CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
Review: N/A

CLEANING VALIDATION PROTOCOL TEMPLATE

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Date:

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Sample protocol for guidance only 1

 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

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 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 Responsibility Position

Protocol Preparation Preparation of protocol against QA Department
cleaning
Protocol Approval for Execution To ensure protocol has met its QA and Engineering
defined purpose. Department
Protocol Execution Execution of test detailed in QA Department
the approved protocol,
compilation of test results.
Review Test Results and Prepare Review the protocol to ensure QA Department
Final Report the correctness in execution
and document in accordance to
specifications.
Final Report Approval To ensure results demonstrate QA and Engineering
objectiveness of protocol. Department

4. REFERENCED DOCUMENTS:

Equipment manual
SOP of cleaning procedure
Chemical and microbiological limits in Pharmacopoeias

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 CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
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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 Criticality rating Rationale

Mixing vessel Critical Direct contact with the
product
Vial filling and closing Critical Direct contact with the
machine product
Labelling machine Non-critical Doesn’t affect quality and
purity (no direct contact)
Cartonator Non-critical Doesn’t affect quality and
purity (no direct contact)
Freeze dryer Non-critical Doesn’t affect quality and
purity (no direct contact)
Rotary Table Non-critical Doesn’t affect quality and
purity (no direct contact)
Conveyor Non-critical 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.

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 CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
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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 Solubility Batch size Decision**

Paracetamol Suspension 120 mg Sparingly 1044 Kg Marker
soluble
Chesty Cough Syrup 200 mg Sparingly 2150 Kg Marker
soluble
Decongestant nasal Spray 0.5 mg Soluble 229.5 Kg

Linctus 7.5 mg Freely 1140 Kg

soluble
Paediatric 0.05 mg Practically 222 Kg Marker
insoluble
Emulsion 250 mg Practically 816 Kg
insoluble

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 CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
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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.

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 CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
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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

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 CLEANING VALIDTION PROTOCOL Document Code: SU 007

Version Number: 007

TITLE:CLEANING VALIDATION OF LIQUID FILLING LINE
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Quality Control Microbiology Laboratory: Cell culture and staining methods are
used for detecting microbes.

VIRUSES BACTERIA PARASITIC

PROTOZOA
Methods for Cell culture and Selective growth Immunological staining
detecting count plaque and count colony and count fluorescent
forming units forming units 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 Valves
S5 Pipes

Flush Number 1000ml of final flush purified water

F1 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 Filling head

Flush Number 1000ml of final flush purified water

F1 Drain line from filler

Sample protocol for guidance only 9