CLEANING VALIDATION PROTOCOL Document Code: CV 117

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Cleaning Validation Protocol

WRITTEN: REVIEWED:
Signature:
Position: Validation Manager Laboratory Manager Microbiology Manager
Date:

APPROVED
Signature:
Position: QA Manager Engineering Manager Production Manager
Date:
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Table of Contents

1. OBJECTIVE

2. SCOPE

3. RESPONSIBILITY AND AUTHORITY

4. REFERENCED DOCUMENTS

5. REVIEW OF CLEANING PROCEDURES

5.1 Equipment to be Cleaned

5.2 Common vs Dedicated Equipment .
5.3 Cleaning Procedure(s) and Cleaning Equipment
5.4 Holding Times

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
6.2 Operator Training
6.3 Cleaning Limits Selection Criteria based on MAC Approach

7. VALIDATION PLAN

7.1 Worst Case Conditions

7.2 Chemical and Microbiological Analytical Method
7.3 Acceptance Criteria:

8. SAMPLING LOCATIONS

8.1 Swab and Flush sampling locations

13. REQUIRED DOCUMENTS

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1. OBJECTIVE

The objective of this protocol is to define the cleaning validation studies and acceptance
criteria for the cleaning (manual and automated ) procedures used to clean the Liquid Filling
line process equipment located in the Liquids Manufacturing Facility – Line #4

To demonstrate the effectiveness of cleaning procedures on the direct product contact

surfaces, a worst case challenge is applied that will evaluate the most difficult to remove
residuals from the most difficult to clean areas of the equipment surfaces.

This protocol will also aim to establish appropriate maximum holding times for dirty equipment
prior to cleaning.

2. SCOPE

The scope of the cleaning validation covers all aspects of the manual and automated cleaning
procedures stated in this protocol and will include both products that are processed in this
equipment:

Products:
The cleaning covers the following product range:
• FCP 50mg, 75mg, 100mg,and 250mg C&C range
• FCP X Strength Elixer
• FCP 100mg C &C (oily excipient)

Equipment:
The product contact surface common equipment is:
• Bulk Manufacturing Tank # xxx
• Transfer piping from the tank to the filling line. Refer P&ID diagram # yyy
• Filling Machine # zzz

The dispensary is also to be validated for cleaning however this is handled via a separate
protocol.

Cleaning Procedures:
Cleaning of the liquid fill process equipment is achieved by common cleaning technologies,
which include an automated CIP system and manual cleaning procedures, as described in
Section 5 of this protocol.

The cleaning procedures to be validated are:

SOP #145 – CIP Cleaning of the Bulk Tank and the Filling Line – Version # 02
SOP #004 – COP (Manual) Cleaning of the Filling Line Components – Version # 07

Note: SOPs # 1 and SOP#2 relate to the Dispensary and will be validated on other protocols
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3. RESPONSIBILITY AND AUTHORITY

The following specific responsibilities and authorities are assigned to this protocol:

Activity Responsibility Position

Protocol preparation Validation Manager
Validation Manager
Protocol approval for execution Production Manager
Quality Assurance Manager
Protocol execution: Production Operator
Validation Supervisor
Microbiologist
Laboratory Manager

Review Test Results and Laboratory Manager

Prepare Final Report Microbiology Manager
Validation Manager
Validation Manager
Final Report Approval Production Manager
Quality Assurance Manager

4. REFERENCED DOCUMENTS

CV VMP 001 Cleaning Validation Master Plan

SOP #145 CIP Cleaning of the Bulk Tank and the Filling Line – Version # 5
SOP #003 COP (Manual) Cleaning of the Filling Line Components – Version #7
QP002 Validation of the Analytical Methodology - LOQ Levels of API on Surfaces
TM 002 Surface Swabbing Procedure

5. REVIEW OF CLEANING PROCEDURES

5.1 Equipment to be Cleaned

This protocol will address the cleaning of the following product contact equipment used to
manufacture liquid products.
• Bulk Tank # 4
• Liquid Filling Line
• Transfer Piping
• Dedicated Flexible hoses to connect the bulk tank to the fill line

5.2 Common vs Dedicated Equipment .

The products chosen for cleaning validation are different strengths of the same actives and
different composition types and cannot be campaigned during manufacture – therefore the
equipment is classified as “common” however the flexible Silastic tubing is dedicated to each
product.

Minor cleaning is required between batches of the same product and major cleaning is
required between product changeover.
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5.3 Cleaning Procedure(s) and Cleaning Equipment

5.3.1 Manual Cleaning Processes

The Cleaning Procedure SOP 145 Ver # 02 provides details of the procedure, equipment and
materials required in order to conduct manual (COP) cleaning of the liquids manufacture
process equipment.

5.3.2 Automated CIP (Product to Product ) Cleaning System

The Cleaning Procedure SOP 003 Ver # 05 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

After mixing and filling has been performed, the equipment can only be left in a dirty state for a
maximum of 4 hours before it must be cleaned. Where practical, all equipment should be
cleaned within the shift of use.

Cleaned Equipment - Maximum Hold Time

After cleaning has been performed the equipment and piping will only be considered clean for
a maximum of 7 calendar days. If the equipment is left unused for more than 7 days it must be
fully cleaned again prior to use.

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
FCP 50mg C&C Liquid 50mg High 50 kg Bracket
FCP 75mg C&C Liquid 75 mg High 100 kg Bracket
FCP 100mg C&C Liquid 100 mg High 100 kg Marker
FCP 250mg C&C Liquid 250 mg High 25 kg Bracket
FCP X Strength C&C Elixer 1000 mg Medium 150 kg Marker
FCP 100mg C&C Oily Liquid 100mg Low 100 kg Marker

Three products were selected for the validation:

(a) FCP 100mg strength because if represents the different strengths of similar products within a
bracket but delivers the largest total amount of active to the equipment.
(b) FCP X strength Elixir because it has a toxic active material in the formulation
(c) FCP 100mg C&C Oily Liquid because it contains an oily excipient and has relative low
solubility in the cleaning agent

Note: For microbial contamination all products are considered equivalent risk.

Each of these products will be manufactured and the cleaning validated on 3 separate occasions –
this means there are 9 cleaning validations required.
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6.2 Operator Training

For the CIP process, the cleaning process is fully automated and has been validated according to
IQ/OQ/PQ program CIP Cycle 01.. This process is not dependant on operator training however staff
must be trained in executing the procedure before commencing the validation.

For the Cop process the cleaning is dependent on operator technique so at least 2 different operators
must be included in the manual cleaning to verify the SOP is robust to different operators.

6.3 Cleaning Limits Selection Criteria based on MAC Approach

(refer to the Laboratory Cleaning Validation Protocol Lab CV 107)

7. VALIDATION PLAN

7.1 Worst Case Conditions

The CIP SOP # 145 Ver 02 contains several worst case conditions. The procedure is as follows. The
worst case conditions are marked in red and bolded.

Summary of the Cleaning Method – use CIP Cycle # 01

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 70oC 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 (set on low speed) for 55 – 65 minutes
6. Drain the tank and flush the detergent residue to drain with a minimum of 100litres of purified
water
7. Apply a final 100 litre flush with hot purified/process water through the spray ball. This will
take approximately 5 minutes to complete. On completion of the final rinse blow filtered
compressed air into the 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 the following 3 locations (a) underneath the lid (b)
any vertical surface (c) underneath the stirrer blade. Inspect the base of the tank, the lowest
point, for any residual pools of water.
9. Record the results of the inspection on the tank cleaning log. The criteria for visual cleanliness
is, with a naked eye, no visible signs of white or off white streaks on the surfaces and no
evidence of water residues

The worst case conditions are therefore as follows:

(a) Hold for 4 hours post use before cleaning
(b) Apply the spray ball for 10 minutes
(c) slow tank agitation (set on low speed) for 55 minutes
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(d) flush the detergent residue to drain with100 litres of purified water
(e) Apply a final 100 litre flush

Ensure these conditions are met and recorded in the cleaning record for each cleaning validation run.

7.2 Chemical and Microbiological Analytical Method

Quality Control Laboratory will analyse all swab samples for product as per the validated method TM
123: Validation of the Analytical Methodology for the Determination of Residual Levels of FPC active in
swab and flush samples.

Quality Control Microbiology Laboratory will analyse all swab samples for microbial bioburden as
per the validated method TMM 124: Validation of the Microbiology Recovery Method for the
Determination of microbial bioburden Levels of FPC active in swab and flush samples.

7.3 Acceptance Criteria:

(a) Three successful chemical residue (swabbing and flushing) evaluations of the equipment after
cleaning of the worst case products.
(b) Three successful visual inspections of the equipment after cleaning of the worst case product, both
initially and after the relevant holding time.
(c) Three successful microbiological evaluations of the equipment after cleaning of the worst case
product, both initially and after the relevant holding time.

SALMONELLA
TPC PSEUDOMONAS COLIFORMS/
sp/100cm2 or
(cfu/100cm2) spp/100cm2 100cm2
swab
Target NMT 1 Not detected Not detected Not detected

Limit NMT 5 Not detected Not detected Not detected

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9. SAMPLING LOCATIONS

8.1 Swab and Flush sampling locations

Sample locations are identified on the schematic diagram included in Appendix 1 and are as
described below:

Swab Number Swab Location (100 square cm area)

S1 Under bulk tank lid
S2 Right side wall surface
S3 Underneath middle rotor blade
S4 Drain valve
S5 Transfer pipe
S6 Filling head

Flush Number 1000 mL of final flush purified water

F1 Drain line from Bulk Tank
F2 Drain Line from Filler

9. REQUIRED DOCUMENTS

The following documents are required to be appended to this protocol in order to complete the
validation report.

No. of
Number Description
Sheets
1 Schematic Diagram of the Equipment Train
2 Record of Cleaning Process (Cleaning records)
3 Chemical Test Results Summary – Swab samples
4 Chemical Test Results Summary – Flush samples
5 Visual Inspection Result Summary
6 Microbiological Result Summary – Swab Samples
7 Microbiological Result Summary – Flush Samples
8 Deviation or Failure Summary Reports