WRITTEN: REVIEWED: APPROVED - GMPSchool

1 Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 001 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINE Page Number: 1of 8 Cleaning Validation Protocol written : reviewed : Signature: Position: Validation Manager Laboratory Manager Microbiology Manager Date: APPROVED Signature: Position: QA Manager Engineering Manager Production Manager Date: Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 001 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINE Page Number: 2of 8 Table of Contents 1. OBJECTIVE 2. SCOPE 3. RESPONSIBILITY AND AUTHORITY 4. REFERENCED DOCUMENTS 5. REVIEW OF CLEANING PROCEDURES Equipment to be Cleaned Common vs Dedicated Equipment.

2 Cleaning Procedure(s) and Cleaning Equipment Holding Times 6. SELECTION OF WORST CASE MARKER OR WORST CASE PRODUCT Evaluation of the Product Mix to select the worst case product or marker product Operator Training Cleaning Limits Selection Criteria based on MAC Approach 7. VALIDATION PLAN Worst Case Conditions Chemical and Microbiological Analytical Method Acceptance Criteria: 8. SAMPLING LOCATIONS Swab and Flush sampling locations 13. REQUIRED DOCUMENTS Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 1 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINEPage Number: 3 of 8 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.

3 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.

4 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 Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 1 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINEPage Number: 4 of 8 3. RESPONSIBILITY AND AUTHORITY The following specific responsibilities and authorities are assigned to this protocol: Activity ResponsibilityPosition Protocol preparation Validation Manager Protocol approval for execution Validation Manager Production Manager Quality Assurance Manager Protocol execution: Production Operator Validation Supervisor Microbiologist Laboratory Manager Review Test Results and Prepare Final Report Laboratory Manager Microbiology Manager Validation Manager Final Report Approval Validation Manager Production Manager Quality Assurance Manager 4.

5 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 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 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.

6 Minor cleaning is required between batches of the same product and major cleaning is required between product changeover. Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 1 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINEPage Number: 5 of 8 Cleaning Procedure(s) and Cleaning Equipment 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. 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. 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.

7 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. 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.

8 (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. Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 1 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINEPage Number: 6 of 8 Operator Training For the CIP process, the cleaning process is fully automated and has been validated according to IQ/OQ/PQ program CIP Cycle 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.

9 Cleaning Limits Selection Criteria based on MAC Approach (refer to the Laboratory Cleaning Validation Protocol Lab CV 107) 7. VALIDATION PLAN 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 and 5. Apply a full soak with slow tank agitation (set on low speed) for 55 65 minutes 6.

10 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 Document Code: CV 117 CLEANING VALIDATION PROTOCOL Version Number: 1 Review: N/A TITLE: CLEANING VALIDATION OF LIQUID FILLING LINEPage Number: 7 of 8 (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.