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

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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

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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:

____________________________________________________________________________________________________

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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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