Parenteral Process Validation[1]

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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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

TABLE OF CONTENTS S.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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SECTION

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 3 of 30

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 ____________________.

Designation

Name

Prepared By

Designation Date Format No.:

Signature

Reviewed by

Date

Approved by

QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 4 of 30

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.

Activity

Responsibility

1.

Preparation of protocol

2.

Chemical analysis and sampling

3.

Microbial analysis & sampling

4.

Preparation of validation Report

5.

Review of validation protocol & report

6.

Approval of protocol & Report

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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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

6. VALIDATION PARAMETERS: Formulation: Parenterals Product’s Name: Reason for Performing the Validity Study: Reason ( tick which ever is applicable)

Remarks

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._______________

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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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 6 of 30

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

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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

Manufacturing

De-cartooning

pH Adjustment and volume makeup

Washing and sterilization

Filtration

Lyophilization

Vials sealing

Vials filling

Optical Inspections

Vials packing

Sampling point Prepared By

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 8 of 30

FORMULATION: Batch Size: Sr No Ingredients

Unit per ml

Quantity in Kgs

Overages

Quantity with Overages

Dispensed Quantity

Function

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 9 of 30

Equipments/ Factory A detailed list of equipment used for validation together with the cleaning status will be provided in the manufacturing documents. List of SOP’S, Validation & Qualification report used as references SrNo 1

Equipment

Equipment No.

SOP No

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 10 of 30

DETAILS OF EQUIPMENT TO BE USED. Equipment

Details Make/Model: ID. No.

S.S. Manufacturing Tank

Capacity: Tag No. RPM

Rubber stopper washing machine

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.

Prepared By Equipment Designation Date Format No.:

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 11 of 30

Make/Model: ID. No.

Autoclave

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

Details Make/Model: Prepared By

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 12 of 30

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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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 13 of 30

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 SPEED

ACTIVE

VOLUME

LEAKAGE SEALING

STIRRER

R.P.M.

R.P.M.

CAKE FORMATION

T MIXING E TIME M P. ADDITION OF EXCIPEINT

pH ADJUSTMENT VOLUME MAKEUP

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PH

LYOPHILIZATION

Reviewed by

COLD STORAGE

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 14 of 30

Critical Process PARAMETERS: Sr. No

Critical process variable

Response parameter

1

Batch Mixing time

Uniformity

2

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

Uniformity of Active Drug

3

4

5 6 7 8 9

Filling Speed of filling machine Lyophilization Sealing Speed of filling machine Leak test Optical inspection Labeling & Packing

Cleaning of rubber stoppers

Cleaning Of vials Washing efficiency

Volume Uniformity

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

Water content Volume Uniformity

Fixed speed Volume variation Leakage

Clarity Clean, Position & Proper Sealing

Clean Label Position Sealing

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Sampling, Test Parameters, Acceptance criteria

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

____________minutes

________ minutes

Total samples:________

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

SAMPLING: Stage / Test Parameter Manufacturing pH Assay

Equipment (Size, Location & Time)

Acceptance Criteria

Sampling

 As specified in the BMR  Assay 90 % to 110 %

Vials washing

Visual inspection,

Inspected for particulate matter

Rubber stopper washing

Visual inspection

Inspected for particulate matter

Filling Volume Appearance Colour lyophilization

Measuring cylinder Visual inspection, Visual inspection lyophilizer

Not less than label claim. As specified in the BMR. As specified in the BMR As specified in the BMR

Sealing

Leak test

Complies leak test

Optical Inspections

Vials checking

Check clarity

Labeling & Packing

Clean, Position & Proper Sealing

Clean label and 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

For recording batch preparation & results

Sheet No 2

For recording of vial washing and sterilization results

Sheet No 3

For recording of Rubber stopper washing and sterilization results

Sheet No 4

For recording Filtration Details

Sheet No 5

For recording of vial filling

Sheet No 6

For recording of lyophilization

Sheet No 7

For recording of vial sealing

Sheet No 8

For recording of labeling and packing

Sheet No 9

For recording of analysis report

Sheet No 10

For recording general utilities /equipment.

Sheet No 11

For recording analytical method validation.

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Data recording sheet -1 Batch preparation: Equipment name

: _______________________

Identification no : _______________________ Date

:____________________

Capacity

: ______________________ltrs / gms.

Ingredients and sequence of material addition: ____________________ Total Volume of ingredients

: _______________ ltrs/gms.

Mixing time

: _______ minutes

Stirrer

: _______rpm

Procedure

: As outlined in the batch manufacturing record.

Plan

: Samples to be drawn at of _______ minutes, _______ minutes, & ______ minutes of mixing from sampling point

For batch preparation result: Assay after mixing pH

Weight per ml

Assay

Time ______Minutes ______Minutes ______Minutes Mean

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Note: pH meter calibration is essential.

Data recording -2 Equipment Name

: vial washing Machine

Identification no : _________________________ Capacity

Date: ___________________

: ______________________ (vials per minutes)

Method reference: Visual inspection. Observation: Washed vials shall be inspected for particulate matter. Stage

Inspected by

1

2

3

4

5

6

7

8

9

10

Beginning of washing Middle of washing End of washing

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

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 20 of 30

Data recording -3 Equipment Name: Rubber stopper washing Machine Identification no : _________________________ Capacity

Date: ___________________

: ______________________

Method reference: Visual inspection. Observation: Washed Rubber stoppers shall be inspected for particulate matter. Stage

Inspected by

1

2

3

4

5

6

7

8

9

10

After washing

Conclusion: _________________________________________________________________________________________

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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

Volume measured in measuring Cylinder 1

Beginning

2

3

4

5

6

7

by 8

of

filling Middle of filling End of filling Conclusion: ____________________________________________________________________________________________ Checked by: ___________________________

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 23 of 30

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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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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

Leak test 1

2

3

4

5

Remarks 6

7

by

8

Beginning of Sealing Middle of sealing End of sealing Conclusion: Checked by: ___________________________

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Protocol No. : Rev. :00 Supersedes: NIL Protocol prepared on: Effective Date: Page 25 of 30

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

No of vials tested

Position of label

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

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Data recording-10 Analysis Report Product Name: Batch No.:

Batch size:

Mfg. Date:

Exp. Date: Composition:

Test method reference: In house Sr. No. Test Description

01 02 03 04 05 5.1

Specification

Results

Remark

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:

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

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Data recording 10 Sr

Name of critical equipment / Utilities

No

Qualification /

Date of Qualification /

Validation file

Validation

reference No 1

S.S. Manufacturing tank

3

Membrane Filter

4

Filtration tank

5

Washing Machine

6

Filling Machine

7

Lyophilization

8

Sealing Machine

9

Labeling Machine

Utilities: 1

AHU System

2

Water System

3

Compressed Air

4

Steam

5

Lightning

6

Drain Prepared By

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Data recording 11 Remark: Attach Analytical Method Validation protocol

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

Conclusion Sr. No.

Stage

Acceptance criteria

1.

Manufacturing

Complies as per BPR

2.

Vial Washing

Complies as per BPR

3.

Rubber stopper washing

Complies as per BPR

4.

Filling

Complies as per BPR

5.

Lyophilization

Complies as per BPR

6.

Sealing

Leak test

7.

Labeling and packing

Observation

Complies as per BPR

Conclusion: Product _______________________manufactured as per B.M.R. No _____________ meets predefined acceptance criteria.

Analysis By

Approved By

Date

Date

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QUALITY ASSURANCE PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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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