CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
CLEANING VALIDATION PROTOCOL TEMPLATE
WRITTEN:
REVIEWED:
Signature:
Position:
Date:
APPROVED
Signature:
Position:
Date:
Sample protocol for guidance only
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CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
TABLE OF CONTENTS
1. OBJECTIVE……………………………………………………..3
2. SCOPE…………………………………………………………...3
3. RESPONSIBILITY AND AUTHORITY………………………...3
4. REFERENCED DOCUMENTS…………………………………3
5. REVIEW OF CLEANING DOCUMENTS……………………..4
5.1 Equipment to be cleaned…………………………………….4
5.2 Common VS Dedicated equipment…………………………4
5.3 Cleaning procedure and cleaning equipment………………..4
5.4 Holding times………………………………………………..5
6. SELECTION OF WORST CASE “MARKER” OR “WORST CASE PRODUCT”
6.1 Evaluation of the product mix to select the worst-case product or marker
product……………………………………………………………...5
6.2 Operator training……………………………………………..5
6.3 Cleaning limits selection criteria based on MAC approach….6
7. VALIDATION PLAN……………………………………………
7.1 Worst-case conditions……………………………………….6
7.2 Chemical and microbiological analytical methods………….6
7.3 Acceptance criteria………………………………………….7
8. SAMPLING LOCATIONS:
8.1 Swab and flush sampling locations…………………………7
Sample protocol for guidance only
2
CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
1. OBJECTIVE:
The objective of this protocol is to define approach to validation of cleaning
procedures for filling and formulation.
2. SCOPE:
This document covers the protocol of cleaning procedures for formulation and
filling
Cleaning Procedures:
3. RESPONSIBILITY AND AUTHORITY:
The following specific responsibilities and authorities are assigned to this
protocol:
Activity
Protocol Preparation
Protocol Approval for Execution
Protocol Execution
Review Test Results and Prepare
Final Report
Final Report Approval
Responsibility
Preparation of protocol against
cleaning
To ensure protocol has met its
defined purpose.
Execution of test detailed in
the approved protocol,
compilation of test results.
Review the protocol to ensure
the correctness in execution
and document in accordance to
specifications.
To ensure results demonstrate
objectiveness of protocol.
Position
QA Department
QA and Engineering
Department
QA Department
QA Department
QA and Engineering
Department
4. REFERENCED DOCUMENTS:
Equipment manual
SOP of cleaning procedure
Chemical and microbiological limits in Pharmacopoeias
Sample protocol for guidance only
3
CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
5. REVIEW OF CLEANING DOCUMENTS:
5.1 Equipment to be cleaned:
This protocol will address the cleaning of the following product contact
equipment used to manufacture liquid products.
Equipment
Mixing vessel
Criticality rating
Critical
Vial filling and closing
machine
Labelling machine
Critical
Non-critical
Cartonator
Non-critical
Freeze dryer
Non-critical
Rotary Table
Non-critical
Conveyor
Non-critical
Rationale
Direct contact with the
product
Direct contact with the
product
Doesn’t affect quality and
purity (no direct contact)
Doesn’t affect quality and
purity (no direct contact)
Doesn’t affect quality and
purity (no direct contact)
Doesn’t affect quality and
purity (no direct contact)
Doesn’t affect quality and
purity (no direct contact)
Hard to clean areas:
 Beneath the mixing blades
 Dead spots in the tank
 Dead legs
5.2 Common vs Dedicated Equipment:
Common Equipment: Equipment used for all types of process.
Dedicated Equipment: Equipment used for only specific process. Liquid filling line is
used as dedicated equipment for filling process.
5.3 Cleaning Procedure and Cleaning Equipment:
5.3.1 Manual Cleaning Process:
The cleaning procedure SOP 256 Ver # 03 provides details of the
procedure, equipment and materia is required in order to conduct manual (COP)
cleaning of the liquids manufacture process equipment.
Sample protocol for guidance only
4
CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
5.3.2 Automated CIP (Product to Product) Cleaning System:
The cleaning procedure SOP 056 Ver # 02 provides details of the
procedure, equipment and materials required in order to conduct automated
(CIP) cleaning of the liquids manufacture process equipment.
5.4 Holding Times:
Dirty Equipment- Maximum hold Time:
Washing time: 30 mins
Rinsing time: 10 mins
Drying time: 10 mins
Cleaned Equipment- Maximum Hold Time:
Washing time: 20 mins
Rinsing time: 5 mins
Drying time: 5 mins
6. SELECTION OF WORST CASE ‘MARKER’ OR ‘WORST-CASE’
PRODUCT:
The ‘Worst-Case’ product range has been determined by several factors
including strength, toxicity, excipients and solubility.
6.1 Evaluation of the product mix to select the worst-case product or marker
product.
Doses and Batch Size Information
Product
Strength
Paracetamol Suspension
120 mg
Chesty Cough Syrup
200 mg
Decongestant nasal Spray
0.5 mg
Linctus
7.5 mg
Paediatric
0.05 mg
Emulsion
250 mg
Sample protocol for guidance only
Solubility
Batch size Decision**
Sparingly
soluble
Sparingly
soluble
Soluble
1044 Kg
Marker
2150 Kg
Marker
Freely
soluble
Practically
insoluble
Practically
insoluble
1140 Kg
229.5 Kg
222 Kg
816 Kg
5
Marker
CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
Three products are selected as marker as their solubilities are very low and toxicity
ranges from high to medium, even more batch size and possibility of residue will be
more.
6.2 Operator Training:
Operator performing the cleaning programme should be properly trained and
assessed before they start cleaning process. The training records and
assessment should be preserved.
6.3 Cleaning Limits Selection Criteria based on MAC Approach:
Maximum Allowable Carryover (MAC )=TD× Batch NP×1000×SF∕LD Dose NP
TD= Smallest therapeutic dose of active just cleaned (mg)
Batch NP= Batch size of next product (Kg)
SF= Safety factor (0.001 is common)
LD Dose NP= Maximum number of daily doses of the next product (mg)
Marker product is Paediatric Elixer. Its MAC is 0.01.
MAC=0.5×0.001×2150×1000×0.001∕6×15×1.113
= 1.075∕100.17
= 0.01
7. VALIDATION PLAN:
7.1 Worst-case conditions:
The CIP SOP # 256 Ver 02 contains several worst-case conditions. The
procedure is as follows.
1. The tank should be washed as soon as possible post use but must be
washed within 4 hours of use.
2. Completely drain any residual bulk product from the tank via the drain
line.
3. Attach the spray ball and apply a 10-15 minute process water rinse to all
surfaces of the tank, including under the lid. Make sure the water is above
70̊ C before commencing the flush.
4. Fill the tank to the high level mark with a freshly prepared 1% v/v of
Decon detergent in purified water. Check that the pH is between 7.8 and
8.3.
5. Apply a full soak with slow tank agitation for 55-65 minutes.
Sample protocol for guidance only
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CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
6. Drain the tank and flush the detergent residue to drain with a minimum
of 100 litres of purified water.
7. Apply a final 100 litre flush with hot purified water through the spray
ball. This will take approximately 5 minutes to complete. On completion
of the final rinse blow filtered compressed air into tank to remove all water
residues.
8. Visually inspect the tank for cleanliness after turning on the pilot light to
illuminate the tank inner surfaces. Be sure to check at least following three
locations underneath the lid, any vertical surface, underneath the stirrer
blade.
9. Record the results of the inspection on the tank cleaning log.
The worst-case conditions are:
Products having high toxicity and low solubility should be considered as marker as if
they can be cleaned without any toxic residue then all others can be cleaned.
High toxicity and low solubility= Paediatric Elixer
Medium toxicity and medium solubility= Chesty cough syrup
High toxicity and high solubility= Dry cough linctus
7.2 Chemical and Microbiological Analytical Methods:
Quality Control Laboratory: For detecting the chemical residues HPLC is used
.
ANALYTE
METHOD
Protein
HPLC
Organic Compounds
HPLC
Inorganic Compounds
Conductivity of rinse water
Sample protocol for guidance only
7
CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
Quality Control Microbiology Laboratory: Cell culture and staining methods are
used for detecting microbes.
Methods for
detecting
VIRUSES
BACTERIA
Cell culture and
count plaque
forming units
Selective growth
and count colony
forming units
PARASITIC
PROTOZOA
Immunological staining
and count fluorescent
cysts
7.3 Acceptance Criteria:
For Chemicals:
1. Not more than 0.1% of the normal daily dose will appear in the maximum
daily dose of the product.
2. Not more than 10 ppm of any product to appear in another product.
3. No residue of hypochlorite should be identified.
8. SAMPLING LOCATIONS:
8.1 Swab and flush sampling locations (for tank):
Swab Number
Swab Location (100 square cm)
S1
Under mixing tank lid
S2
Right side wall surface
S3
Under the mixing blade
S4
S5
Flush Number
Valves
Pipes
1000ml of final flush purified water
F1
Sample protocol for guidance only
Drain line from bulk tank
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CLEANING VALIDTION PROTOCOL
Document Code: SU 007
Version Number: 007
TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A
Swab and flush sampling locations (for filling line):
Swab Number
Swab Location (100 square cm)
S1
Flush Number
Filling head
1000ml of final flush purified water
F1
Sample protocol for guidance only
Drain line from filler
9