Prepared By Reviewed by Approved by
PROCESS
VALIDATION
PROTOCOL FOR TABLETS
Protocol No.
:
xxxxxxxx
Prepared By Reviewed by Approved by
TABLE OF CONTENTS
S.NO. SECTION Page
No 1. Protocol approval 2. Purpose 3. Responsibilities 4. Requirements 5. Personnel Responsibilities 6. Validation parameters 7. Limits 8. Conclusion report
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1. PROTOCOL APPROVAL
This document is prepared by the validation and the GMP compliance (QA) team of xxxxxxxxxxxxxxxxx under the authority of Manager QC & A. Hence this document before being effective shall be approved by xxxxxxxxxxxxxxx QA team.
Name Signature Date
Manager production Manager Engineering
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2. PURPOSE
Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as manufacturer of pharmaceutical dosages forms) will consistently produce a product meeting its predetermined specifications and quantity characteristics.
3. RESPONSIBILITIES
4. REQUIRMENTS: NIL
5. PERSONNEL RESPONSIBILITIES:
The perfect validation program necessitates various departments involvement mainly to balance the total system functioning for its effective utilization for success criteria compliance on regular basis. Quality assurance department initiates validation program with protocol, specified procedure and success criteria. Quality control personnel are responsible for the validation run as per the protocol and during validation maintenance departments have to cooperate to the quality control personnel.
S.NO. Activity Responsibility
1. Preparation of protocol QA chemist 2. Chemical analysis and sampling QC chemist 3. Microbial analysis & sampling Microbiologist 4. Preparation of validation Report Dy Manager QC
5. Review of validation protocol & report QA department, Production Department 6. Approval of protocol & Report Plant Head
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6. VALIDATION PARAMETERS:
Process Description / Flow Sheet
The information given below provides a general description of the process. Detailed information for the manufacturing will be supplied separately in the Batch Processing Record.
1 Prepare production order and according to that issue the BPR 2 RM dispensing as per Bill of material
3 Input check in presence of QA person 4 Granulation
4.1 Sifting 4.2 Pre–mixing
4.3. (a) Wet granulation Binder Preparation Mixing
Wet milling Drying Dry milling
Slugging, Milling (if required) Lubrication
4.3 (b) Dry Granulation Mixing
Slugging, Milling (if required) Lubrication
5 Tablet compression 6 Tablet coating 7 Tablet packing
Prepared By Reviewed by Approved by Batch Size:
Sr No
Ingredients/Excipients Unit per Tablet Std. Qty. Overages Dispensed Quantity Weight by Checked by 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 FLOW SHEET:
Prepare production order and according RM dispensing as per Bill of material to that issue the BPR
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Input check in presence of QA person GRANULATION
Shifting
Dry Granulation Premixing
Mixing Binder preparation
Wet Granulation milling
Drying
Dry milling Slugging, Milling (if required) Mixing
Coating Compression Lubrication
(Blending)
Tablet packing
Sampling point
Prepared By Reviewed by Approved by Equipments
A detailed list of equipment used for validation together with the cleaning status will be provided in the manufacturing documents.
S. No. Process step Control variables Measured responses 1. Pre-blending Blending time
RPM Load size Order of addition
Blend uniformity
2. Granulating Load size
Amount of granulating agent Solvent addition rate
RPM
Granulation time
Density Yield
3. Drying Initial temperature Load size
Drying temperature program Air flow program
Drying time Cooling time
Density
Moisture content Yield
4. Sizing Screen type
Screen size Feed rate
Granule size distribution Loose drying
Packed density
5. Blending Load size
RPM
Blending time
Blend uniformity Flow characteristics Particle size distribution
6. Tableting Compression rate Granule feed rate Pre-compression force Compression force Weight variation Friability Hardness Thickness Disintegration time Dissolution
Prepared By Reviewed by Approved by List of SOP’S, Validation & Qualification report used as references
Sr. No. Name of Equipment Equipment ID. Qualification details SOP No 1 2 3 4 5 6 7 8 9 10 11 12
Critical Process Parameters:
Critical stages: Following critical stages required to be validated to provide a high degree of assurance for the manufacturing of tablets.
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1. Premixing RPM of mixer blade
Load size
Total time of mixing
Uniform mixing by Assay analysis 2. Granulation Mixer blade speed
Load size Binder Quantity Binder addition rate Binder addition time Temperature of binder
Mixing time after binder addition /Total granulation time Uniformity of granulated mass (Visual Checking)
3. Drying Dryer outlet temperature
Dryer inlet temperature Drying load
Total drying time
Weight of the Dried granules
4. Milling Speed of machine
Direction of knives
5. Lubrication Load size
Occupancy
Speed of equipment (RPM) Total time of mixing
Prepared By Reviewed by Approved by Assay - (individual sample)
6. Compression Temperature of area Humidity of area Machine Details
Weight variation of 20 tablets Average weight of tablet Disintegration time Friability Diameter (Length) Thickness Hardness Assay Content uniformity Dissolution
7. Coating Temperature of area
Temperature of blower Speed of Coating Pan (RPM) Spray Rate
Bed Temperature Air Pressure
Total Coating solution used Weight Built up
Prepared By Reviewed by Approved by Assay
Disintegration time Dissolution
8. Packaging Forming roller temperature. (for Blister Packing) Sealing roller temperature
Sealing roller Pressure Speed of machine Seal integrity Assay Dissolution 9. Packaging (bulk packing) Sealing temperature Seal integrity
Counter Checking from 10 Jars at different Time intervals
Sr. No Process / Variable Machine setting
( Control Variables) Remarks
1
Blend Manufacturing Sifting
Visually Inspection No visible foreign particulate matter is observed
Prepared By Reviewed by Approved by Premixing Stage
Uniform mixing by Assay analysis Variation between the results shall not be more than 2%
2
Granulation
Binder Preparation
Granulation Finely divided material without free powder and excessive wetted lumps. Wet milling Material was finely divided
Drying Loss on drying Between 2.0 to 5.0%
Dry milling Finely divided granules are observed Lubrication
Assay and Sieve analysis Variation between the results shall not be more than 2% 3 Tablet compression Physical Parameter
Wt. Variation, Hardness, Thickness, DT, Dissolution and Assay
4 Tablet coating Weight gain, weight variation
and DT
5 Tablet packing Leak Test
PREMIXING:
Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total mixing time) While mixing is on: -
Prepared By Reviewed by Approved by After ___ minutes,
After _____ minutes ______ minutes
(Top , Middle & Bottom)
_______ minutes
(Top , Middle & Bottom)
______ minutes
(Top , Middle & Bottom) Total samples: 9 Samples
MIXING:
Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total mixing time) While mixing is on: -
After ____ minutes, After ___ minutes, After _____ minutes ______ minutes
(Top , Middle & Bottom)
_______ minutes
(Top , Middle & Bottom)
______ minutes
(Top , Middle & Bottom) Total samples: 9 Samples
DRYING:
Sampling point for drying stage: Top View Sampling
Top TOP VIEW T2 B2 B3
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Front side Bottom
--- Sampling Points
Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total mixing time) While Drying is on: -
After ____ minutes, After ___ minutes, After _____ minutes ______ minutes
(Top , Middle & Bottom)
_______ minutes
(Top , Middle & Bottom)
______ minutes
(Top , Middle & Bottom) Total samples: 9 Samples
MILLING:
Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total milling time) While milling is on: -
After ____ minutes, After ___ minutes, After _____ minutes T3 T1 B1
Prepared By Reviewed by Approved by ______ minutes
(Top , Middle & Bottom)
_______ minutes
(Top , Middle & Bottom)
______ minutes
(Top , Middle & Bottom) Total samples: 9 Samples
SAMPLING POINT FOR LUBRICATION (BLANDING) STAGE: Name of Blender: (DOUBLE CONE BLENDER)
Loading Valve Sampling Points T2 B3 B2 T3
Prepared By Reviewed by Approved by M
Sampling points T1, T2, T3 for top T4 B4 for middle, B1, B2, B3 for bottom sampling.
T3 T1 T4 T 1 B1 B4 B1 B2 B3
Prepared By Reviewed by Approved by Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total mixing time) While mixing is on: -
After ____ minutes, After ___ minutes, After _____ minutes ______ minutes
(Top , Middle & Bottom)
_______ minutes
(Top , Middle & Bottom)
______ minutes
(Top , Middle & Bottom) Total samples: 9 Samples
COMPRESSION:
Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (bracketing the time between 2 to 3 intervals of total compression time) After ____ minutes,
After ___ minutes, After _____ minutes
______ minutes _______ minutes ______ minutes
Total samples: 3 Samples
Prepared By Reviewed by Approved by Sampling Qty.: -Depends on quantity required for analysis.
Sampling Time: - (Bracketing the time between 2 to 3 intervals of total coating time) While coating is on: -
After ____ minutes, After ___ minutes, After _____ minutes
______ minutes _______ minutes ______ minutes
Total samples: 3 Samples
Sampling:
Stage / Test Parameter Equipment (Size, Location & Time)
Acceptance Criteria
Premixing Stage Variation between the results of Assay shall
not be more than 2% Mixing
Drying Loss on drying Between 2.0 to 4.0%
Mixing
Lubrication Variation between the results of assay shall
not be more than 2%
Tablet compression Physical Parameter (I.P.Q.C)
Tablet coating Weight Gain
Tablet packing Leak Test
Recording of data & Data treatment: Data Recording:
Prepared By Reviewed by Approved by The data obtained from the various analysis & observations shall be recorded in the Data recording sheet for first three commercial batches.
Data Recording Sheet No.
Sheet No 1 For recording Mixing stage data Sheet No 2 For recording Loss on drying data Sheet No 3 For recording Lubrication stage data Sheet No 4 For recording Compression stage data Sheet No 5 For recording Coating stage data Sheet No 6 For recording Packing stage data Sheet No 7 For recording of analysis report
Sheet No 8 For recording general utilities /equipment / method qualitical /results.
Prepared By Reviewed by Approved by Data recording sheet no I
Mixing Stage: Date
Equipment name :
Identification no :
Ingredients and sequence of material addition :
RPM of Mixer Blade :
Capacity :
Mixing time : Minutes
Standard Weight of Tablet :
Method reference: As per assay procedure given in finished product specification. Blended material to be analyzed for ______________________________
Plan: Samples to be drawn of mixing from 3 different locations (Top, Middle & Bottom) Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom
Mean
Standard Deviation % Relative standard deviation
Prepared By Reviewed by Approved by Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom Mean
Standard Deviation % Relative standard deviation
Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom Mean
Standard Deviation % Relative standard deviation
Analyst: Date
Remarks:
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Data recording sheet no II
Loss on Drying Stage: Date
Equipment name :
Dryer outlet temperature :
Dryer inlet temperature :
Drying Load :
Total Drying time : Minutes
Weight of the dried granules :
Method reference: Loss on drying procedure by IR moisture balance. Plan: Material to be analyzed for Loss on drying
Samples to be drawn from 3 different locations
Sample East West North South Average Limit
Weight taken % LOD
Remarks:
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Data recording sheet III
Lubrication Stage: Date
Equipment name :
Identification no :
Capacity :
Occupancy :
Speed of equipment :
Mixing time : Minutes
Standard Weight of Tablet :
Method reference: As per assay procedure given in finished product specification.
Lubricated material to be analyzed for % of active content ______________________________
Plan: Samples to be drawn at of blender from 3 different locations (Top, Middle & Bottom)
Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom
Prepared By Reviewed by Approved by Mean
Standard Deviation % Relative standard deviation
Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom
Mean
Standard Deviation % Relative standard deviation
Result after mixing _________________ minutes
Sampling Detail Results
Top Middle Bottom
Prepared By Reviewed by Approved by Standard Deviation
% Relative standard deviation
Remarks:
Checked By: _________________________ Date: ____________________
Data recording sheet IV
Compression Stage Date
Prepared By Reviewed by Approved by Identification no : Capacity : RPM : 13 to 28 RPM Punch Size : Temperature of area : Humidity of area : Weight of 20 Tablets :
Average Weight of tablet :
Disintegration Time : NMT 15 minutes
Dissolution (If required) :
Friability : NMT 1.0%
Thickness :
Hardness :
Assay :
Content of uniformity (If required) : Method reference: As per In-process check procedure.
Plan: Compressed tablets to be analyzed for: Average weight, Weight variation and Physical parameter at an interval of 2 hours
Requirement RPM: RPM: RPM:
Prepared By Reviewed by Approved by Average weight Thickness mm Hardness in kg./sq. cm2 Friability in % DT in min.
Weight variation after validated RPM __________
Time Average Weight Thickness Hardness Friability Disintegration
Weight variation:
Prepared By Reviewed by Approved by Remarks:
Checked By: _________________________ Date: ____________________
Data recording sheet V
Coating Stage Date
Name of equipment :
Identification no :
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Speed of coating pan :
Temperature of area :
Temperature of blower :
Spray rate :
Bed temperature :
Air Pressure :
Total coating solution used :
Weight build up :
Weight of 20 Tablets :
Average Weight of tablet :
Disintegration Time : Not more than
Dissolution (If required) :
Assay
Method reference: As per In-process check procedure.
Plan: Coated tablets to be analyzed for Weight gain, weight variation and DT. At an interval of __ hours Date Time Initial
weight Average weight Final weight Average weight
Prepared By Reviewed by Approved by Weight variation:
Time
Weight variation
Remark:
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Data recording sheet VI
Packing Stage Date
Name of equipment :
Identification no :
Capacity :
Forming roller temperature (For blister packing) :
Sealing roller temperature :
Sealing roller pressure :
Speed of machine :
Seal integrity (Leak test) :
Method reference: As per In-process check procedure.
Plan: Packed tablets to be analysed for Leak test at an interval of __ hours
Date Time Leak Test Results Remarks
No of strips to be taken
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Data recording sheet VII Analysis Report
Product Name:
Batch No.: Batch size:
Mfg. Date: Exp. Date:
Composition: Test method reference: In house
Sr. No. Test Specification Results Remark
01 Description 02 03 04 05 5.1 5.2 5.3 5.4 Remark:
Result: The sample referred above complies / does not comply with the standard prescribed as per In house Specification.
Prepared By Reviewed by Approved by Sr
No
Name of critical equipment / Utilities Qualification / Validation file reference No Date of Qualification / Validation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Sr No
Name of critical equipment / Utilities Qualification / Validation file reference No
Date of Qualification / Validation 15
Prepared By Reviewed by Approved by 16 17 18 19 20 21 22 23 24 25 26 27 28 Utilities: 1 AHU System 2 Water System 3 Compressed Air 4 Steam 5 Lightning 6 Drain
Prepared By Reviewed by Approved by Remark:
Prepared By Reviewed by Approved by Conclusion
Sr. No. Stage Acceptance criteria Observation
1. Sifting No visible foreign particulate matter is observed 2. Premixing
Stage
Variation between the results shall not be more than 2%
3. Drying Between 2.0 to 4.0%
4. Lubrication Variation between the results shall not be more than 2%
5. Tablet compression
Average weight of tablets is within ± ____of std. weight.
Tablets shall meet requirement of physical parameter and FP specification.
6. Tablet coating Tablets shall meet the requirements for weight gain, weight variation and disintegration.
Coated tablets shall meet FP Specification 7. Tablet
packing
Packed tablet shall meet the requirement for leak test
Conclusion:
Product _________________________________ manufactured as per B.M.R. No _____________ meets predefined acceptance criteria.
Analysis By Approved By
Prepared By Reviewed by Approved by 7.
LIMITS: As pre relative STPs
8. CONCLUSION REPORT
Summary report will contain discussion and conclusion , which clearly states the successful achievement of objective of validation studies and recommended concentrations required for sanitization, disinfections and equipment sanitization.
