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Cleaning Validation Protocol - Liquid Filling Line

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 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 approach to 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 in accordance to specifications.

QA Department

Final Report Approval

To ensure results demonstrate objectiveness of protocol.

QA and Engineering Department



REFERENCED DOCUMENTS:
  1. Equipment manual
  2. SOP of cleaning procedure
  3. 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

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

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.

Cleaning Procedure and Cleaning Equipment:

Manual Cleaning Process:
The cleaning procedure SOP provides details of the procedure, equipment and material is 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 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:
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


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

 

Paediatric

0.05 mg

Practically insoluble

222 Kg

Marker

Emulsion

250 mg

Practically insoluble

816 Kg

 


  • 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.

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.
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.

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.
  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.
  6. Drain the tank and flush the detergent residue to drain with a minimum of 100 liters 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:
  1. 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.
  2. High toxicity and low solubility= Paediatric Elixer
  3. Medium toxicity and medium solubility= Chesty cough syrup
  4. 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 fluorescent cysts


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.

SAMPLING LOCATIONS:

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


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

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