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Process Validation Protocol for Parenteral

TABLE OF CONTENTS
  1. Protocol Approval
  2. Purpose
  3. Responsibilities
  4. Requirements
  5. Personnel Responsibilities
  6. Validation parameters
  7. Limits
  8. Conclusion Report

PROTOCOL APPROVAL
This document is prepared by the validation and the GMP compliance (QA) team. Hence this document before being effective shall be approved by QA Head.

Designation

Name

Signature

Date

 

 

 

 

 

 

 

 

 

 

 

 


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.

RESPONSIBILITIES

Sr. 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

 


REQUIREMENTS
Nil

PERSONNEL RESPONSIBILITIES
The perfect validation program necessitates various department's 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.


VALIDATION PARAMETERS
Formulation: 
Product’s Name:
Reason for Performing the Validity Study:

Reason (tick whichever 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.

List of Documents for Validation:
  1. Validation protocol
  2. Details of sampling for the validation batches, test parameters (Product performance characteristics) with reference to test methods & Acceptance criteria. (acceptable Limit)
  3. Methods for recording / evaluating results including statistical analysis.
  4. 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.
  • Prepare production order and according to that issue the BPR 
  • RM dispensing as per Bill of material
  • Input checks in presence of QA person
  • De-cartoning of vials and rubber stoppers 
  • Washing and Sterilization
  1. Vial washing
  2. Sterilization of vials by DHS
  3. Rubber stoppers washing
  4. Steam heat sterilization of rubber stoppers, Garments and Machine parts. 
  • Manufacturing/ Batch preparation
  • pH adjustment and volume makeup 
  • Filtration
  • Vial filling
  • Lyophilization
  • Vials sealing
  • Optical inspections
  • Vials packing


Flow Sheet




Formulation

Batch Size:

Sr. No

Ingredients

Unit / ml

Quantity in Kgs

Overages

Quantity with Overages

Dispensed Quantity

Function

1

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

3

 

 

 

 

 

 

 

4

 

 

 

 

 

 

 

5

 

 

 

 

 

 

 

6

 

 

 

 

 

 

 

7

 

 

 

 

 

 

 

8

 

 

 

 

 

 

 

9

 

 

 

 

 

 

 

10

 

 

 

 

 

 

 


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.

Sr. No.

Equipment

Equipment No.

SOP No

1

 

 

 

2

 

 

 

3

 

 

 

4

 

 

 

5

 

 

 

6

 

 

 

7

 

 

 

8

 

 

 

9

 

 

 

10

 

 

 


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.

 



 

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.

 


 

 

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:
____________________________________________________________________________________________________


Identification of Critical Process Variables Parameter

Probable causes that may affect final product:




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


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:        


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


Recording of Data and 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.




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 _______ minutes, _______ minutes, &
______ minutes of mixing from the sampling point

For Batch Preparation Result:

Assay after mixing

 

Time

pH

Weight per ml

Assay

 

 

 

            Minutes

 

 

 

            Minutes

 

 

 

            Minutes

 

 

 

Mean

 

 

 


Note: pH meter calibration is essential.


Data Recording Sheet - 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 quality of the vials and report to your vendor. More than 0.3% of rejections are considered very high.



Data Recording Sheet - 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:
____________________________________________________________________________________________________



Data Recording Sheet - 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 appara



Data Recording Sheet - 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 the beginning of filling, middle of filling and end of filling (Depending 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______________




Data Recording Sheet - 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.



Data Recording Sheet - 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)

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_____________


Data Recording Sheet - 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

 

 



Data Recording Sheet - 9

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 to above complies/does not comply with the standard prescribed as per In house Specification.


Data Recording Sheet - 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

 

 




Data Recording Sheet - 11

Remark:



Attach Analytical Method Validation protocol


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

 



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

Analysis By

Approved By

Date

Date



LIMIT
Based on respective Standard Testing Procedures.

CONCLUSION REPORT
The summary report will contain a discussion and conclusion, which clearly states the successful achievement of objective of validation studies and recommended concentrations required for sanitisation, disinfections and equipment sanitization.


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