QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 1 of 30

PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Protocol No. Effective Date. : :

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TABLE OF CONTENTS
S.NO. 1. 2. 3. 4. 5. 6. 7. 8. SECTION Protocol approval Purpose Responsibilities Requirements Personnel Responsibilities Validation parameters Limits Conclusion report Page No

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1. PROTOCOL APPROVAL
This document is prepared by the validation and the GMP compliance (QA) team of ______________under the authority of _____________. Hence this document before being effective shall be approved by ____________________.

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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
S.NO. 1. 2. 3. 4. 5. 6. Activity Preparation of protocol Chemical analysis and sampling Microbial analysis & sampling Preparation of validation Report Review of validation protocol & report Approval of protocol & Report Responsibility

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.

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6. VALIDATION PARAMETERS:
Formulation: Parenterals Products Name: Reason for Performing the Validity Study: Reason ( tick which ever is applicable) Department New product Modification in the manufacturing process. Change in Facility and / or location of manufacturing. Batch fails to meet product & process specifications. Number of batches studied: Batch numbers: First Three Batches 1. ____________2.______________ 3._______________ Remarks

Validation activity Approved by: _____________________________Date:_______________________

GENERAL:
Introduction: The process validation will be performed as prospective validation. The complete documentation for the validation comprises several independent documents; references to relevant documents will be given as part of this protocol, (find below). The results of the validation activities will be summarized in the validation report.

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List of Documents for Validation: Validation protocol, Details of sampling for the validation batches, test parameters (Product performance characteristics) with reference to test methods & Acceptance criteria. (acceptable Limit) Methods for recording / evaluating results including statistical analysis. Reference to relevant documents. Batch manufacturing records. Detailed manufacturing instructions for the production of the validation batches. 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 checks in presence of QA person 4 De-cartoning of vials and rubber stoppers 5 Washing and Sterilization 5.1 vial washing 5.2 Sterilization of vials by DHS 5.3 Rubber stoppers washing 5.4 Steam heat sterilization of rubber stoppers, Garments and Machine parts. 6 Manufacturing/ Batch preparation 7 pH adjustment and volume makeup 8 Filtration 9 Vial filling 10 Lyophilization 11 Vials sealing 12 Optical inspections 13 Vials packing Prepared By Reviewed by Approved by

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FLOW SHEET:
Prepare production order and according to that issue the BPR RM dispensing as per Bill of material

Input check in presence of QA person

De-cartooning

Manufacturing

pH Adjustment and volume makeup

Filtration

Washing and sterilization

Lyophilization

Vials filling

Vials sealing

Optical Inspections

Vials packing

Sampling point Prepared By Reviewed by Approved by

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FORMULATION: Batch Size: Sr No Ingredients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Unit per ml Quantity in Kgs Overages Quantity with Overages Dispensed Quantity Function

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Equipments/ Factory A detailed list of equipment used for validation together with the cleaning status will be provided in the manufacturing documents. List of SOPS, Validation & Qualification report used as references SrNo 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Equipment Equipment No. SOP No

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DETAILS OF EQUIPMENT TO BE USED. Equipment Make/Model: ID. No. S.S. Manufacturing Tank Capacity: Tag No. RPM M.O.C. Model: ID. No. Capacity: Tag No. M.O.C. Make/Model: Vials washing machine ID. No. Capacity: Speed Tag No. M.O.C. DHS Make/Model: ID. No. Capacity: Tag No. M.O.C. Details

Rubber stopper washing machine

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Make/Model: Autoclave ID. No. Capacity: Tag No. M.O.C. Make/Model: Membrane filter Capacity: Tag No. M.O.C. Make/Model: ID. No. Capacity: Filling Machine Tag No. Speed M.O.C. Make/Model: ID. No. Lyophilizer Capacity: Tag No. M.O.C. Equipment Make/Model: Prepared By Reviewed by Approved by Details

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ID. No. Capacity: Sealing Machine Speed Tag No. M.O.C. Make/Model: ID. No. Labeling Machine Capacity: Speed Tag No. M.O.C. Make/Model: ID. No. Cold storage Capacity: Tag No. M.O.C. Remarks:

____________________________________________________________________________________________

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IDENTIFICATION OF CRITICAL PROCESS VARIABLES PARAMETER: Probable causes that may affect final product:
DISPENSING OF MATERIAL BATCH PREPARATION WASHING FILLING SEALING

FINAL WASH
LOAD SIZE ACTIVE SPEED

VOLUME STIRRER

LEAKAGE SEALING

R.P.M.

R.P.M. CAKE FORMATION

T MIXING E TIME M P.
ADDITION OF EXCIPEINT pH ADJUSTMENT VOLUME MAKEUP

PH

LYOPHILIZATION

COLD STORAGE

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Critical Process PARAMETERS: Sr. No 1 2 Critical process variable Batch Mixing time Final mixing and volume make up Mixing time Rubber stopper washing Detergent with heating Purified water WFI washing Siliconization Vial washing Purified Water pressure WFI Water temperature Compressed air pressure Washing cycle Alignment & blockage of needles Filling Speed of filling machine Lyophilization Sealing Speed of filling machine Leak test Optical inspection Labeling & Packing Response parameter Uniformity Uniformity of Active Drug Cleaning of rubber stoppers Remarks Fixed speed. Fixed batch size Fixed speed. Fixed batch size Clarity checking Avoid the Clumping Fixed pressure for washing. Fixed temperature for washing Fixed pressure of air Fixed cycle Fixed direction Fixed speed Volume variation Leakage Fixed speed Volume variation Leakage Clean Label Position Sealing

Cleaning Of vials Washing efficiency

5 6 7 8 9

Volume Uniformity Water content Volume Uniformity Clarity Clean, Position & Proper Sealing

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Sampling, Test Parameters, Acceptance criteria

BOTTOM VALVE Sampling site: - use bottom valve for Sampling Sampling Qty.: -As per testing requirements. Sampling Time: __________ minutes Total samples:________ ____________minutes ________ minutes

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SAMPLING: Stage / Test Parameter Manufacturing pH Assay Vials washing Rubber stopper washing Filling Volume Appearance Colour lyophilization Sealing Optical Inspections Labeling & Packing Equipment (Size, Location & Time) Sampling Acceptance Criteria As specified in the BMR Assay 90 % to 110 % Inspected for particulate matter Inspected for particulate matter Not less than label claim. As specified in the BMR. As specified in the BMR As specified in the BMR Complies leak test Check clarity Clean label and proper sealing

Visual inspection, Visual inspection Measuring cylinder Visual inspection, Visual inspection lyophilizer Leak test Vials checking Clean, Position & Proper Sealing

Note: The assay value should be decided based up the product in use. If it is biological take concerned pharmacopeia and refer to the guidance values.(Especially in case of Fertility hormones). Leak test and its methodology must be properly understood as per equipment used. Optical Inspection: Refer to the guidance about visual inspection methodologies and Knapp test.

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RECORDING OF DATA & DATA TREATMENT: Data Recording: 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 Sheet No 2 Sheet No 3 Sheet No 4 Sheet No 5 Sheet No 6 Sheet No 7 Sheet No 8 Sheet No 9 Sheet No 10 Sheet No 11 For recording batch preparation & results For recording of vial washing and sterilization results For recording of Rubber stopper washing and sterilization results For recording Filtration Details For recording of vial filling For recording of lyophilization For recording of vial sealing For recording of labeling and packing For recording of analysis report For recording general utilities /equipment. For recording analytical method validation.

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Data recording sheet -1 Batch preparation: Equipment name Date Capacity : _______________________ :____________________ : ______________________ltrs / gms. : _______________ ltrs/gms. : _______ minutes : _______rpm : As outlined in the batch manufacturing record. : Samples to be drawn at of _______ minutes, _______ minutes, & ______ minutes of mixing from sampling point For batch preparation result: Assay after mixing pH Time ______Minutes ______Minutes ______Minutes Mean Weight per ml Assay Identification no : _______________________

Ingredients and sequence of material addition: ____________________ Total Volume of ingredients Mixing time Stirrer Procedure Plan

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Note: pH meter calibration is essential.

Data recording -2 Equipment Name Capacity : vial washing Machine Date: ___________________ : ______________________ (vials per minutes) Identification no : _________________________ Method reference: Visual inspection. Observation: Washed vials shall be inspected for particulate matter. Stage Beginning of washing Middle of washing End of washing Inspected by 1 2 3 4 5 6 7 8 9 10

Conclusion: ___________________________________________________________________________________________

Note: If you have a procedure or methodology to remove the vials as per non-conformity attach a table how many vials were fed and how many were removed. This is a key point to track the vials quality and report to your vendor. More than 0.3% of rejections is considered very high. Prepared By Reviewed by Approved by

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Data recording -3 Equipment Name: Rubber stopper washing Machine Identification no : _________________________ Capacity : ______________________ Method reference: Visual inspection. Observation: Washed Rubber stoppers shall be inspected for particulate matter. Stage After washing Inspected by 1 2 3 4 5 6 7 8 9 10 Date: ___________________

Conclusion: _________________________________________________________________________________________

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Data recording 4 Filtration Parameters: Type of Filter used and Its manufacturer:________________ Membrane filter holder or Cartridge housing number:________ Nitrogen gas or a Pump :________________ Details about sanitization of Pump if it is used:_____________ Integrity check details of Nitrogen filter:_____________ Capacity of Pressure vessel used:_________ Details of pressure vessel :____________

Pressure at which the Filtration is Performed:____________ Results of Pre and Post Integrity tests:_______ & ___________. Filtration is Pass/ Fail. Note: Always use a validated and calibrated integrity testing apparatus

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Data recording 5 Equipment Name: Filling machine Identification no: ________________________________ Machine Speed: _________________________________ Standard volume: ________________________________ Procedure: As per In-process check procedure for volume check. Observation: Volume shall be as per the limit. Plan: Samples to be drawn from beginning of filling, middle of filling and end of filling (Depends upon batch size) Inspected Stage 1 Beginning filling Middle of filling End of filling Conclusion: ____________________________________________________________________________________________ Checked by: ___________________________ Date_________________________ of Volume measured in measuring Cylinder 2 3 4 5 6 7 8 by

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Data recording -6 Equipment Name: Lyophilization Identification no: ________________________________ Machine Capacity: ________________________________ Procedure: Filled vials send to the lyophilizer for lyophilization process.

SAMPLING: Sampling should be done after the competition of the lyophilization cycle and check all Parameters mentioned in BPR

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Data recording -7 Equipment Name: Sealing machine Identification no: ________________________________ Machine Speed: _________________________________ Procedure: As per In-process check procedure for sealing check Observation: Sealing should be proper. Plan: Samples to be drawn from beginning of filling, middle of filling and end of filling (Depends upon batch size) Inspected Stage 1 Beginning of Sealing Middle of sealing End of sealing Conclusion: Checked by: ___________________________ Date_________________________ 2 3 Leak test 4 5 6 7 8 Remarks by

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Data recording -8 Equipment Name: vial labeling machine Identification no: ________________________________ Machine Speed: ________________________________ Procedure: Labeling should be as per the specifications. Method reference: Leak test procedure for Sealed vials.

Stage After machine Setting Beginning of Setting Middle of Setting At the end of Setting

No of vials tested

Position of label

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Data recording-10 Analysis Report Product Name: Batch No.: Mfg. Date: Batch size: Exp. Date: Composition: Test method reference: In house Sr. No. 01 02 03 04 05 5.1 5.2 5.3 5.4 Test Description pH Specific Gravity Uniformity Of volume Assay % Labeled amount: 90 % - 110 % Quantity Found: % Labeled amount: 90 % - 110 % Quantity Found: % Labeled amount: 90 % - 110 % Quantity Found: % Labeled amount: 90 % - 110 % Quantity Found: Specification Results Remark

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

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Data recording 10 Sr No 1 3 4 5 6 7 8 9 Utilities: 1 2 3 4 5 6 AHU System Water System Compressed Air Steam Lightning Drain Prepared By Reviewed by Approved by S.S. Manufacturing tank Membrane Filter Filtration tank Washing Machine Filling Machine Lyophilization Sealing Machine Labeling Machine Name of critical equipment / Utilities Qualification / Validation file reference No Date of Qualification / Validation

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Data recording 11 Remark: Attach Analytical Method Validation protocol

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Conclusion Sr. No. 1. 2. 3. 4. 5. 6. 7. Stage Manufacturing Vial Washing Rubber stopper washing Filling Lyophilization Sealing Labeling and packing Conclusion: Product _______________________manufactured as per B.M.R. No _____________ meets predefined acceptance criteria. Complies as per BPR Complies as per BPR Complies as per BPR Complies as per BPR Leak test Acceptance criteria Complies as per BPR Complies as per BPR Observation

Analysis By Date

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7. LIMIT: Based on respective Standard Testing Procedures. 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 sanitisation, disinfections and equipment sanitization.

Note: Extra pages for conclusions can be used as per requirement. ..

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