILS:
Name of product (to be cleaned): Ibuprofen Oral Suspension 100 mg / 5 ml
Product formulation: Reference Batch Record: BMR/09/2000L/2
Label Claim: Each 5 ml contains: Ibuprofen 100 mg
Solubility: Practically insoluble in water

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Product Kimsy Ibuprofen Oral Suspension 100 mg / 5
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Pharmacopoeial
Sr. No. Name of Material Qty per 5 ml
Status
1. Ibuprofen BP 100mg
2. Sucrose BP 1250mg
3. Sorbitol 70% non-crystallizing. BP 150mg
4. Anhydrous colloidal silica BP 25mg
5. Xanthan gum BP 10mg
6. Carmellose sodium BP 25mg
7. Glycerin BP 150mg
8. Propylene glycol BP 50mg
9. Citric acid anhydrous BP 30mg
10. Disodium edetate BP 2.5mg
11. Sodium benzoate BP 10mg
12. Sodium propyl paraben BP 1mg
13. Sodium methyl paraben BP 10mg
14. Polysorbate 80 BP 5mg
15. Orange flavor Food grade 15mg
16. Sunset yellow Food grade 0.25mg

8.0 Equipment Train Matrix for Suspension:

The following equipments are to be used for manufacturing of the product.
Sr. Equipment Name Equipment Surface Area Surface Area
No. I.D. mm2) (cm2)
DISPENSING & SAMPLING:
1. 1kg Open Stainless-steel PDN-TL/ 83291.48
832.91
Scoops 042S
2. 1kg Close Stainless-steel PDN-TL/ 113794.93
1137.94
Scoops 044
3. 500g Open Stainless-steel PDN-TL/ 60514.93
605.14
Scoops 048S
4. 500g Close Stainless-steel PDN-TL/ 91695.24
916.95
Scoops 050
5. 250g Open Stainless-steel PDN-TL/ 42411.51
424.11
Scoops 053
6. 100g Close Stainless-steel PDN-TL/ 39858.96
398.58
Scoops 057
7. Dispensing booth HEPA filter PDN-E/004 5046000
50460
grills
8. Sugar dispensing booth HEPA PDN-E/004 5120000
51200
filter grills
9. 3 Kg Weighing Balance PDN-E/013 61600 616

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Sr. Equipment Name Equipment Surface Area Surface Area

No. I.D. mm2) (cm2)
10. 300 Kg Weighing Balance PDN-E/008 360000 3600
11. PDN-TL/ 1610448.04
50 L plastic bucket 16104.48
059
12. PDN-TL/ 1606348.68
50 L HDPE bucket 16063.48
068
13. Barrel pump PDN-E/071 255731.92 2557.31
14. PDN-TL/ 424743.33
15 L Stainless-steel Bucket 4247.43
012
15. PDN-TL/ 815588.87
30 L Stainless-steel Bucket 8155.88
005
16. PDN-TL/ 177386.73
80 L Stainless-steel Bucket 1773.86
002
17. PDN-TL/ 251916.46
5 L Stainless-steel Bucket 2519.16
019
18. PDN-TL/ 62831.85
1 L Stainless-steel Jug 628.31
109
19. PDN-TL/ 1151110.96
50 L Stainless-steel Bucket 11511.10
009
20. Stainless-Steel Stirring Rod- PDN-TL/ 128190.15
1281.90
Long 034
21. Stainless-Steel Stirring Rod- PDN-TL/ 104628.20
1046.28
Short 041
22. Stainless-Steel Sampling PDN 40312.92
403.12
scoop
MANUFACTURING AREA:
23. Pipe work PDN-E/037 4336747.79 43367.47
24. 150 L Sugar Dissolving Tank- PDN-E/058 2617908.79 26179.08
25. 1000 L Pre-Mixing Tank PDN-E/017 8633253.69 86332.53
26. 2000 L Main Mixing Tank PDN-E/018 14325662.49 143256.62
BOTTLE CLEANING AREA:
27. Bottle cleaning Machine PDN-E/036
28. Dust Collector PDN-E/036
FILLING AREA:
29. Holding tank-Liquid PDN-E/044 13225533.3 132255.33
30. Transfer pump case PDN-E/044 186765.27 1867.65
31. Reservoir Tank PDN-E/046 2069300 20693.00
32. Reservoir Tank discharge PDN-E/045 21626.61
216.26
nozzle

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Sr. Equipment Name Equipment Surface Area Surface Area

No. I.D. mm2) (cm2)
33. Piston Pump Case PDN-E/045 203575.20 2035.75
34. Piston Pump discharge hose PDN-E/ 249756.62
2497.56
Pipe 045S
35. Piston Pump suction hose PDN-E/ 400515.36
4005.15
Pipe 045S
36. 6 Nozzle pipes PDN-E/045 17190.80 171.90
37. Pipe work PDN-E/044 301739.02 3017.39
Total Surface Area 64237980.1 642379.63
Note: Refer Attachment 03.

9.0 REQUIRED MATERIALS FOR CLEANING:

9.1 For cleaning :
9.1.1Purified water
9.1.2RO Water
9.1.3S.S. strip, Sponge, nylon brushes, lint free cloth
9.2 For sampling :
9.2.1Swab dipped in swab solvent (i.e. Purified water).
9.2.2Cleaned rubber gloves
9.2.3Cleaned glass tube with plastic lid for collecting rise sample
9.2.4Plain aluminum foil to cover rinse sample.
9.3 For chemical testing :
9.3.1pH meter
9.3.2Conductivity meter
9.3.3High Performance Liquid Chromatography
9.3.4Reagents (Purified Water)
9.3.5Glass wares
9.4 For Microbial testing :
9.4.1Normal Saline (Sterile)
9.4.2Reagents
9.4.3Colony Counter
9.4.4Incubators
9.4.5Glass wares

10.0 ELEMENTS OF CLEANING VALIDATION:

10.1 Clean the product manufacturing, product storage, equipments, machines,
utensils, vessels and area as per their respective SOP.
10.2 Check the training reports of cleaning operators and record the same in the
validation report.
10.3 List of equipment involved in process of manufacturing area of Worst Case
Product that is Ibuprofen Oral Suspension are follows the respective Cleaning
SOP Number in below table.

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Sr. No. Equipment Name Equipment I.D. Cleaning SOP

DISPENSING AND SAMPLING:
1. 1kg Open Stainless-steel Scoops PDN-TL/042 PDN/012
2. 1kg Close Stainless-steel Scoops PDN-TL/044 PDN/012
3. 500g Open Stainless-steel Scoops PDN-TL/048S PDN/012
4. 500g Close Stainless-steel Scoops PDN-TL/050 PDN/012
5. 250g Open Stainless-steel Scoops PDN-TL/053 PDN/012
6. 100g Close Stainless-steel Scoops PDN-TL/057 PDN/012
7. Dispensing booth HEPA filter grills PDN-E/004 PDN/013
8. Sugar dispensing booth HEPA filter grills PDN-E/004 PDN/013
9. 3 Kg Weighing Balance PDN-E/013 PDN/017
10. 300 Kg Weighing Balance PDN-E/008 PDN/004
11. 50 L plastic bucket PDN-TL/059 PDN/012
12. 50 L HDPE bucket PDN-TL/068 PDN/012
13. Barrel pump PDN-E/071 PDN/012
14. 15 L Stainless-steel Bucket PDN-TL/012 PDN/012
15. 30 L Stainless-steel Bucket PDN-TL/005 PDN/012
16. 80 L Stainless-steel Bucket PDN-TL/002 PDN/012
17. 5 L Stainless-steel Bucket PDN-TL/019 PDN/012
18. 1 L Stainless-steel Jug PDN-TL/109 PDN/012
19. 50 L Stainless-steel Bucket PDN-TL/009 PDN/012
20. Stainless-Steel Stirring Rod-Long PDN-TL/034 PDN/012
21. Stainless-Steel Stirring Rod-Short PDN-TL/041 PDN/012
22. Stainless-Steel Sampling scoop PDN PDN/012
MANUFACTURING:
23. Pipe work-Oral liquid PDN-E/037 PDN/022
24. 150 L Sugar Dissolving Tank PDN-E/058 PDN/006
25. 1000 L Pre-Mixing Tank PDN-E/017 PDN/006
26. 2000 L Main Mixing Tank PDN-E/018 PDN/006
BOTTLE CLEANING AREA:
27. Bottle cleaning Machine PDN-E/036 PDN/018
28. Dust Collector PDN-E/036 PDN/018
FILLING AREA:
29. Holding tank PDN-E/044
30. Transfer pump case PDN-E/044
31. Reservoir Tank PDN-E/046
32. Reservoir Tank discharge nozzle PDN-E/045
33. Piston Pump Case PDN-E/045 PDN/019
34. Piston Pump discharge hose Pipe PDN-E/045 PDN/019
35. Piston Pump suction hose Pipe PDN-E/045 PDN/019
36. 6 Nozzle pipes PDN-E/045 PDN/019
37. Pipe work PDN-E/044 PDN/019

11.0 VALIDATION METHODOLOGY :

11.1 Validation Approach:

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 Since the study is based on worst case, the cleaning process used to clean the
product which is a worst case i.e. Ibuprofen Oral Suspension covered shall be
considered valid after successful validation of cleaning process.
 The cleaning process shall be validated for product contact equipments
/accessories, as a measure to ensure that residual drug product, Active
Pharmaceutical Ingredient (API), Microbial bioburden are below maximum
allowable level for the next batch of product manufactured with that equipment
in a particular production area. This shall also ensure that equipments are free
from pathogens after cleaning.
 If the cleaning process meets the acceptance criteria, the cleaning procedure
shall be considered validated. If it does not meet in any case, the cleaning
procedure shall be changed for improvement and the procedure shall be re
validated. The method employed for cleaning validation shall be validated for at
least Limit of Quantification (LOQ), Limit of Detection (LOD), linearity & Range,
Accuracy /recovery from swab and precision study at the level of limit to be
quantified.
 The acceptance criteria shall be calculated as quantity of residue and bioburden
per swab ar

11.2 List of equipment’s, machines for sampling.

 Location of Swab sample/Rinse sample shall be as per below table:
Sr. Name of Location Type Equipme Swab Sample ID No.
No. of nt ID No. For For
Sampl Chemical Microbial
e
 Scoop (Collect all scoops and each scoop rinse with 1000 ml water.)
1 Sample for Inner surface Rinse PDN-TL/
of Scoop, 042
2 Sample for Outer PDN-TL/
Surface of Scoop 044 PDN-
TL/048
PDN-TL/05
0
PDN-TL/05
3
PDN-TL/05
7
PDN-TL/
 RLAF (Dispensing Booth)
3 Riser Swab PDN-E/004
4 Left Wall of RLAF
5 Riser
6 Right Wall of RLAF
RLAF (Sugar Dispensing Booth)

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Sr. Name of Location Type Equipme Swab Sample ID No.

No. of nt ID No. For For
Sampl Chemical Microbial
7 Riser e
Swab PDN-E/004
8 Left Wall of RLAF
9 Riser
10 Right Wall of RLAF
Weighing Balance (3 KG)
11 Balance Platform Swab PDN-E/013
12 Table Platform Swab
Weighing Balance (300 KG)
13 Balance Platform Swab
14 Table Platform Swab
 BUCKET (50 L Plastic Bucket)
15 inside surface of Rinse PDN-TL/
container lid 059
16 Gasket
17 inside surface container
BUCKET (50 L HDPE Bucket)
18 inside surface of Rinse PDN-TL/068
container lid
19 Gasket
20 inside surface container
 BARREL PUMP
21 inside portion of the Rinse PDN-E/071
pump
 Stainless-steel Bucket
22 inside surface of Rinse PDN-TL/
container lid 012
Gasket (15L)
inside surface container PDN-TL/
005
(30 L)
PDN-TL/
002
(80L)
PDN-TL/
019
(5L)
PDN-TL/
009
(50L)
STAINLESS STEEL ROD
23 inside portion of the Rinse PDN-TL/
pump (Long) 034
inside portion of the Rinse PDN-TL/

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Sr. Name of Location Type Equipme Swab Sample ID No.

No. of nt ID No. For For
Sampl Chemical Microbial
pump (Short) e 041
MIXING AREA
24 inside surface of Lid Rinse PDN-E/058
25 Rinse for Discharge Rinse 150 L
point SUGAR
26 inner surface of Tank Rinse DISSOLVIN
27 Rinse for stirrer Rinse G TANK
28 inside surface of Lid Rinse PDN-E/017
29 Rinse for Discharge Rinse 1000 L
point Pre-Mixing
30 inner surface of Tank Rinse Tank
31 Rinse for stirrer Rinse
32 inside surface of Lid Rinse PDN-E/018
33 Rinse for Discharge Rinse 2000 L
point Main
34 inner surface of Tank Rinse Mixing
35 Stirrer Rinse Tank
36 Manufacturing Pipe Rinse PDN-E/037
work
BOTTLE CLEANING MACHINE
37 Machine Table Swab PDN-E/036
38 Nozzles Swab
FILLING
39 Holding Tank Rinse PDN-E/044
40 Transfer Pump Case
Rinse
41 Reservoir Tank Rinse
42 Reservoir Tank Nozzles Rinse
43 Piston Pump Case Rinse
44 Piston Pump discharge Rinse PDN-E/045
hose Pipe
45 Piston Pump suction Rinse PDN-E/045
hose Pipe
46 6 Nozzle pipes Rinse PDN-E/045
47 Filling Area Pipe work Rinse PDN-E/044

12.0 SAMPLING PROCEDURE:

 In Cleaning validation, swab sample and Rinse sample locations are selected
based on hard to clean area.
 Collection of Swab sample is considered for hard to clean area.
 Collection of Rinse sample is considered for Easy to clean area.

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 Declaring the hard to clean part as the worst-case swab limit for the whole
equipment train.
12.1 Visual Inspection of the equipment’s:
 Cleaned equipment surface shall be visually examined under appropriate light.
 If appropriate light is not available, torch with adequate white luminance shall be
used. Also, equipment surface shall be verified at tilted angle for better eye view,
if required.
 Lint free cloth shall be used, if required, for checking any residue leftover in the
crevices or perforated surfaces.
 Wiping of surface under visual inspection shall be done for at least 3 times and
lint free cloth shall be checked for any adhered residue over it.
 Visual cleaning shall be used as cleaning validation criteria once cleaning
validation study is over.
 All the visual cleaning observations shall be recorded in the relevant equipment
cleaning checklist.
 As per above point, if any residue is observed during visual inspection, incidence
shall be handled through deviation procedure and equipment shall be re-cleaned
before use.
 Maximum two re-cleaning stages are allowed. Cleaning validation study shall be
initiated thereafter.

12.2 Swab Sampling (Direct Surface Sampling) Techniques.

 Swab area to be sampled : 5 cm X 5 cm (25 cm2)
 Swab sample for Chemical analysis:
 Perform the sampling after visual inspection of all equipment and the respective
area as mentioned in the table from 5 cm x 5 cm area by wiping the surface of
equipment or of respective area horizontally lifting the swab at the end of each
wipe without wiping in and fro movement as per below diagram.
 Turn the swab over to unused side and wipe vertically lifting the swab at the end
of each wipe without wiping in and fro movement, as per below diagram.

Swab -1

Swab-
1

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 After swabbing each sample shall be placed inside the stoppered test tube and
duly mentioned sample ID on each tube and submitted to QC along with the
intimation slip as per Annexure QA
 Swab sample for Microbial analysis:
 Swab sampling shall be carried out. for microbial testing sterile cotton swab stick
shall be used for swabbing.
 The swab shall be wet in sterile saline, swab samples from different areas (these
areas shall not be same as that used for chemical testing, but should be
adjustment) shall be collected.
 After swabbing each sample shall be placed inside the stoppered test tube and
duly mentioned sample ID on each tube and submitted to QC along with the
intimation slip as per Annexure QA
 Rinse Water Sampling for analysis.
 Rinse method is not as direct as swabbing but it shall cover the entire surface of
the equipment or equipment that is inaccessible to swabs.
 After Swab sampling, the equipment shall be rinsed with approx. 500 ml volume
of purified water.
 Collected the rinse sample in a glass bottle by holding it below the equipment
surface during rinsing with purified water. If it is not possible to collect the rinse
by holding the glass bottle below equipment surface, then collect the rinse
purified water in a clean bowl and transfer 100 milliliter (ml) quantity to sample
collection in a glass bottle.
 Pull out 100 ml sample from the above rinsed sample, after collection the sample,
mentioned the sample ID on each glass bottle and send to QC for analysis with
respective annexure of along with the intimation slip as per Annexure QA
 Prefer to collect the samples from nozzles, pipe, and valve etc. so that maximum
contamination can be collected.
 Note:-For Microbial analysis sterile glass bottle shall be used.

13.0 CALCULATION FOR MAXIMUM ALLOWABLE CARRY OVER (MACO) :

13.1 Maximum allowable Carry over (MACO) value shall meet most stringent of
following criteria.
13.2 ADE Criteria: A substance specific dose that is unlikely to cause an adverse effect
if an individual is exposed at or below this dose every day for a lifetime.

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Product Kimsy Ibuprofen Oral Suspension 100 mg / 5
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No.

13.3 MACO value shall be calculated considering all criteria which are mentioned in its
calculation and the lowest MACO value based on dose and PDE criteria shall be
considered as the limit of worst case product in cleaning validation study.
13.4 The MACO value shall be calculated based on PDE. PDE is expressed as mg per
day.
13.5 Calculation of MACO based on ADE:
For Ibuprofen Oral Suspension (A) , (Next product is Metronidazole Oral
Suspension (B))
PDE (mg/day) (A) x SBS (mg) (B)
 MACO (mg) =
LRDD (mg) (B)
1.56 x 2000
MACO (mg) =
2250
MACO (mg) = 1.386 = 1.39 mg

Where,
PDE = Permitted Daily Exposure
SBS = Smallest batch size for the product(s) from matrix
LRDD= Largest recommended Daily Dose for the Product to be manufactured in
the same equipment.
MACO= Maximum Allowable Carryover
MACO X Swab Surface Area 1.39 x 25
SWAB LIMIT: = ------------------------------------------------ = -----------------------
Total Surface Area 642379.63
= 0.000054 mg / swab
= 0.0541 ppm

14.0 ANALYTICAL TEST METHODS:

14.1 Limits of detection and limit of quantitation of analytical method shall be determined

Analytical Method Purpose

Analytical Method Test Protocol of API-
Protocol No.-
Ibuprofen
SOP No.: Microbial Testing for Cleaning Validation

Protocol No.- Swab Recovery Test

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Protocol No.- Rinse Recovery Test

14.2 LOQ and LOD Limit:

Ref. Protocol No.: (AMVCP/RIS/22/001–00) for LOQ and LOD.
LOQ From HPLC method is ppm

LOD From HPLC method is ppm

14.3 Recovery From Swab Sample: -

Product solution of 50%, 100% & 150 % are prepared and spiked on the model
surface equivalent to the swab surface area i.e. 5 cm x 5 cm.
Surface is dried under the gentle airflow for 15 min and sampled as per the standard
swabbing technique, as used for the sampling during validation.
The swab is tested by UV method.
Acceptance criteria: The percentage recovery should not be less than 80%
recovery.
Reference Protocol No: -
On the basis of QC testing by spiking studies the swab recovery is SS Plate:
________ %.
This is used for calculation.
15.0 DETERMINATION OF FINAL ACCEPTANCE CRITERIA

15.1 Visual Inspection: The visible internal equipment surface and all critical and
difficult to clean parts is optically free from residue and the colour of final rinse
water is comparable to purified water.
15.2 Determination of Final acceptance criteria for Swab:-
MACO (mg/swab) x 1000
Ls =
Amount of Swab diluent

0.000054 x 1000
Ls =
10
Ls = 0.0054 mg/ mL
Where,
Ls = Final acceptance criteria for swab sample (µg/ mL)
MACO = Maximum Allowable Carry Over (mg/swab)

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Amount of swab diluent = Volume of swab diluent used for swab extraction as per
STP.
1000 = Conversion factor from mg to µg.

15.3 The following calculation shall be followed to determine equipment wise or

component wise rinse concentration.
15.4 Recovery Factor for Swab
MACO (µg/ mL) x 25
MACO Conc. =
Swab Recovery
0.0054 x 25
= ------------------------
95.0
= 0.0014 µg/ml. (acceptance limit for swab)
15.5 Determination of Final acceptance criteria for Rinse:-
Sr. Equipment Name Equipment Surface Area Rinse
No. I.D. (cm2) Conc.µg / ml.
DISPENSING AND SAMPLING:
1. 1kg Open Stainless-steel PDN-TL/ 0.0036
832.91
Scoops 042S
2. 1kg Close Stainless-steel PDN-TL/ 0.0049
1137.94
Scoops 044
3. 500g Open Stainless-steel PDN-TL/ 0.0026
605.14
Scoops 048S
4. 500g Close Stainless-steel PDN-TL/ 0.0039
916.95
Scoops 050
5. 250g Open Stainless-steel PDN-TL/ 0.0018
424.11
Scoops 053
6. 100g Close Stainless-steel PDN-TL/ 0.0017
398.58
Scoops 057
7. Dispensing booth HEPA filter PDN-E/004 0.2183
50460
grills
8. Sugar dispensing booth HEPA PDN-E/004 0.2215
51200
filter grills
9. 3 Kg Weighing Balance PDN-E/013 616 0.0265
10. 300 Kg Weighing Balance PDN-E/008 3600 0.0155
11. PDN-TL/ 0.0696
50 L plastic bucket 16104.48
059
12. 50 L HDPE bucket PDN-TL/ 16063.48 0.0695

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Product Kimsy Ibuprofen Oral Suspension 100 mg / 5
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No.

Sr. Equipment Name Equipment Surface Area Rinse

No. I.D. (cm2) Conc.µg / ml.
068
13. Barrel pump PDN-E/071 2557.31 0.0111
14. PDN-TL/ 0.0184
15 L Stainless-steel Bucket 4247.43
012
15. PDN-TL/ 0.0353
30 L Stainless-steel Bucket 8155.88
005
16. PDN-TL/ 0.0077
80 L Stainless-steel Bucket 1773.86
002
17. PDN-TL/ 0.0109
5 L Stainless-steel Bucket 2519.16
019
18. PDN-TL/ 0.0027
1 L Stainless-steel Jug 628.31
109
19. PDN-TL/ 0.0498
50 L Stainless-steel Bucket 11511.10
009
20. Stainless-Steel Stirring Rod- PDN-TL/ 0.0055
1281.90
Long 034
21. Stainless-Steel Stirring Rod- PDN-TL/ 0.0045
1046.28
Short 041
22. Stainless-Steel Sampling PDN 0.0017
403.12
scoop
MANUFACTURING AREA:
23. Pipe work PDN-E/037 43367.47 0.1877
24. 150 L Sugar Dissolving Tank PDN-E/058 26179.08 0.1133
25. 1000 L Pre-Mixing Tank PDN-E/017 86332.53 0.3736
26. 2000 L Main Mixing Tank PDN-E/018 143256.62 0.6199
FILLING AREA:
27. Holding tank PDN-E/044 132255.33 0.5724
28. Transfer pump case PDN-E/044 1867.65 0.0081
29. Reservoir Tank PDN-E/046 20693.00 0.0896
30. Reservoir Tank discharge PDN-E/045 0.0001
216.26
nozzle
31. Piston Pump Case PDN-E/045 2035.75 0.0088
32. Piston Pump discharge hose PDN-E/ 0.0108
2497.56
Pipe 045S
33. PDN-E/ 0.0173
Piston Pump suction hose Pipe 4005.15
045S
34. 6 Nozzle pipes PDN-E/045 171.90 0.0007
35. Pipe work PDN-E/044 3017.39 0.0131

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CALCULATION FOR RINSE LIMIT:

MACO x ESA x 1000
RC =
TSA x RV
1.39 x 216.26 x 1000
RC =
642379.63 x 500
RC = 0.0001µg/ mL
Where,
RC = Rinse Concentration (in µg/ mL)
MACO = Maximum Allowable Carry Over (in mg)
ESA = Equipment product contact Surface Area or total area to be rinsed during
sampling. (cm2)
1000 = Conversion factor from mg to µg.
TSA = Total product contact surface area of complete equipment train (in cm 2).
RV = Rinse Volume (in mL)
15.6 Based on the Acceptance criteria, the least surface area of equipment is
considered to find out the worst rinse concentration among the Equipment
matrix.
15.7 As per Equipment matrix the least surface area identified is of Reservoir Tank
discharge nozzle-6 Nozzle filling machine, hence the lowest rinse
concentration obtained as 0.0001 µg/ mL.
15.8 Based on matrix Ibuprofen Oral Suspension obtained as worst case while
considering PDE, solubility & other criteria mentioned in matrix the lowest MACO
obtained as a 0.0054 mg/swab for Ibuprofen Oral Suspension for cleaning
validation study.
15.9 Microbial Enumeration (Bio-burden)

Swab Rinse
Total Aerobic Microbial Count (TAMC): NMT 100 CFU/ cm2 NMT 100 CFU/ ml
Total combined Yeast/Moulds Count
NMT 10 CFU/ cm2 NMT 10 CFU/ ml
(TYMC):

16.0 Revalidation Criteria:

 Revalidation of cleaning procedure is required if there is
- Change in the cleaning procedure.
- Change in the Cleaning Agent

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- Introduction of new products if falls under worst case.

17.0 ABBREVIATION:
Abbreviatio
Full Form
ns
Mg Milligram PDE Permitted Daily Exposure
No observed adverse effect
Gm Gram NOAEL
level
LOQ Limit of Quantification SBS Smallest batch size
LOD Limit of Detection LDD Largest Daily Dose
Nos. Numbers STD Smallest Therapeutic Dose
Standard Operating
SOP SF Safety Factor
Procedure
NMT Not More Than ml Milliliter
Cfu Colony Forming Unit RSD Relative Standard Deviation
Maximum Allowable Carry
MACO
Over

18.0 List of Attachments:

Attachments Document Title
No.
I
II

19.0 Revision History:

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