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Sample cleaning validation protocol

Aravindsai (www.pharmacygraduates.org

Cleaning Validation
Protocol
For formulation and filling
Supervised and controlled by QA

2010
WRITTEN: REVIEWED:
Signature:
Position: Validation manager Laboratory Manager Microbiology Manager
Date: 22/05/2010 23/05/2010 24/05/2010

APPROVED
Signature:
Position: QA Manager Engineering Manager Production Manager
Date: 24/05/2010 24/05/2010 24/05/2010
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 Possible residues
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 methods
7.3 Acceptance criteria

8. SAMPLING LOCATIONS

8.1 Swab and flush sampling locations


8.2 Sampling method

13. REQUIRED DOCUMENT


1. OBJECTIVE

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

2. SCOPE
This document covers the protocols of cleaning validation for formulation and filling equpments

3. RESPONSIBILITY AND AUTHORITY

Validation unit Production Engineering QA R&D QC


Analytical
development

Preparation Approve Assist in Approvin Developin Perform


of protocol validation identifyin g g recover
plan and g hard to protocols analytical studies
working clean method
plan areas

Calculate Verifying Oversee Testing


contaminatio accuracy the samples
n limits for of process and
active cleaning preparin
ingredient procedure g
and cleaning analytic
agent al report

Conduct Identifyin Approvin


validation g hard to g report
including clean
sampling areas

Preparing Performin
validation g cleaning
report
4. REFERENCED DOCUMENTS

5. REVIEW OF CLEANING PROCEDURES

5.1 Equipment’s

 Mixing vessels
 Transfer pipes
 Vial Filling and closing machine

Equipment Criticality rating Rationale


Mixing vessel Critical Direct contact with the
product
Vial filling and closing Critical Direct contact with the
machine product
Labelling machine Non-critical for cleaning Doesn’t affect quality and
purity of the drug
substance
(no direct contact)
Cartonator Non-critical for cleaning Doesn’t affect quality and
purity of the drug
substance
(no direct contact)
Freeze dryer Non-critical for cleaning Doesn’t affect quality and
purity of the drug
substance
(no direct contact)
Rotary table Non-critical for cleaning Doesn’t affect quality and
purity of the drug
substance
(no direct contact)
Coveyor Non-critical for cleaning Doesn’t affect quality and
purity of the drug
substance
(no direct contact)

Hard to clean areas:


 Beneath the mixing blades
 Dead spots in the tank
 Dead legs
5.2 Potential residues
 By products or degradation products of Active pharmaceutical ingredients
 Previous product
 Microbes
 Solvents or chemicals used during manufacturing
 Cleaning agents and lubricants used for cleaning
5.3 Cleaning procedure(s) and cleaning equipment
Cleaning method: Clean in place
 Pre-wash: Use tap water to clean the parts of equipment.
 Clean applying cleaning solution to the pre-washed parts.
 Blow out using compressed air
 Rinse the Equipment parts using tap water
 Again rinse it with purified water
 Dry using hot and compressed air.
Cleaning Agents: Water and hypochlorite

5.4 Holding times

 Pre-washing or pre-rinsing 10 minutes


 Washing 30 minutes
 Rinsing 10 minutes
 Drying 10 minutes

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

Doses and Batch Size


Information

Batch
Product Strength Solubility Toxicity Decision**
Size

FCP 50mg C&C Liquid 50mg High High 50 kg

FCP 75mg C&C Liquid 75 mg High Low 100 kg Bracket

FCP 100mg C&C Liquid 100 mg High Low 100 kg Marker

FCP 250mg C&C Oily Liquid 250 mg Low Medium 25 kg Bracket

FCP X Strength C&C 1000 mg High 150 kg Ma


Medium
FCP 100mg C&C Liquid 100mg High 100 kg Marker
Low
FCP 100mg C&C Liquid is marker as its solubility is low and toxicity is high ,since as it is of
more batch size, they possibility of residue will be more. Hence if it can be cleaned without toxic
residue the rest all can be cleaned.

6.2 Operator training


Operator performing the cleaning programme should be trained and assessed before they start
the cleaning process.

Records of their training and assessment should be preserved.

6.3 Cleaning limits selection criteria based on MAC approach

Maximum allowable carryover (ppm) =

Maximum allowed concentration from previous batch x minimum batch size of next product

7. VALIDATION PLAN

The worst-case conditions are as follows:

Products having high toxicity and low solubility should be considered as marker because if they
can be cleaned without any toxic residue all the others can be cleaned

High toxicity and low solubility=FCP 100mg C&C Liquid

High toxicity and medium solubility= FCP X Strength C&C

Medium toxicity and Low solubility =FCP 250mg C&C Oily Liquid

7.2 Chemical and microbiological analytical methods

For detecting the chemical residues HPLC is used and for detecting microbial contamination

Analyte Method

Protein HPLC

Organic compounds HPLC

Inorganic compounds Conductivity of rinse water

For detecting microbial contamination


Viruses Bacteria Parasitic protozoa

Method for detecting Cell culture and count Selective growth on Immunological
plaque forming units agar and count colony staining and count
forming units fluorescent cysts

7.3 Acceptance criteria


For chemicals:
1. Not more than 0.1% of the normal therapeutic dose of any product to appear in the maximum
daily dose of the following product;
2. Not more than 10 ppm of any product to appear in another product
3. No residue of hypochlorite (cleaning agent) should be identified

For microbes (USP)

Medium used Total Total Staphylococcus Pseudomonas E.coli Salmonella


aerobic yeast aureus aeruginosa
count and
mold
count

Alginic acid Not more Should Should not


than 200 not be be present
total present
bacterial
count

Benzalkonium Should not be


chloride present
(<5%)

Sugar spheres 100 Should not be Should not be Should Should not
present present not be be present
present

Lactose 100 50 Should Should not


monohydrate not be be present
present
8 SAMPLING LOCATIONS

8.1 Swab and flush sampling locations (For tank)

Swab
Swab Location (100 square cm area)
Number
S1 Under mixing tank lid
S2 Right side wall surface
S3 Under the mixing blade
S4 Valves
S5 Pipes

Flush
1000 mL of final flush purified water
Number
F1 Drain line from Bulk Tank

Swab and flush sampling locations (for filling equipment)

Swab Number Swab Location (100 square cm area)


S6 Filling head

Flush Number 1000 mL of final flush purified water


F2 Drain Line from Filler

8.1 Sampling method

 Pre-treat the swab in the solvent and squeeze it

 Swab in the mixing vessel with one side in horizontal direction and other side in the
vertical direction, back and forth to cover the entire area (in the locations mentioned
above)

 Cut off the handle of swab into centrifuged tube

 Use recovery solvent to extract drug residue by sonication

 The filtered extract is analyzed through HPLC