Company Name and Logo
CLEANING VALIDATION SUMMARY
TABLE OF CONTENTS
1.0 Introduction
2.0 Objective
3.0 Scope
4.0 Cleaning Validation Approach
5.0 Responsibility
6.0 Reference Documents
7.0 Product details (Previous Product)
8.0 Equipments Detail
9.0 Cleaning Procedure
10.0 Sampling Procedures and Sampling Plan
11.0 Analytical Procedures
12.0 Result of Analysis
13.0 Documentation
14.0 Conclusion
15.0 Abbreviations
1.0 INTRODUCTION
Cleaning Validation is documented evidence, which gives high degree of assurance that the cleaning method is consistent and reproducible and brings the residue levels below the total allowable carryover residue levels.
The cleaning methods must be validated to demonstrate the efficacy of the cleaning methods during product changeover. It is important to ensure that the carryover of the active ingredient of earlier product in the next batch is within the acceptance criteria. The validated cleaning method shall ensure that there is no cross contamination of the product in the next product.
The cleaning after product changeover is done as per approved cleaning method. These methods shall be validated for their effectiveness considering the worst case.
"Cleaning" is a part of GMP requirements (21CFR 211.67). The Schedule M of the Drugs & Cosmetics Act 1940 and the rules there under requires that manufacturer's must take adequate precautions to prevent cross-contamination of drugs.
2.0 OBJECTIVE
This validation protocol shall be applicable to validate the cleaning method used to clean the Sifter, Mixer Granulator, Fluidized Bed Drier, Sifter, Mutimill, Compression machine, Coating machine and blister/strip machine and other equipments used in Manufacturing plant.
This protocol will define the methods and documentation that will be used to evaluate the efficacy of the cleaning procedures in accordance with acceptance criteria used considering the worst scenario with respect to solubility, potency and batch size. Validation exercise shall be carried out on three consecutive batches.
Cleaning of the equipment will be done using soft water and final rinsing shall be done with Purified water IP/BP.
3.0 SCOPE
The scope of this protocol is to evaluate the acceptability of cleaning procedure used for the cleaning equipment in Granulation area, Compression Machine and Packing Machine using well-established analytical and Microbiological method to determine the chemical and microbiological burden.
This will also cover the responsibilities, sampling plan, acceptance criteria and analytical method.
The equipments shall be sampled for the residue of the earlier product by visual inspection & chemical testing method, residue of the detergent by chemical testing method and bioburden using validated analytical methods. Sampling shall be carried out using swab and rinse techniques.
The Analytical method used for analysis of residue traces after cleaning shall be validated for limit of detection, specificity and linearity at the minimum. The microbiological test method shall be concurrently validated using positive and negative controls.
4.0 RESPONSIBILITY
The validation group comprising of a representative from each of the following departments shall be responsible for the overall compliance of this protocol:
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DEPARTMENTS
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RESPONSIBILITIES
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Production
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· To help in execution of Cleaning validation
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Quality Assurance
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· Preparation of Cleaning validation
· Co-ordination with Production and QC to carryout Cleaning validation
· Monitoring and sampling at the different stages of cleaning as per Cleaning validation Protocol
· Preparation of a Cleaning validation Summary Report
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Quality Control
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· Analysis of Cleaning validation Samples.
· Preparation of Analysis Report and submission to Quality Assurance Dept.
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Engineering
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· Calibration of measuring devices and Preventive Maintenance of Machines as per schedule
· Rectification of Breakdown during Manufacturing (If any)
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5.0 REFERENCE DOCUMENTS
The following documents are required to prepare the Cleaning validation Protocol.
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S. No.
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Documents
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Ref. No.
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A.
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Master Formula Card
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MFR/RNT/01
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B.
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Batch Manufacturing Record
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BPR/File 8/Sr. No. 9
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D.
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Finish Product Specification
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T/RNT/035/2010A
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6.0 PRODUCT DETAILS
Product: (Previous Product: Product Name Tablets)
(Metformin Hydrochloride & Gliclazide tablets)
B.No. XXX B.Size.4.5lac Mfg 05/2010 Exo. 04/2012
Product Design:
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Active Ingredient
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Metformin Hydrochloride I.P.& Gliclazide I.P.
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Pharmacopoeial Grade
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IP
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Strength
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Metformin Hydrochloride I.P.– 500mg
Gliclazide I.P. – 80 mg
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Label Claim
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Each uncoated tablet contains
Metformin Hydrochloride I.P.– 500mg
Gliclazide I.P. – 80 mg
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Description
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White elongated, biconvex, scored uncoated tablets
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Overages (%w/w)
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2% each
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Avg.weight/Fill
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640±20mg
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Shelf Life
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24 months
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Batch Size
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4.5 Lac
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7.0 EQUIPMENTS DETAIL
The following equipments are to be used for Manufacturing and packing of the product.
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SR. NO.
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EQUIPMENT ID NO.
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EQUIPMENT NAME
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MAKE
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CONTACT WITH PRODUCT
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1.
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NWTM-01
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Vibratory Sifter
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Kothari
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Yes
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2.
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NWTM-10
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Octagonal blender
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R.P. Products
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Yes
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3.
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NWTM-02
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Steam kettel
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Kothari
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No
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4.
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NWTM-05
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Multimill-I
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Kothari
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Yes
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5.
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NWTM-04
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F.B.D
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Solace
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Yes
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6.
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NWTM-03
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R.M.G
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Sams Techno
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Yes
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7.
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NWTM-07
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Sifter-II
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Kothari
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Yes
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8.
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NWTM-09
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Multimill-II
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Kothari
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Yes
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9.
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NWTM-08
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F.B.P
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Solace
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Yes
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SELECTION OF HARD TO CLEAN LOCATIONS OF EQUIPMENT FOR SAMPLING
The swab samples of the equipment sampled shall be from such parts that are the most difficult to clean which are listed below.
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Name of equipment
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Part of equipment to be sampled
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SOP No.
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Sifter
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1. Edges of sieve
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PRT-006
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Rapid Mixer Granulator
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1. Discharge Valve
2. Base of chopper
3. Base of mixer
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PRT-008
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Fluid Bed Drier
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1. Edges of sieve of FBD bowl
2. View glass of bowl
3. View glass of body
4. Rim of the sieve of bowl
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PRT-009
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Fluid Bed Processor
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1. Edges of sieve of FBP bowl
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PRT-012
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Mutimill
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1. Blades of mutimill
2. Sieve of mutimill
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PRT-010
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Blender
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1. Discharge valve
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PRT-011
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Compression Machine
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1. Hopper
2. Forced feeder
3. Turret
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PRT-013
PRT-014
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8.0 Selection of the worst case AND ACCEPTANCE CRITERIA FOR THE CONTAMINATION
8.1 MAXIMUM ALLOWABLE CARRYOVER (MACO)
TD X BS X SF
MACO = ……………………
LDD
Where,
MACO : The maximum allowable carryover of previous product into next product.
TD : Minimum therapeutic dose of previous product A.
BS : Batch Size of the next product.
SF : Safety factor (1/1000)
LDD : Largest daily dose of the next product.
A) For Swab,
mg of permissible active per swab = MACO X Swab Area
-----------------------------------
Common Surface Area
B) Maximum Allowable residue per swab based on 10 ppm Criteria, mg of permissible active per swab
10 X B S (kg)
= --------------------------- X Swab Area
Common Surface Area
9.0 ACCEPTANCE CRITERIA:
A. For Visual Inspection Criteria:
· There shall not be any visual evidence of previous product on the product contact parts and other equipment surface after cleaning.
B. 10 ppm Criteria:
· Not more than 10 ppm of previous product residue shall appear in the Next Product.
C. 0.001 % Dose Criteria:
· Not more than 0.001 % of previous product residue shall appear in the maximum daily dose of the next product.
D. For Microbial Contamination:
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Sr. No.
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Swab Sample
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Acceptance limit
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01
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Total Bacterial Count
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NMT 100 CFU/Swab
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02
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Total Fungal Count
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NMT 10 CFU/Swab
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Based on these acceptance criteria lowest value shall be considered for determination of cleaning validity.
Cleaning Procedure: Reference SOP (Page No. 7/17) & SOP No. PRT-022
10.0 SAMPLING PROCEDURES & SAMPLING PLAN:
I. SAMPLING PROCEDURE
· Prior to swab sampling, cleaned equipment shall meet “Visual Clean” criteria.
· After cleaning of the equipment visual inspection shall be done and reported in report.
· After Visual Inspection is found satisfactory sampling shall be carried out.
· Use Hand gloves and mask during sampling.
A). For Swab Sampling:
Soak the swab for about 10 minutes in Purified water in a test tube. Swab the area of not less than 100 cm2 and transfer the swab back into the test tube containing Purified water and cover the same. Sonicate the test tube for about 2 minutes and filter the solution
· The Swabbing shall be done in horizontal or vertical strokes like below shown procedure in the marked area assuring that the entire area is swabbed.
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·
·
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· After swabbing, rinse the swabbing location by purified water to remove the traces of solvent.
· through Whatman No. 2 filter paper.
B). For Rinse Sampling:
· Rinse the entire equipment with the specified quantity of the Purified water and collect the rinse in a clean container. Remove appropriate quantity of rinse sample and filter through Whatman No. 2 filter paper.
Prior to sampling, cleaned equipment shall meet “Visual Clean” criteria.
Sampling shall be carried out as per current version of SOP No. SQA- 075 according to sampling diagram attached in the Annexure I. Number Of locations shall be sampled as mentioned below.
II. SAMPLING PLAN:
a. Swab sample for chemical/Microbial analysis
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Name of Equipment
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Product Contact Surface Area
(In cm2)
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Sampling Locations
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Total Nos. of Swabs
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Sifter
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100
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· Gasket of Sifter Ring (S6)
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4
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Rapid Mixer Granulator (RMG)
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100
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4
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FBD/FBP
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100
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4
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Multimill
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100
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· Blades of multimill (S15)
· Sieve of multimill (S16)
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2
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Blender
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100
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· Gasket (S19)
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3
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Compression Machine
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100
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5
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b. Rinse Sampling For Chemical/ Microbial Analysis
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Name of Equipment
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Sampling Locations
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Quantity of rinse (ml)
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FBD/FBP
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Outlet of hose pipe (R1)
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Collect the 500 ml rinse samples after rinsing the equipment with purified water.
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Compression machine
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Outlet of hose pipe (R2)
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Collect the 500 ml rinse samples after rinsing the equipment with purified water.
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III. SAMPLING PLAN FOR CHEMICAL ANALYSIS
(NON CONTACT PARTS):
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Sr. No.
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Equipment Name
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Swab Location
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Sample No
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1.
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Granulation area
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Wall
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NC 1
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Ceiling
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NC 2
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Return Grill
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NC 3
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2.
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Compression area
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Wall
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NC 4
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Ceiling
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NC 5
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Return Grill
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NC 6
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IV. SCHEMATIC DIAGRAM WITH SAMPLING LOCATIONS FOR EQUIPMENTS:
a) SIFTER
b) RMG
c) FBP/FBD
d) MULTIMILL
e) CAGE BLENDER
f) COMPRESSION M/C
11.0 ANALYTICAL PROCEDURES
Analytical methods for Specific analysis were validated as per Analytical Method Validation Protocol. Specific analysis shall be carried out using HPLC method.
Validated methods shall be employed to analyse the cleaning validation samples.
12.0 RESULT OF ANALYSIS
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Parameter
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Observation
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Acceptance
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Inference
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Visual Inspection
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Cleaned equipment shall not contain any visible residue
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After final cleaning, equipment shall be inspected for the visual clean criteria. Cleaned equipment shall not contain any visible residue
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Complies
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Chemical Analysis
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Cleaned equipments
Sifter 0.849 ppm
R.M.G. 0.617 ppm
F.B.D. 4.68o ppm
Multimill 3.530 ppm
Blender0.640 ppm
Compression Machine 2.760 ppm
Walls 0.730 ppm
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Cleaning validation samples shall meet the criteria of maximum allowed residue of NMT 10 ppm
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Complies
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Microbial Analysis
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Yeast and Mould
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Absent
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Should be absent
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Complies
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E.Coli & Salmonella
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Absent
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Should be absent
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Complies
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Total viable count
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10 cfu/swab
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NMT 100cfu/swab
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Complies
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13.0 DOCUMENTATION
Final Cleaning validation Report will be comprised of following documents.
I. Cleaning validation Protocol
II. Cleaning validation Report
III. Analytical Method Validation Report
IV. Analytical Report
14.0 CONCLUSION
A Cleaning validation Report shall be prepared after completion of validation cycle, to include evaluation of analytical results, recommendations and conclusions of the cleaning validation study for approval of Cleaning Methods of each piece of equipment.
15.0 ABBREVIATIONS
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API
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:
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Active Pharmaceutical Ingredient
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Ltd.
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:
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Limited
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SOP
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:
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Standard Operating Procedure
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BMR
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:
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Batch Manufacturing Record
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MFC
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:
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Master Formula Card
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QC
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:
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Quality Control
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QA
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:
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Quality Assurance
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IP
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:
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Indian Pharmacopoeia
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USP
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:
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United State Pharmacopoeia
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RM
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:
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Raw Material
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IH
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:
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In-House
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IPC
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:
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In-Process Container
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FBP
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:
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Fluidized Bed Processor
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M/C
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:
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Machine
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HPLC
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:
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High Performance Liquid Chromatography
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ppm
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:
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parts per million
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NMT
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:
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Not More Than
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