CLEANING VALIDATION PROTOCOL
Document Code: CV 117
Version Number:
TITLE:
CLEANING VALIDATION OF LIQUID FILLING LINE
001
Review:
N/A
Page Number:
1of 8
Cleaning Validation Protocol
WRITTEN:
REVIEWED:
Signature:
Position:
Validation Manager
Laboratory Manager
Microbiology Manager
Date:
APPROVED
Signature:
Position:
Date:
QA Manager
Engineering Manager
Production Manager
CLEANING VALIDATION PROTOCOL
Document Code: CV 117
Version Number:
TITLE:
CLEANING VALIDATION OF LIQUID FILLING LINE
001
Review:
N/A
Page Number:
2of 8
Table of Contents
1.
OBJECTIVE
2.
SCOPE
3.
RESPONSIBILITY AND AUTHORITY
4.
REFERENCED DOCUMENTS
5.
REVIEW OF CLEANING PROCEDURES
5.1
5.2
5.3
5.4
6.
Equipment to be Cleaned
Common vs Dedicated Equipment .
Cleaning Procedure(s) and Cleaning Equipment
Holding Times
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
13.
Swab and Flush sampling locations
REQUIRED DOCUMENTS
CLEANING VALIDATION PROTOCOL
Document Code: CV 117
Version Number:
TITLE:
CLEANING VALIDATION OF LIQUID FILLING LINE Review:
1
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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
CLEANING VALIDATION PROTOCOL
Document Code: CV 117
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3.
RESPONSIBILITY AND AUTHORITY
The following specific responsibilities and authorities are assigned to this protocol:
Activity
Responsibility
Protocol preparation
Protocol approval for execution
Protocol execution:
Review Test Results and
Prepare Final Report
Final Report Approval
4.
Validation Manager
Validation Manager
Production Manager
Quality Assurance Manager
Production Operator
Validation Supervisor
Microbiologist
Laboratory Manager
Laboratory Manager
Microbiology Manager
Validation Manager
Validation Manager
Production Manager
Quality Assurance Manager
REFERENCED DOCUMENTS
CV VMP 001
SOP #145
SOP #003
QP002
TM 002
5.
Position
Cleaning Validation Master Plan
CIP Cleaning of the Bulk Tank and the Filling Line – Version # 5
COP (Manual) Cleaning of the Filling Line Components – Version #7
Validation of the Analytical Methodology - LOQ Levels of API on Surfaces
Surface Swabbing Procedure
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.
CLEANING VALIDATION PROTOCOL
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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
FCP 50mg C&C Liquid
FCP 75mg C&C Liquid
FCP 100mg C&C Liquid
FCP 250mg C&C Liquid
FCP X Strength C&C Elixer
FCP 100mg C&C Oily Liquid
Strength
50mg
75 mg
100 mg
250 mg
1000 mg
100mg
Solubility
High
High
High
High
Medium
Low
Batch Size
50 kg
100 kg
100 kg
25 kg
150 kg
100 kg
Decision
Bracket
Bracket
Marker
Bracket
Marker
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.
CLEANING VALIDATION PROTOCOL
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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
CLEANING VALIDATION PROTOCOL
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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.
TPC
(cfu/100cm2)
SALMONELLA
sp/100cm2 or
swab
PSEUDOMONAS
spp/100cm2
COLIFORMS/
100cm2
Target
NMT 1
Not detected
Not detected
Not detected
Limit
NMT 5
Not detected
Not detected
Not detected
CLEANING VALIDATION PROTOCOL
Document Code: CV 117
Version Number:
TITLE:
CLEANING VALIDATION OF LIQUID FILLING LINE Review:
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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
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
9.
Swab Location (100 square cm area)
S1
1000 mL of final flush purified water
F1
Drain line from Bulk Tank
F2
Drain Line from Filler
REQUIRED DOCUMENTS
The following documents are required to be appended to this protocol in order to complete the
validation report.
Number
Description
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
No. of
Sheets