parenteral process validation[1]

QUALITY ASSURANCE

PROCESS VALIDATION PROTOCOL FOR PARENTERALS

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PROCESS VALIDATION

PROTOCOL FOR PARENTERALS

Protocol No.

:

Effective Date. :

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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 ______________under the authority of _____________. Hence this document before being effective shall be approved by ____________________.

Designation

Name

Signature

Date

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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

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

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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: First Three Batches

Batch numbers: 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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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

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FLOW SHEET:

Sampling point

Input check in presence of QA person De-cartooning

Washing and sterilization Filtration

Prepare production order and according to that issue the BPR

RM dispensing as per Bill of material

Manufacturing

Vials filling Lyophilization

Vials sealing

Optical Inspections

pH Adjustment and volume makeup

Vials packing

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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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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 Equipment Equipment No. SOP No

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

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DETAILS OF EQUIPMENT TO BE USED.

Equipment Details

S.S. Manufacturing Tank

Make/Model:

ID. No.

Capacity:

Tag No.

RPM

M.O.C.

Rubber stopper washing

machine

Model:

ID. No.

Capacity:

Tag No.

M.O.C.

Vials washing machine

Make/Model:

ID. No.

Capacity:

Speed

Tag No.

M.O.C.

DHS

Make/Model:

ID. No.

Capacity:

Tag No.

M.O.C.

Equipment

Details

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Autoclave

Make/Model:

ID. No.

Capacity:

Tag No.

M.O.C.

Membrane filter

Make/Model:

Capacity:

Tag No.

M.O.C.

Filling Machine

Make/Model:

ID. No.

Capacity:

Tag No.

Speed

M.O.C.

Lyophilizer

Make/Model:

ID. No.

Capacity:

Tag No.

M.O.C.

Equipment Details

Make/Model:

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Sealing Machine

ID. No.

Capacity:

Speed

Tag No.

M.O.C.

Labeling Machine

Make/Model:

ID. No.

Capacity:

Speed

Tag No.

M.O.C.

Cold storage

Make/Model:

ID. No.

Capacity:

Tag No.

M.O.C.

Remarks:

____________________________________________________________________________________________

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ACTIVE

LOAD SIZE

T

E

M

P.

R.P.M.

PH

R.P.M.

LEAKAGE

SEALING

IDENTIFICATION OF CRITICAL PROCESS VARIABLES PARAMETER:

Probable causes that may affect final product:

ADDITION OF

EXCIPEINT

STIRRER

SPEED

MIXING

TIME

FINAL WASH

VOLUME

DISPENSING OF

MATERIAL

BATCH

PREPARATION

WASHING

pH ADJUSTMENT

VOLUME MAKEUP

LYOPHILIZATION

SEALING

CAKE

FORMATION

FILLING

COLD STORAGE

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Critical Process PARAMETERS:

Sr. No Critical process variable Response parameter Remarks

1 Batch Mixing time Uniformity Fixed speed.

Fixed batch size

2 Final mixing and volume make up Mixing time

Uniformity of Active Drug Fixed speed. Fixed batch size

3

Rubber stopper washing Detergent with heating

Purified water WFI washing Siliconization

Cleaning of rubber

stoppers

Clarity checking

Avoid the Clumping

4

Vial washing Purified Water pressure WFI Water temperature

Compressed air pressure Washing cycle

Alignment & blockage of needles

Cleaning Of vials

Washing efficiency

Fixed pressure for washing. Fixed temperature for washing

Fixed pressure of air Fixed cycle

Fixed direction

5 Filling

Speed of filling machine

Volume Uniformity

Fixed speed

Volume variation

Leakage

6 Lyophilization Water content

7 Sealing

Speed of filling machine Leak test

Volume Uniformity

Fixed speed

Volume variation

Leakage

8 Optical inspection Clarity

9 Labeling & Packing Clean, Position & Proper

Sealing

Clean Label

Position

Sealing

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Sampling, Test Parameters, Acceptance criteria

Sampling site: - use bottom valve for Sampling

Sampling Qty.: -As per testing requirements.

Sampling Time: -

__________ minutes ____________minutes ________ minutes

Total samples:________

BOTTOM VALVE

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SAMPLING:

Stage / Test Parameter

Equipment (Size, Location & Time)

Acceptance Criteria

Manufacturing pH

Assay

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

Measuring cylinder Visual inspection, Visual inspection

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

lyophilization lyophilizer 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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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

Time

pH Weight per ml Assay

______Minutes

______Minutes

______Minutes

Mean

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Note: pH meter calibration is essential.

Data recording -2

Equipment Name : vial washing Machine

Identification no : _________________________ Date: ___________________

Capacity : ______________________ (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.

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Data recording -3

Equipment Name: Rubber stopper washing Machine

Identification no : _________________________ Date: ___________________

Capacity : ______________________

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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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)

Stage

Volume measured in measuring Cylinder

Inspected

by

1 2 3 4 5 6 7 8

Beginning of

filling

Middle of filling

End of filling

Conclusion:

____________________________________________________________________________________________

Checked by: ___________________________ Date_________________________

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Data recording -6

Equipment Name: Lyophilization


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


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)

Stage

Leak test

Remarks

Inspected

by

1 2 3 4 5 6 7 8

Beginning of

Sealing

Middle of

sealing

End of sealing

Conclusion:

Checked by: ___________________________ Date_________________________

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Data recording -8

Equipment Name: vial labeling machine


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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Data recording-10 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 pH

03 Specific Gravity

04 Uniformity Of volume

05 Assay

5.1 % Labeled amount: 90 % - 110 %

Quantity Found:

5.2 % Labeled amount: 90 % - 110 %

Quantity Found:

5.3 % Labeled amount: 90 % - 110 %

Quantity Found:

5.4 % Labeled amount: 90 % - 110 %

Quantity Found:

Remark:

Result: The sample referred above complies / does not comply with the standard prescribed as per In house

Specification.

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Data recording 10

Sr

No

Name of critical equipment / Utilities Qualification /

Validation file

reference No

Date of Qualification /

Validation

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

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Data recording 11

Remark:

Attach Analytical Method Validation protocol

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Conclusion

Sr. No. Stage Acceptance criteria Observation

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

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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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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