Equipment to be cleaned Possible residues Cleaning procedure(s) and cleaning equipment Holding times
SELECTION OF WORST CASE “M ARKER” 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 8.2
13.
Swab and flush sampling locations Sampling method
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 Analytical
QC
development Preparation
Approve
Assist in
Approvin
Developin
Perform
of protocol
validation plan and working plan
identifyin g hard to clean areas
g protocols
g analytical method
recover studies
Calculate contaminatio n limits for active
Verifying accuracy of cleaning
ingredient and cleaning agent
procedure
Conduct validation including sampling
Identifyin g hard to clean areas
Preparing
Performin
validation report
g cleaning
Oversee the process
Testing samples and preparin g analytic al report
Approvin g report
4.
REFERENCED DOCUMENTS
5.
REVIEW OF CLEANING PROCEDURES
5.1
Equipment’s
Mixing vessels Transfer pipes Vial Filling and closing machine Equipment Mixing vessel
Criticality rating Critical
Vial filling and closing machine Labelling machine
Critical
Cartonator
Non-critical for cleaning
Freeze dryer
Non-critical for cleaning
Rotary table
Non-critical for cleaning
Coveyor
Non-critical for cleaning
Hard to clean areas: Beneath the mixing blades Dead spots in the tank Dead legs
Non-critical for cleaning
Rationale Direct contact with the product Direct contact with the product Doesn’t affect quality and purity of the drug substance (no direct contact) Doesn’t affect quality and purity of the drug substance (no direct contact) Doesn’t affect quality and purity of the drug substance (no direct contact) Doesn’t affect quality and purity of the drug substance (no direct contact) Doesn’t affect quality and purity of the drug substance (no direct contact)
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
SELECTION OF WORST CASE “M ARKER” 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
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
FCP 100mg C&C Liquid
100mg
High
100 kg
Marker
Medium Low
Size
Decision**
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-cas e 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 contaminatio n
Method for detecting
Viruses
Bacte ria
Parasitic protozoa
Cell culture and count plaque forming units
Selective growth on agar and count colony forming units
Immunological staining and count 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 aerobic count
Total yeast and
Staphylococcus aureus
Pseudomonas aeruginosa
E.coli
Salmonella
Should not be present
Should not be present
Should not be
Should not be present
mold count
Alginic acid
Not more than 200 total bacterial count
Benzalkonium chloride (<5%) Sugar spheres
Should not be present
100
Should not be present
Should not be present
present Lactose monohydrate
100
50
Should not be present
Should not be present
8
SAMPLING LOCATIONS 8.1
Swab and flush sampling locations (For tank)
Swab Number S1 S2 S3 S4 S5 Flush Number F1
Swab Location (100 square cm area)
Under mixing tank lid Right side wall surface Under the mixing blade Valves Pipes 1000 mL of final flush purified water
Drain line from Bulk Tank
Swab and flush sampling locations (for filling equipment)
8.1
Swab Number S6
Swab Location (100 square cm area) Filling head
Flush Number F2
1000 mL of final flush purified water Drain Line from Filler
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
