Cleaning Validation Protocol for Liquid Oral Products

TABLE OF CONTENTS

OBJECTIVE

SCOPE

RESPONSIBILITY AND AUTHORITY

REFERENCED DOCUMENTS

REVIEW OF CLEANING DOCUMENTS

1. Equipment to be cleaned
2. Common vs. dedicated equipment
3. Cleaning procedure and cleaning equipment
4. Holding times

SELECTION OF WORST-CASE “MARKER” OR “WORST CASE PRODUCT”

1. Evaluation of the product mix to select the worst-case product or marker product
2. Operator training
3. Cleaning limits selection criteria based on the MAC approach

VALIDATION PLAN

1. Worst-case conditions
2. Chemical and microbiological analytical methods
3. Acceptance criteria

SAMPLING LOCATIONS

1. Swab and flush sampling locations

OBJECTIVE

The objective of this protocol is to define an approach to the validation of cleaning procedures for filling and formulation.

SCOPE

This document covers the protocol of cleaning procedures for formulation and filling, Cleaning Procedures.

RESPONSIBILITY AND AUTHORITY

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

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

REFERENCED DOCUMENTS

• Equipment manual
• SOP of cleaning procedure
• Chemical and Microbiological Limits in Pharmacopoeias

REVIEW OF CLEANING DOCUMENTS

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 machine	Critical	Direct contact with the product
Labeling 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

Common vs Dedicated Equipment:

Common Equipment: Equipment used for all types of processes.

Dedicated Equipment: Equipment used for only specific processes. The liquid filling line is used as dedicated equipment for the filling process.

Cleaning Procedure and Cleaning Equipment:

Manual Cleaning Process:

The cleaning procedure SOP provides details of the procedure, equipment, and material required to conduct manual (COP) cleaning of the liquids manufacture process equipment.

Automated CIP (Product to Product) Cleaning System:

The cleaning procedure SOP provides details of the procedure, equipment, and materials required to conduct automated (CIP) cleaning of the liquid manufacturing process equipment.

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

ALSO READ: Cleaning Validation Protocol

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
Paracetamol Suspension	125 mg	Sparingly      soluble	1044 Kg	Marker
Chesty Cough Syrup	200 mg	Sparingly soluble	2150 Kg	Marker
Decongestant Nasal Spray	0.5 mg	Soluble	229.5 Kg
Linctus	7.5 mg	Freely soluble	1140 Kg
Pediatric	0.05 mg	Practically insoluble	222 Kg	Marker
Emulsion	250 mg	Practically insoluble	816 Kg

• Three products are selected as markers as their solubilities are very low and toxicity ranges from high to medium, even more batch size and possibility of residue will be more.

Operator Training:

Operators performing the cleaning program should be properly trained and assessed before they start the cleaning process. The training records and assessment should be preserved.

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)

The marker product is Paediatric Elixer. Its MAC is 0.01.

So,

MAC=0.5×0.001×2150×1000×0.001∕6×15×1.113

= 1.075∕100.17

= 0.01

VALIDATION PLAN

Worst-case conditions:

The CIP SOP contains several worst-case conditions. The procedure is as follows.

• The tank should be washed as soon as possible post-use but must be washed within 4 hours of use.
• Completely drain any residual bulk product from the tank via the drain line.
• 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.
• 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.
• Apply a full soak with slow tank agitation for 55-65 minutes.
• Drain the tank and flush the detergent residue to drain with a minimum of 100 liters of purified water.
• 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 the tank to remove all water residues.

• Visually inspect the tank for cleanliness after turning on the pilot light to illuminate the tank's inner surfaces. Be sure to check at least the following three locations underneath the lid, any vertical surface, underneath the stirrer blade.
• Record the results of the inspection on the tank cleaning log.

ALSO READ: Requirement for Equipment Cleaning Validation

The worst-case conditions are:

• Products having high toxicity and low solubility should be considered as markers 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

Chemical and Microbiological Analytical Methods:

Quality Control Laboratory: 

For detecting the chemical residues HPLC is used.

ANALYTE	METHOD
Protein Organic Compounds Inorganic Compounds	HPLC HPLC Conductivity of rinse water

Quality Control Microbiology Laboratory: 

Cell culture and staining methods are used for detecting microbes.

	VIRUSES	BACTERIA	PARASITIC PROTOZOA
Methods for detecting	Cell culture and count plaque-forming units	Selective growth and count colony-forming units	Immunological staining and count of fluorescent cysts

Acceptance Criteria:

For Chemicals:

• Not more than 0.1% of the normal daily dose will appear in the maximum daily dose of the product.
• Not more than 10 ppm of any product to appear in another product.
• No residue of hypochlorite should be identified.

SAMPLING LOCATIONS

Swab and flush sampling locations (for tank):

Swab Number	Swab Location (100 square cm)
S1	Under the 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

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

ALSO READ: SOP for Cleaning Validation – Manufacture of APIs