Report Esomeprazole IV Inj (Guide Batch 03)

Document No.
: 058/SLI/VPP/07/22/V/01
Revision No. : 04
Issued Date :
The information contain herein is the property of PT Darya-Varia Laboratoria Tbk Citeureup Plant.
It is SECRET and / or CONFIDENTIAL and should be kept safely and prevention of unauthorized
appropriation, use or disclosure.
PT DARYA-VARIA LABORATORIA Tbk

CITEUREUP PLANT
Process Validation Report

ESOMEPRAZOLE IV INJ 40MG
PT Darya-varia Laboratoria Tbk Citeureup Plant

Factory : Desa Karang Asem Barat, Citeureup, Kabupaten Bogor
Phone : +62(21) 8751066, 8758539, 8758540. Fax : +62(21) 8754094
Head Office : South Quarter, Tower C, 18th – 19th Floor Jl. R. A. Kartini Kav. 8, Jakarta 12430,
Indonesia
Telephone : +62(21)22768000. Fax : +62(21) 22768016
PT Darya-Varia Laboratoria Tbk Citeureup Plant
Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 2 of 60
Table of Contents
Page
1 Introduction 4
1.1 Scope of Validation 4
1.2 Objective 4
2 General Overview 4
3 Acceptance Criteria 5
4 Validation Procedures 5
5 Attachments 6
6 Validation Team 6
7 Change Control Procedures 7
8 Final Approval 8
9 Document History 9
List of Attachments
Page
1 GMP Compliance 11
2 Raw Material Quality 21
3 Packaging Material Quality 22
4 List of Equipments Used 23
5 Analytical Methods and Testing Procedures 24
6 Critical Parameters of Process 25
7 Environmental Monitoring 32
8 Sampling and Testing Plan to In-Process of Mixing 35
9 Sampling and Testing Plan to In-Process of Filling 41
10 Sampling and Testing Plan to In-Process of Finished Product 48
11 Documentation 57
12 Summary, Conclusion and Recommendations 58
13 Deviation and Discrepancy Report 59
DVL-VMP-014/02/01NOV2016
1. Introduction
1.1 Scope of Validation
This process validation report is applicable to conduct process validation of

Esomeprazole/Esozid IV Inj 40 mg manufacturing process in order to satisfy both the c-
GMP requirements and PT Darya-Varia Laboratoria Tbk Citeureup Plant Standard.
1.2 Objective
The objective is to demonstrate by testing and documented evidence that the
manufacturing process of Esomeprazole/Esozid IV Inj 40 mg will consistently produce
the product meeting its pre-determined specifications and quality attributes. This report
is created to follow up change control:
Change Control No. Issued Date Change
Alternate source addition of Esomeprazole

Sodium (RAI-00000003) ex. Metrochem API
CC-2-22-0219 22-Jun-22
Private Limited, India for Esomeprazole
IV/Esozid IV Inj 40 mg
2. General Overview
Validation will be conducted as traditional validation to three consecutive pilot batches of
Esomeprazole/Esozid IV Inj 40 mg with a batch size of 12,500 vials. It starts from
manufacturing until primary packaging. Secondary packaging will be validated (if
necessary) in separated validation. Validation execution covers selection and evaluation of
critical parameters of process by performing testing at each process step. Critical
parameters and testing conducted are included in process validation report. Validation
report will be developed after three consecutive batches were successfully completed and
meet the pre-determined acceptance criteria.
Manufacturing of Esomeprazole/Esozid IV Inj 40 mg will be conducted with lyophilization

method. The process starts by sterilizing all equipments, followed by performing line
clearance. Mixing process is then conducted by adding Water For Injection (WFI) and
Sodium Hydroxide Pellet Pharma Grade into a beaker glass and mix them for 10 minutes
DVL-VMP-014/02/01NOV2016
(10% NaOH Solution), and set aside. Next, add WFI and Edetate Disodium to the Mixing
Tank and mix for 15 minutes.
Esomeprazole Sodium is then added to the solution within the mixing tank and mix for 15
minutes. Finally, add the 10% NaOH solution into the mixing tank and mix for 5 minutes.
Check the final pH before continuing to the next process (Specification: 11.0 – 12.5). After
the pH is ensured to have met the specification, ad the solution with WFI until either the
load cell shows 30.02 kg, or, it has reached the 30.0 L limit using deep stick. The final
solution is then filtered with 0.45 and 0.2 micron filter and then filled into 10 mL
Lyophilizer vial using Bausch Strobel Filling Machine. The target bulk volume that will be
lyophilized with the Tofflon 7.5 Lyophilizer, is 2.1 mL (2.0 – 2.2 mL).
3. Acceptance Criteria
Acceptance criteria will depend on the certification that manufacturing process of

Esomeprazole/Esozid IV Inj 40 mg is able to meet the requirements of the report.
4. Validation Procedures
 Manufacturing process will be validated by monitoring all critical parameters of

process, on-line inspection, in-process, bulk and finished product testing, and
evaluation of the related document and confirmation that product conforms to
design requirement as well as all associated specifications.
 An executor’s signature and/or initials and date within the designated area indicate
that the particular item has been checked and found to be acceptable. Validation
Coordinator or an individual of validation team will review each attachment section
and sign and date the bottom of the page to indicate that all validation
requirements have been met and all documentation have been properly completed.
 If the inspection or verification test is not satisfactory, Deviation and Discrepancy

Form is available to address this issue.
 Upon successful completion of the Process Validation, the Final Approval Section
will be completed.
5. Attachments
DVL-VMP-014/02/01NOV2016
Data collection forms are provided as Attachments to this report. These documents will
cover the necessary information required to meet the process validation requirements of
Esomeprazole/Esozid IV Inj 40 mg. Additional forms may be used to include all necessary
essential information.
6. Validation Team
The following personnel comprise the validation team responsible for the execution of the
Process Validation.
Name Title Signature Initial
Nabila Alhaura MTU Pharmacist NAH
MTU Supervisor
PWO
Prastomo Wibisono SLI Production Supervisor
YRP
Yani Risaini Putri Chemical Supervisor
SYR
Sherly Yunilara R. Microbiological Supervisor
TAW
Thomas Aquino Aditya IPC Supervisor
ARQ
Abdul Rofiq Maintenance Supervisor
7. Change Control Procedures
DVL-VMP-014/02/01NOV2016
Any change to raw material, packaging material, manufacturing and packaging process,
formulation, equipment, or critical system that have been validated should be proceeded
through a change control procedure and should be documented. Re-validation may be
necessary to check its validation status.
8. Final Approval
DVL-VMP-014/02/01NOV2016
After reviewing this report and its attachments, we the undersigned approved that this
report can be used to validate manufacturing process of Esomeprazole/Esozid IV Inj 40
mg in order to apply for regular production.
Title Name Signature Date
Prepared by :
MTU Pharmacist Nabila Alhaura
Reviewed by :
Validation & Calibration

Muhammad Rifqi Akram
Supervisor
MTU Head Aprilia Primadawaty
Quality Control Head Dewi Sulistyowati
Production Head Antonius Raino Dymita
Engineering Head Wasana Saputra
Approved by :
Quality Assurance Head Siti Lathifah Noor Amir
Citeureup Plant Division

Ganggas Cahyono
Head
9. Document History
DVL-VMP-014/02/01NOV2016
Revision Issued Change Change

No. Date Control No.
00 17-Jun-15 N/A  New Document
01 28-Feb-17 N/A  Initial Production
 Change volume batch size from 27.5 L to

02 25-Sep-17 DVL-17-288
30.0 L
 Changed of product filling volume of

03 12-Sep-19 DVL-18-420
Esomeprazole and Esozid IV
 Alternate source addition of Esomeprazole

Sodium (RAI-00000003) ex. Metrochem
04 CC-2-22-0219
API Private Limited, India for Esomeprazole
IV/Esozid IV Inj 40 mg
DVL-VMP-014/02/01NOV2016
Attachment Section
Process Validation
Data Collection Forms
Attachment 1
Test No. 1
DVL-VMP-014/02/01NOV2016
General Manufacturing Process Compliance
a. Product Description
1. Product Name : 1. Esomeprazole IV Inj 40 mg
2. Esozid IV Inj 40 mg
2. Product code : 1. 3ID-00000033
2. 3ID-00000034
3. Dosage Form : Vials
4. Batch Size : 30.00 L / 12,500 Vials
5. Batch No. : a. T94RM23-01 Manufacturing date : May 2023
b. T94RM23-02 Manufacturing date : May 2023
c. T94RM23-03 Manufacturing date : May 2023
b. Formula
Label Actual/ Per MO
Item Code Raw Material UoM UoM
claim Vial 12,500 Vials
Esomeprazole
RAI-00000038TRL 40.00 43.536 mg 653.040 g
As Esomeprazole Sodium
REX-00000228 Edetate Disodium - 1.500 mg 22.500 g
Sodium Hydroxide,
REX-00000130 - 2.000 mg 30.000 g
Pharma Grade
N/A Water for Injection - Ad 2.0 mL Ad 30.0 L
Total 2.0 mL 30.00 L
Note:
1. Esomeprazole
Chemical : C17H18N3O3S
MW of Esomeprazole : 345.417
MW of Esomeprazole Sodium : 368.397
40 mg Esomeprazole is equivalent to 42.661 mg of Esomeprazole Sodium
Computation: ((368.397 x 40)/345.417) =42.661 mg)
2. Contain per vial is 43.536 as Esomeprazole Sodium with water content 2%
Computation: Esomeprazole Sodium + (2% x Esomeprazole Sodium)
: 42.661 mg + (2% x 42.661 mg) = 43.536 mg
1. Manufacturing
DVL-VMP-014/02/01NOV2016
Perform the manufacturing according to Batch Manufacturing Record No.

BMR-D/03.05/SE/66/04/T01; BMR-M/03.05/SE/66/04/T01; BPR-P/03.05/SE/66/04/T01 and
PS&AP No. E-045 Rev. 3.
A. Mixing
1. Perform CIP and SIP of Mixing Tank 60 L with the following setting:
Temperature : 121°C
Time : 30 minutes
2. Sterilize the following equipments that will be used:
2.1. Magnetic stirrer
2.2. Magnetic stirrer rod
2.3. 1000 mL Volumetric glass
2.4. 1000 mL Beaker glass
2.5. Housing and cartridge for 0.2 and 0.45 micron Sartopore filter
2.6. Sterile; Gloves, Shoe Cover, Hair Net, and Mask
Using the Autoclave with the following setting (Choose one):
a. Autoclave Last (M/SLI/P/055):
Time : 30 minutes
b. Autoclave Meco (M/SLI/P/002):
Temperature : 121.5°C
Time : 60 minutes
3. Perform and record Line Clearance.
4. Conduct filter integrity testing before usage, and then set-up the filter for the
Mixing Tank 60 L output pipe.
5. Ensure that the Water For Injection (WFI) used is already released by QC.
6. Conduct tare using the load cell and deep stick by adding the chilled WFI (30 –
40°C) until it is measured to 30.0 L.
7. Set aside 1000 mL of WFI from the Mixing Tank 60 L into the 1000 mL volumetric
glass.
8. Into a 1000 mL beaker glass, pour 250.0 mL WFI, add 30.000 g of Sodium
Hydroxide Pellet Pharma Grade and mix for 10 minutes or until dissolved. Finally,
ad the solution using WFI until 300.0 mL (10% NaOH Solution).
9. Into the Mixing Tank 60 L that has been tared to 30.0 L, pour 26.5 L WFI, add
22.500 g of Edetate Disodium and mix for 10 minutes with the speed of 450 – 550
rpm, or until dissolved.
10. Add 653.000 g of Esomeprazole Sodium into the Mixing Tank 60 L and mix for 15
minutes with the speed of 450 – 550 rpm, or until dissolved.
11. Pour the 10% NaOH Solution into the Mixing Tank 60 L and mix for 5 minutes with
the speed of 450 – 550 rpm.
12. Perform pH testing to ensure the pH meets the specification (11.0 – 12.5). If the
pH still has not met the specification, subsequently add 10% NaOH to reach the
specified pH, and document the amount of 10% NaOH used (mL).
13. Add WFI until either the load cell has shown 30.02 kg, or, the WFI has reached the
30.0 L shown on the deep stick, and then mix for 15 minutes with the speed of
450 – 550 rpm or until homogenous.
14. Add a pressure of 0.3 – 0.5 bar from N2 gas to the Mixing Tank 60 L, maintain the
pressure until the filtration process is finished.
15. Filter with the 0.45 micron first, then filter with the 0.2 micron filter.
DVL-VMP-014/02/01NOV2016
16. Collect composite sample from top, middle and bottom for QC testing.
17. Perform filter integrity testing to the filter that has been used for filtering.
18. Perform and record Line Clearance.
B. Primary Packaging
Filling Process:
1. Prepare and sterilize the 10 mL Lyophilizer Vial using Hot Air Sterilizer with the
following setting:
Time : 2 hours
2. Sterilize the following equipments that will be used:
2.1. Scaled, stainless steel scoop
2.2. 5 mL Volumetric Glass
2.3. Bausch Strobel Filling & Sealing Machine Dispensing Pump
2.4. 2 set of Silicone hose
a. Autoclave Last (M/SLI/P/055):
Time : 30 minutes
b. Autoclave Meco (M/SLI/P/002):
Time : 60 minutes
3. Prepare and sterilize the following primary packaging materials:
3.1. Flip Off
3.2. Rubber Stopper
c. Autoclave Last (M/SLI/P/055):
Time : 30 minutes
d. Autoclave Meco (M/SLI/P/002):
Time : 30 minutes
4. Perform and record line clearance.
5. Set-up the 0.2 micron filter before the buffer tank of the Bausch Strobel Filling &
Sealing Machine.
6. Turn on the mobile LAF 15 minutes before using the Bausch Strobel Filling &
Sealing Machine.
7. Run the Bausch Strobel Filling & Sealing Machine and fill the filtrated bulk into the
transparent 10 mL Lyophilizer vial with a volume of 2.1 mL (2.0 – 2.2 mL).
8. Conduct IPC testing (Description and Filling Volume) and record in the IPC
attachment. If the results meet the specifications, run the Bausch Strobel Filling &
Sealing Machine again until the bulk filling is finished.
9. Insert the rubber stopper to the vial until the position is half closed, so air can
still pass through when vacuumed.
10. Put the vials into mobile LAF, after the space in the LAF is full, move the vials into
the Lyophilizer.
11. Perform filter integrity testing to the filter that has been used for filtering.
Lyophilization and Sealing Process
DVL-VMP-014/02/01NOV2016
1. Perform CIP and SIP to the Tofflon 7.5 Lyophilizer machine with the following
setting:
Time : 15 minutes
2. Perform and record Line clearance.
3. Check whether there is leakage from the Tofflon 7.5 Lyophilizer machine with the
pressure range of 0.1 – 0.2 mbar.
4. Set-up the Tofflon 7.5 Lyophilizer machine as such:
4.1. Ensure that the temperature condenser 1 and 2 is within -45°C until -
50°C.
4.2. Ensure the Chiller position is on.
4.3. Ensure that the Silicon Oil Level is on the standard level.
4.4. Ensure that the machine setting is according to the FAT PRODUCT
program.
5. Automatically seal the vial using flip off with the Bausch Strobel Filling & Sealing
Machine
Manufacturing Flow Diagram

STAGE OF EQUIPMENT CRITICAL
MATERIAL TESTING POINT SUCCESS CRITERIA
PRODUCTION USED PARAMETER
Mixing
o Magnetic stirrer
o Magnetic stirring
rod
o 1000 mL Volumetric
Autoclave Meco
glass
No. ID:
o 1000 mL Beaker
M/SLI/P/002
glass o Sterilization
o Scaled, stainless Temperature
OR Sterility Sterile
steel scoop o Sterilization
o Housing and Time
Sterilization for Autoclave LAST
cartridge for 0.2 No. ID:
and 0.45 micron Mixing Process
M/SLI/P/055
Sartopore filter
o Sterile; Gloves,
Shoe cover, hair
net, and mask
Mixing Tank o CIP Time

60 L o SIP Time
o Mixing Tank 60 L Sterility Sterile
No. ID: o SIP
M/SLI/P/038 Temperature
Mixing Tank oWFI

o WFI WFI Preparation pH 5.00 – 7.00
60 L Specifications
DVL-VMP-014/02/01NOV2016

TOC ≤ 500 ppb
Water
≤ 1.3 microsiemen/cm
Conductivity
No. ID:
M/SLI/P/038
Bacterial
≤ 0.25 EU/mL
Endotoxin
Total Plate Count < 10 cfu/ 100 mL
o WFI 10% NaOH o Beaker Glass

o Sodium Hydroxide solution o Magnetic oMixing Time Homogeneity Homogen
Pellet Pharma Grade Preparation Stirrer
o WFI oMixing Time

Mixing I Homogeneity Homogen
o Edetate Disodium oMixing Speed
o Mixing I solution
oMixing Time
o Esomeprazole Mixing II Homogeneity Homogen
Mixing Tank oMixing Speed
Sodium
60 L
No. ID:
M/SLI/P/038
Homogeneity Homogen
o Mixing II solution oMixing Time
Mixing III
o 10% NaOH Solution oMixing Speed
pH 11.0 – 12.5
Clear, colorless
Description
solution
pH 11.0 – 12.5
Mixing Tank
o Mixing III Solution 60 L oMixing Time
Final Mixing
o WFI No. ID: oMixing Speed
M/SLI/P/038
Specific Gravity 1.00 – 1.03 g/mL
Assay
36.0 – 44.0 mg/
Esomeprazole
90.0 – 110.0%
(40 mg/2 mL)
Housing and oIntegrity Test

o Final Mixing Solution Filtration Filter Type Sartopore
Cartridge of (Before Usage)
DVL-VMP-014/02/01NOV2016

Filter Size 0.2 µm
Integrity Test ≥3,200 mbar

0.2 and 0.45
micron Filter Type Sartopore
Sartopore
Filter oIntegrity Test Filter Size 0.2 µm
(After Usage)
Integrity Test ≥3,200 mbar
Primary Packaging
Hot Air o Sterilization

Sterilizer Temperature
o 10 mL Lyophilizer Vial Sterility Sterile
No. ID: o Sterilization
M/SLI/P/003 Time
o Flip Off
o Housing and
cartridge for 0.2
micron Sartopore
filter
o 5 mL Volumetric
Glass Sterility Sterile
o Bausch Strobel
Filling & Sealing
Machine Dispensing Sterilization for Autoclave Meco
Pump Filling Process No. ID:
2 set of Silicone M/SLI/P/002
o o Sterilization
Hose Temperature
OR
o Sterilization
Time
Autoclave LAST
No. ID: Sterility Sterile
M/SLI/P/055
o Rubber Stopper
Bacterial
NMT 0.25 EU/mL
Endotoxin
Bausch Strobel o Filling Volume

Filling & Sealing o Filling speed Bioburden of
o Filtered Solution Filling < 10 cfu/100 mL
Machine o Bulk filtered bulk
No. ID: Temperature
DVL-VMP-014/02/01NOV2016

2.1 mL
M/SLI/P/041 Volume Uniformity
(2.0 – 2.2 mL)
Tofflon 7.5 o CIP Time

Sterilization For
o Tofflon 7.5 Lyophilizer o SIP Time
Lyophilization Sterility Sterile
Lyophilizer No. ID: o SIP
Process
Lyophilized Powder
White to off white

Description
cake
- Stage I: AV10
≤L1%
Uniformity of - Stage II: AV30
Dosage Unit ≤L1% and no
o Preparation (Weight Variation) individual content
o Freezing L1 = 15.0 is less than [1-
o Condensor L2 = 25.0 (0.01)(L2)M], nor
more than
Freezing
[1+(0.01)(L2)M]
o Chamber
Tofflon 7.5
Evacuation
Lyophilizer
o Filled Vial Lyophilization o Primary Drying Water Content NMT 8.00%
No. ID:
o Secondary
M/SLI/P/042
Drying
o Pressure Rise Sterility Sterile
Test
o Vacuum Break
Bacterial
& Stoppering NMT 2.5 EU/mg
Endotoxin
Reconstituted Solution1)
Clear and colorless

Description
solution
pH 8.5 – 11.5
DVL-VMP-014/02/01NOV2016

Particulate
Matter2)
o Microscopy
Method:
≥ 10 µm NMT 3000/container
o Preparation ≥ 25 µm NMT 300/container
o Freezing o LOPC Method
o Condensor ≥ 10 µm NMT 6000/container
Freezing ≥ 25 µm NMT 600/container
o Chamber
Tofflon 7.5
Evacuation The retention time of
Lyophilizer
o Filled Vial Lyophilization o Primary Drying the major peak in the
No. ID:
o Secondary chromatogram
M/SLI/P/042
Drying obtained from sample
o Pressure Rise solution corresponds
Identification by
Test to that in the
HPLC
o Vacuum Break chromatogram
& Stoppering obtained from
standard solution, as
obtained in the test
for Assay
Assay
36.0 – 44.0 mg/
Esomeprazole
90.0 – 110.0%
(40 mg/vial)
Note :
NMT : Not More Than
NLT : Not Less Than
1)
Reconstituted Solution is obtained by mixing Esomeprazole IV Inj 40 mg with 0.9% NaCl solution.
2)
Choose one of the methods
DVL-VMP-014/02/01NOV2016
2. Manufacturing Flowchart
DVL-VMP-014/02/01NOV2016
Test Attribute General Manufacturing Process Compliance
Acceptance Criteria General Manufacturing Process and Manufacturing Flow Diagram in

Drug Master File are consistent to Master Batch Record
Actual General Manufacturing Process and Manufacturing Flow Diagram in

Drug Master File are consistent to Master Batch Record
Result  Accepted
 Not Accepted
(necessary measure to be described)
 Accepted after realization of the described measure
Comments :
Verified by : Date :
Reviewed by : Date :
DVL-VMP-014/02/01NOV2016
Attachment 2
Test No. 2
Raw Material Quality
Identify all raw materials used in validated batch. Verify that all raw materials are in raw
material specification and are not expired.
Product Name : Esomeprazole IV Inj 40 mg

Batch No. : T94RM23-03
Exp. Material
No. Description Material Code Function QC Lot# Manufacturer
Date Quality
Metrochem API
Esomeprazole as Active 2R22-1069 Meets the
1 RAI-00000038TRL Private Limited, 30/04/27
Esomeprazole Sodium Ingredient 2R22-1070
India
requirements
Chelating Meets the

2 Edetate Disodium REX-00000228 2R21-1767 02/07/24
Agent requirements
Sodium Hydroxide, Meets the

3 REX-00000130 Adjusting pH 2R22-0710 31/08/24
Pharma Grade requirements
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 3
Test No. 3
Packing Material Quality
Identify all packaging materials used in validated batch. Verify that all packaging materials are
in packaging material specification.

Retest. Material
No. Description Material Code QC Lot# Manufacturer
Date Quality
Meets the
1 10 mL Lyophilizer Vial PGV-00000002 2P22-1057 06/04/24
requirement
Rubber Stopper Lyo 20 2P22-1079; Meets the

2 PRS-00000005 08/04/24
mm one foot “C” SS 2P22-1080 requirement
2P22-0030; 09/01/24 Meets the

3 Flip Off Yellow 20 mm PPP-0000001212 2P23-1094 05/04/25 requirement
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 4
Test No. 4
List of Equipments and Premises Used
Identify all equipments for process, sampling and testing that will be used in process
validation, as well as premises used. Verify that those have been qualified and calibrated.

Equipment/ Date of Date of Date of
No Capacity Identity No.
Machine Qualification Calibration Recalibration
Lupa nyatet
1 Autoclave Meco* 1,500 L M/SLI/P/002 euy (Ask QA 27/04/23 27/04/24
nanti)
2 Autoclave LAST* 1,500 L M/SLI/P/055
Lupa nyatet
10,000 –
3 Hot Air Sterillizer M/SLI/P/062 euy (Ask QA 25/03/23 25/03/24
13,000 vials
nanti)
IQ: 14/06/13
4 Mixing Tank 60 L M/SLI/P/038 18/05/22 18/05/23
OQ:14/06/13
Bausch Strobel
5,000 – IQ: 04/04/13
5 Filling & Sealing M/SLI/P/041 Ask QA Ask QA
6,000 vials/hr OQ:04/04/13
Machine
Tofflon 7.5 IQ: 18/02/13
6 N/A M/SLI/P/042 Ask QA Ask QA
Lyophilizer OQ:18/02/13
IQ: 13/03/18
7 Mobile LAF N/A M/SLI/P/058 24/06/22 24/06/23
OQ:13/03/18
Building of Sterile
8 N/A N/A N/A? (Ask QA) 17/03/23 17/03/24
Liquid Injection
Note: *Choose one

Comments :
DVL-VMP-014/02/01NOV2016
Attachment 5
Test No. 5
Analytical Methods and Testing Procedures
Identify all analytical methods and testing procedures that will be used in Process Validation.
Those are included in-process control. Verify that all methods have been qualified.
Date of Date of
No. Kind of Testing Procedure No. Analyst
Validation Qualification
Total Organic
1 WI-05.02-116 N/A Tanya ke QC
Carbon
2 Water Conductivity WI-05.02-026 N/A Tanya ke QC
3 Description WI-05.06-027 N/A Tanya ke QC
4 pH WI-05.02-030 N/A Tanya ke QC
5 Specific Gravity WI-05.02-054 N/A Tanya ke QC

Uniformity of
6 WI-05.04-006 N/A Tanya ke QC
Dosage Unit
WI-05.02-028
7 Water Content or N/A Tanya ke QC
WI-05.02-029
WI-05.02-020
8 Particulate Matter or N/A Tanya ke QC
WI-05.02-021
WI-05.02-084
9 Sterility or N/A Tanya ke QC
WI-05.02-085
10 Total Plate Count WI-05.01-002 N/A Tanya ke QC
11 Bioburden WI-05.06-031 N/A Tanya ke QC

WI-05.02-093
11 Bacterial Endotoxin or N/A Tanya ke QC
WI-05.02-094
Assay of
12 PS&AP No. E-045 Tanya ke QC
Esomeprazole
Identification by
13 PS&AP No. E-045 Tanya ke QC
HPLC
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 6
Test No. 6
Critical Parameters of Process
Determine Critical Parameters of Process such as mixing time, mesh size and heating
temperature. Run the process at minimum, optimum and maximum of allowed range.

Machine/ Actual
No. Stage of Process Parameter Operation limit Setting
Equipment Display
o Magnetic Stirrer
o Magnetic Stirring Sterilization
Autoclave 121.5°C 121.5°C 121.5°C
Rod Temperature
Meco
o 1000 mL
No. ID:
Volumetric glass Sterilization
M/SLI/P/002 60 minutes 60 minutes 60 minutes
o Scaled, stainless Time
steel scoop
o Housing and
Cartridge for 0.2 Sterilization
Autoclave 121°C 121°C 121°C
and 0.45 micron Temperature
Sterilization for LAST
1 Sartopore Filter
Mixing Process No. ID:
o Sterile; Gloves, Sterilization
M/SLI/P/055 30 minutes 30 minutes 30 minutes
Shoes cover, hair Time
net and mask
CIP Time 30 minutes 30 minutes 30 minutes

Mixing Tank
60 L SIP Time 30 minutes 30 minutes 30 minutes
o Mixing Tank 60 L
No. ID:
M/SLI/P/038 SIP
121°C 121°C 121°C
Temperature
o WFI o1000 mL
10% NaOH 10 minutes
o Sodium Hydroxide Beaker Glass
2 Solution Mixing Time or 10 minutes 10 minutes
Pellet Pharma oMagnetic
Preparation Until dissolved
Grade Stirrer
10 minutes
Mixing Time or 10 minutes 10 minutes
Mixing Tank Until dissolved
o WFI 60 L
3 Mixing I
o Edetate Disodium No. ID:
M/SLI/P/038
Mixing Speed 450 – 550 rpm 500 rpm 500 rpm
15 minutes
Mixing Tank Mixing Time or 15 minutes 15 minutes
o Mixing I solution
60 L Until dissolved
4 Mixing II o Esomeprazole
No. ID:
Sodium
M/SLI/P/038 Mixing Speed 450 – 550 rpm 500 rpm 500 rpm
DVL-VMP-014/02/01NOV2016

Machine/ Actual
Equipment Display
Mixing Time 5 minutes 5 minutes 5 minutes

o Mixing II solution
5 Mixing III
o 10% NaOH Solution
Mixing Tank
60 L
No. ID: 15 minutes
M/SLI/P/038 Mixing Time or 15 minutes 15 minutes
o Mixing III Solution Until homogenous
6 Final Mixing
o WFI
Filter Type Sartopore Sartopore Sartopore
Filter Size 0.2 µm 0.2 µm 0.2 µm

Housing and
Cartridge of
o Final Mixing
7 Filtration 0.2 µm Integrity Test
Solution ≥ 3,200 mbar N/A 3878 mbar
Sartopore (Before Usage)
Filter
Integrity Test
≥ 3,200 mbar N/A 3877 mbar
(After Usage)
Sterilization
260°C 260°C 260°C
Hot Air Temperature
o 10 mL Lyophilizer Sterilizer
Vial No. ID:
M/SLI/P/003 Sterilization
2 hours 2 hours 2 hours
Time
Sterilization
121.5°C 121.5°C 121.5°C
Autoclave Temperature
Sterilization for o Flip Off Meco
8 o Rubber Stopper No. ID:
Filling Process
o 5 mL Volumetric M/SLI/P/002 Sterilization
30 minutes 30 minutes 30 minutes
Glass Time
o Bausch Strobel
Filling & Sealing
Machine Dispensing Sterilization
121°C
Pump Autoclave Temperature
o 2 set of Silicone LAST
Hose No. ID:
60 minutes
Time
Sterilization for Autoclave Sterilization

8 o Flip Off 121.5°C 121.5°C 121.5°C
Filling Process Meco Temperature
DVL-VMP-014/02/01NOV2016

Machine/ Actual
Equipment Display
No. ID: Sterilization

30 minutes 30 minutes 30 minutes
M/SLI/P/002 Time
Sterilization
o Rubber Stopper Autoclave 121°C
Temperature
LAST
No. ID:
30 minutes
Time
0,000
Bausch Filling Speed TBR N/A
vials/minute
Strobel
Filling &
2.1 mL
9 Filling Filtered Solution Sealing Filling Volume 2.1 mL 2.1 mL
(2.0 – 2.2 mL)
Machine
No. ID:
M/SLI/P/041 Bulk
≤ 35°C 31°C 31°C
Temperature
CIP Time 15 minutes 15 minutes 15 minutes
Tofflon 7.5
Sterilization for
Tofflon 7.5 Lyophilizer SIP Time 15 minutes 15 minutes 15 minutes
10 Lyophilization
Lyophilizer No. ID:
Process
M/SLI/P/042
SIP
121°C 121°C 121°C
Temperature
Preparation
Condenser 1
-45°C to -50°C -45°C -45°C
Temperature
Condenser 2
-45°C to -50°C -45°C -45°C
Tofflon 7.5 Temperature
Lyophilizer
11 Lyophilization Filled Vial
No. ID:
Chiller ON ON ON
M/SLI/P/042
Silicon Oil Level Standard Standard Standard
Lyophilization FAT FAT

FAT PRODUCT
Program PRODUCT PRODUCT
Freezing – Ramp Soak 1

Tofflon 7.5
11 Lyophilization Filled Vial Lyophilizer Final
No. ID: -2.0°C -2.0°C -2.0°C
Temperature
DVL-VMP-014/02/01NOV2016

Machine/ Actual
Equipment Display
Ramp Duration 5 minutes 5 minutes 5 minutes
Soak Duration 30 minutes 30 minutes 30 minutes
Freezing – Ramp Soak 2
Final
-45.0°C -45.0°C -45.0°C
Temperature
180
Ramp Duration 180 minutes 180 minutes
minutes
120
Soak Duration 120 minutes 120 minutes
minutes
Condenser Freezing
M/SLI/P/042
Final
-45.0°C -45.0°C -45.0°C
Temperature
Chamber Evacuation
Alarm: P1 0.350 mbar 0.350 mbar 0.350 mbar
Alarm: P2 0.800 mbar 0.800 mbar 0.800 mbar
Continue
evacuation 60 seconds 60 seconds 60 seconds
under P2
Tofflon 7.5 Primary Drying – Ramp Soak 1

Lyophilizer
No. ID: Final
20.0°C 20.0°C 20.0°C
DVL-VMP-014/02/01NOV2016

Machine/ Actual
Equipment Display
180
Ramp Duration 180 minutes 180 minutes
minutes
720
minutes
Pressure 0.350 mbar 0.350 mbar 0.350 mbar
Maximum
Increase 0.030 mbar 0.030 mbar 0.030 mbar
Pressure
Duration 2 minutes 2 minutes 2 minutes
Test Times 10 minutes 10 minutes 10 minutes
Interval 30 minutes 30 minutes 30 minutes
Secondary Drying – Ramp Soak 1
Final
30.0°C 30.0°C 30.0°C
Temperature
180
minutes
Tofflon 7.5 Secondary Drying – Ramp Soak 2

Lyophilizer
No. ID: Final
30.0°C 30.0°C 30.0°C
DVL-VMP-014/02/01NOV2016

Machine/ Actual
Equipment Display
Pressure Rise Test
Maximum
Increase 0.200 mbar 0.200 mbar 0.200 mbar
Pressure
Duration 2 minutes 2 minutes 2 minutes
Test Times 3 minutes 3 minutes 3 minutes
Interval 30 minutes 30 minutes 30 minutes
Vacuum Break & Stoppering
105.999 105.999
Set Pressure 105.999 mbar
mbar mbar
Stoppering
1 1 1
Times
Holding Times 20 seconds 20 seconds 20 seconds
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 7
Test No. 7
Environmental Monitoring
Where and When samples to be taken :
DVL-VMP-014/02/01NOV2016
For Pressure, Temperature and Relative Humidity will be conducted before and during the
process.

Parameter Specification Result Conducted
A. Particle Count (At Rest) ≥0.5 µm ≥5.0 µm ≥0.5 µm ≥5.0 µm by/Date
1 0 0
1. Surround
Non-Aseptic 2 352,000 2,900 0 0
Mixing
3 0 0 HHN
1 0 0 12/05/23
2. LAF Non-Aseptic Mixing 2 352,000 2,900 0 0
3 0 0
1 0 0
3. Surround Aseptic Filling 2 3,520 29 0 0
3 0 0 RIK
1 0 0 12/05/23
4. LAF Aseptic Filling 2 3,520 20 0 0
3 0 0
Parameter Specification Result Conducted
B. Particle Count (In Operation) ≥0.5 µm ≥5.0 µm ≥0.5 µm ≥5.0 µm by/Date
1 0 0
1. Surround
Non-Aseptic 2 3,520,000 29,000 0 0
Mixing
3 0 0 HHN
1 1270 0 12/05/23
2. LAF Non-Aseptic Mixing 2 3,520,000 29,000 105 0
3 760 10
1 1131 3
3. Surround Aseptic Filling 2 352,000 2,900 35 0
3 28733 37 SPN
1 7 0 12/05/23
4. LAF Aseptic Filling 2 3,520 20 4 0
3 0 0
Specification Result Conducted
C. Room Temperature & RH
( C)
o
(%) ( C)
o
(%) by/Date
HHN
1. Mixing Room ≤ 25 ≤ 60 21 52
12/05/23
DW
2. Filling Room ≤ 25 ≤ 60 23 49
12/05/23
Specification Result Conducted

D. Settling Plate
(cfu/ 4 hours) (cfu/ 4 hours) by/Date
FF
1. Surround Filling Max. 5 0
12/06/23
2. LAF Filling <1 0
DVL-VMP-014/02/01NOV2016

Specification Actual (cfu) Conducted
E. Swab Test by/Date
(cfu) Wall Floor
FF
1. Surround Filling Max. 25 N/A N/A 12/06/23
2. LAF Filling <1 0 0
Specification Actual Conducted

F. Air Sampling by/Date
(cfu) (cfu)
FF
1. LAF Filling <1 0
12/06/23
Specification Actual Conducted
G. Differential Pressure
(Pa) (Pa) by/Date
HHN
1. Mixing Room ≥ 10 20
12/05/23
2. Surround Filling ≥ 10 19
DW
3. Mobile LAF 120 - 375
12/05/23
4. LAF Filling 120 - 375
Specification Actual (cfu) Conducted

H. Swab Operator
(cfu) Operator 1 Operator 2 by/Date
FF
1. Forehead <3 0 0 12/06/23
2. Mouth <3 0 0
3. Left Armpit <3 0 0
4. Bottom <3 0 0
5. Left Glove <1 0 0
6. Right Glove <1 0 0
Comments :
DVL-VMP-014/02/01NOV2016
DVL-VMP-014/02/01NOV2016
Attachment 8
Test No. 8
Sampling & Testing Plan to In-Process Mixing
A. Sampling & Testing Plan

1. Where and When samples to be taken
a. Before mixing process, WFI samples have to be taken from user point, and then tested
for testing pH, TOC, Water Conductivity, Bacterial Endotoxin and Total Plate Count.
b. After final mixing, samples have to be taken from top, middle and bottom part of
mixing tank for testing Description, pH, Specific Gravity and Assay Esomeprazole.
2. Quantity of samples required

a. Samples required for pH and TOC = 100 mL of WFI.
b. Samples required for Water Conductivity = 100 mL of WFI.
c. Samples required for Bacterial Endotoxin = 100 mL of WFI.
d. Samples required for Total Plate Count = 100 mL
e. Samples required for Description, pH and Specific Gravity = 100 mL of final mix bulk
per segment.
f. Samples required for Assay Esomeprazole = 100 mL of final mix bulk per segment.
3. Size of Each Sample

a. Samples for pH and TOC = 1 x 100 mL = 100 mL of WFI.
b. Samples for Water Conductivity = 1 x 100 mL = 100 mL of WFI.
c. Samples for Bacterial Endotoxin = 1 x 100 mL = 100 mL of WFI.
d. Samples for Total Plate Count = 1 x 100 mL = 100 mL of WFI
e. Samples for Description, pH and Specific Gravity = 3 x 100 mL = 300 mL of Final Mix
Bulk.
f. Samples for Assay Esomeprazole = 3 x 100 mL = 300 mL of Final Mix Bulk.
4. Particular Instruction
Requirement for temperature of mixing room is ≤ 25 oC and the requirement for Relative
Humidity of mixing is ≤ 60%.
5. Analytical Method
a. pH have to be performed according to WI-05.02-030.
b. TOC have to be performed according to WI-05.02-116.
c. Water Conductivity have to be performed according to WI-05.02-026.
d. Bacterial Endotoxin have to be performed according to WI-05.02-093 or WI-05.02-094.
e. Total Plate Count have to be performed according to WI-05.01.002
f. Description have to be performed according to WI-05.06-027.
g. Specific Gravity have to performed according to WI-05.02-054.
h. Assay Esomeprazole have to be performed according to Product Specifications and
Analytical Methods No. E-045.
6. Acceptance Criteria for each testing

a. pH of water sample must be in specification of 5.00 – 7.00.
b. TOC of water sample must be in specification of ≤ 500 ppb.
c. Water Conductivity of water sample must be in specification of ≤ 1.3 microsiemen/cm.
DVL-VMP-014/02/01NOV2016
d. Bacterial Endotoxin of water sample must be in specification of ≤ 0.25 EU/mL.

e. Total Plate Count of water sample must be in specification of < 10 cfu/100 mL
f. Description of final mix bulk sample must be a Clear, colorless solution.
g. pH of final mix bulk sample must be in specification of 11.0 – 12.5.
h. Specific Gravity of final mix bulk sample must be in specification of 1.00 – 1.03 g/mL.
i. For Assay of active ingredient (After Final Mixing in Mixing Tank 60 L)
No Assay Specification
.
Esomeprazole 36.00 – 44.00 mg/
1
(as Esomeprazole Sodium) 90.0 – 110.0%
Size for Method/

Process Sampling Quantity of Acceptance
Parameter each Testing
Stage Point Sample Criteria
Sample Equipment
pH 1 x 100 WI-05.02-030 5.00 – 7.00

mL =
TOC 100 mL WI-05.02-116 ≤ 500 ppb
1 x 100
Water ≤ 1.3
mL = WI-05.02-026
Conductivity microsiemen/cm
100 mL
WFI From User
100 mL
Testing Point 1 x 100 WI-05.02-093
Bacterial
mL = or ≤ 0.25 EU/mL
Endotoxin
100 mL WI-05.02-094
1 x 100
Total Plate
mL = WI-05.01-002 < 10 cfu/100 mL
Count
100 mL
Clear, colorless
Description WI-05.06-027
solution
3 x 100
pH 100 mL for mL = WI-05.02-030 11.0 – 12.5
Top, Middle
Final each 300 mL
and Bottom
Mixing sampling
Specific Gravity of Mixer WI-05.02-054 1.00 – 1.03 g/mL
point
Assay of 3 x 100
PS&AP No. E- 36.00 – 44.00 mg/
Esomeprazole mL =
045 90.0 – 110.0%
(40 mg/ 2 mL) 300 mL
DVL-VMP-014/02/01NOV2016
B. Data of testing result to In-Process of Compounding

Batch No : T94RM23-03 Conducted
by/ Date
Acceptance
Parameter Result
Criteria
WFI Testing
1. pH For top, middle and bottom: (Ini harus
6.25 cek logbook
QC yang LB-
QC-KIU2-23-
1)
From User Point 5.00 – 7.00
Comments:
Meets the requirements
2. TOC For top, middle and bottom: (Ini harus

31.5 ppb cek logbook
QC yang LB-
QC-KIU2-23-
1)
From User Point ≤ 500 ppb
Comments:
3. Water For top, middle and bottom: (Ini harus

Conductivity 0.6 microsiemen/cm cek logbook
QC yang LB-
QC-KIU2-23-
1)
≤ 1.3
From User Point microsiemen/cm
Comments:
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
4. Bacterial For top, middle and bottom: (Ini harus
Endotoxin <0.03 EU/mL cek logbook
QC yang LB-
QC-M048-23-
1/034)
From User Point ≤ 0.25 EU/mL
Comments:
5. Total Plate Count
< 10 cfu/100 mL
From User Point
Comments:
Mixing
1. Description For top, middle and bottom: SMN?
Clear, Colorless solution 12/05/23
Top, Middle and Clear, colorless

Bottom of Mixer solution
Comments:
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
2. pH T: 11.8 MUI
M: 11.4 16/05/23
B: 11.9
Top, Middle and

Bottom of Mixer 11.0 – 12.5
Comments:
3. Specific Gravity T: 1.01 MUI

M: 1.01 16/05/23
B: 1.01
Top, Middle and

Bottom of Mixer 1.00 – 1.03 g/mL
Comments:
4. Assay T: 39.6 mg (99.1%) MUI

Esomeprazole M: 39.4 mg (98.5%) 16/05/23
(40 mg/2 mL) B: 39.4 mg (98.4)
36.0 – 44.0 mg/

Top, Middle and 90.0 – 110.0%
Bottom of Mixer
Comments:
Meets the requirements.
x bar(avg.): 39.5 mg (98.7%)
DVL-VMP-014/02/01NOV2016
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 9
Test No. 9
Sampling & Testing Plan to In-Process Filling

1. Where and When samples have to be taken
a. After final mixing process, filtered bulk samples have to be taken from beginning,
middle and end of filtration process from the second last vent of 0.2 µm for testing
Bioburden.
b. After sterilization process, empty vials, rubber stoppers and flip offs have to be taken
from top, middle and bottom of packaging for testing Sterility.
c. After sterilization process, a sample of 20 rubber stoppers within a bottle containing
200 mL of WFI is taken from composite of top, middle and bottom of packaging for
testing Bacterial Endotoxin.
d. During filling process, 6 filled vials have to be taken each 30 minutes for Volume
Uniformity.
2. Quantity of sample required

a. Samples required for Bioburden testing for filtered bulk are 100 mL per segment.
b. Samples required for sterility testing of packaging material are 10 vials, 10 rubber
stoppers and, 10 flip offs per segment.
c. Samples required for Bacterial Endotoxin testing of packaging materials are 20 rubber
stoppers within a bottle containing 200 mL of WFI
d. Samples required for Volume Uniformity are 6 vials per 30 minutes.
3. Size of each sample

a. Samples required for Bioburden testing of filtered bulk = 3 x 100 mL = 300 mL
b. Samples required for Sterility of packaging materials = 3 x 10 =
- 30 vials
- 30 rubber stoppers
- 30 flip offs
c. Samples required for Bacterial Endotoxin of packaging materials = 20 rubber stoppers
d. Samples required for Volume Uniformity = 6 vials / 30 minutes of filling process
4. Particular Instruction
Requirement for temperature of filling cabinet is ≤ 25°C and the requirement for Relative
Humidity of mixing is ≤ 60%.
a. Sterility have to be performed according to WI-05.02-084 or WI-05.02-085.
b. Bioburden have to be performed according to WI-05.02-031.
c. Bacterial Endotoxin have to be performed according to WI-05.02-093 or WI-05.02-094.
d. Volume Uniformity have to be performed by checking the measured volume of 6 filled
vials and calculating the average volume. The individual vial volume is then compared
to the average vial volume to obtain the result.
a. For Bioburden of filtered bulk, samples must be in specification of < 10 cfu/100 mL.
b. For Sterility, packaging materials must be in specification of sterile.
DVL-VMP-014/02/01NOV2016
c. For Bacterial Endotoxin of packaging materials must be in specification of NMT 0.25

EU/mL
d. For Volume Uniformity, samples must be in specification of 2.1 mL (2.0 – 2.2 mL).
Process Sampling Quantity of Method/Testing

Parameter Sample size Acceptance Criteria
Stage Point sample Equipment
Top, 30 vials
Middle 10 of each
WI-05.02-084
packaging 30 rubber
Sterility and or Sterile
material per stoppers
Bottom of WI-05.02-085
segment
Packaging 30 flip offs
Sterilization
for Filling Composite
Process of Top,
Middle WI-05.02-093
Bacterial 20 rubber 20 rubber
or NMT 0.25 EU/mL
Endotoxin and stoppers stoppers
WI-05.02-094
bottom of
packaging
Beginning,
Bioburden of Middle 100 mL per
300 mL WI-05.02-031 < 10 cfu/100 mL
filtered bulk and End of segment
Process
Filling
Every 30 6 filled vials/
Volume minutes of 30 minutes 2.1 mL
6 filled vials N/A
Uniformity Filling of Filling (2.0 – 2.2 mL)
Process Process
Note :
NMT : Not More Than
DVL-VMP-014/02/01NOV2016
Data of Testing Result to Finished Product

by/ Date
Acceptance
Parameter Result
Criteria
Sterilization for Filling Process
1. Sterility of Vials For Top, Middle and Bottom:
Sterile AKL
27/05/23
Top, Middle and

Bottom of Sterile
Packaging
Comments:
2. Sterility of For Top, Middle and Bottom: AKL

Rubber Stoppers Sterile 27/05/23
Top, Middle and

Bottom of Sterile
Packaging
Comments:
3. Sterility of Flip For Top, Middle and Bottom:

Offs Sterile
AKL
Top, Middle and Sterile 27/05/23
Bottom of
Packaging
Comments:
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
4. Bacterial The result for 20 rubber stoppers: SUI
Endotoxin <0.25 EU/mL 19/05/23
20 rubber stoppers
NMT 0.25 EU/mL
Comments:
Filling
1. Bioburden For top, middle and bottom: FF
(of filtered bulk) <1 cfu/100 mL 18/05/23
Beginning, Middle
and End of Process < 10 cfu/100 mL
Comments:
2. Volume 1. 2.1 mL 4. 2.1 mL

Uniformity
2. 2.1 mL 5. 2.1 mL
3. 2.1 mL 6. 2.1 mL
Every 30 minutes of
Filling Process 2.1 mL
(2.0 – 2.2 mL) Average Volume: 2.1 mL
Date: 12/05/23
Comments:
Time: 09:00 Meets the requirements
AUI
12/05/23
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
3. Volume
Uniformity 1. 2.1 mL 4. 2.1 mL
2. 2.1 mL 5. 2.1 mL
Every 30 minutes of 3. 2.1 mL 6. 2.1 mL

Date: 12/05/23
Comments:
Time: 09:30
AUI
12/05/23
4. Volume
2. 2.1 mL 5. 2.1 mL

(2.0 – 2.2 mL)
Average Volume: 2.1 mL
Date: 12/05/23
Comments:
Time: 10:00 Meets the requirements AUI
12/05/23
5. Volume
1. 2.1 mL 4. 2.1 mL
Uniformity
2. 2.1 mL 5. 2.1 mL

Date: 12/05/23
Comments:
AUI
12/05/23
6. Volume
2.1 mL 1. 2.1 mL 4. 2.1 mL
Uniformity AUI
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
2. 2.1 mL 5. 2.1 mL

Filling Process
(2.0 – 2.2 mL)
Date: 12/05/23
Comments:
Time: Meets the requirements
11:00 (Page 1)
20:00 (Page 2) 12/05/23
7. Volume
2. 2.1 mL 5. 2.1 mL

(2.0 – 2.2 mL)
Date: 12/05/23
Time: Comments:
19:00 (Page 1) Meets the requirements
AUI
20:30 (Page 2) 12/05/23
8. Volume
2. 2.1 mL 5. 2.1 mL

(2.0 – 2.2 mL)
Date: 12/05/23
Comments:
Time: Meets the requirements AUI
19:30 (Page 1) 12/05/23
21:00 (Page 2)
9. Volume
2.1 mL AUI
(2.0 – 2.2 mL) 12/05/23
2. 2.1 mL 5. 2.1 mL
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria

Filling Process
Date: 12/05/23
Comments:
10. Volume
2. 2.1 mL 5. 2.1 mL

Date: 12/05/23
Time: 22:00 Comments:

AUI
12/05/23
Comments :
Attachment 10
Test No. 10
Sampling & Testing Plan to In-Process Finished Product

DVL-VMP-014/02/01NOV2016
1. Where and When samples have to be taken

a. After lyophilization, lyophilized vials have to be taken from beginning, middle and end
for Description, Uniformity of Dosage Unit, Water Content, Sterility and Bacterial
Endotoxin.
b. For reconstituted solution, lyophilized vials have to be taken from beginning, middle
and end for Description, pH, Particulate Matter, Identification by HPLC and Assay
Esomeprazole
2. Quantity of sample required

a. Samples required for Lyophilized Powder:
- Description and Water Content requires 2 vials per segment.
- Uniformity of Dosage Unit requires 30 vials per segment.
- Sterility requires 20 vials per segment.
- Bacterial Endotoxin requires 1 vial per segment.
b. Samples required for Reconstituted Solution
- Description and pH requires 2 vials per segment.
- Particulate Matter requires 5 vials per segment.
- Identification by HPLC and Assay Esomeprazole requires 3 vials per segment.
3. Size of each sample

a. Samples required for Lyophilized Powder:
- Description and Water Content = 3 x 2 = 6 vials.
- Uniformity of Dosage Unit require 3 x 30 = 90 vials.
- Sterility = 3 x 20 = 60 vials.
- Bacterial Endotoxin = 3 x 1 = 3 vials.
b. Samples required for Reconstituted Solution:
- Description and pH = 3 x 2 = 6 vials.
- Particulate Matter = 3 x 5 = 15.
- Identification by HPLC and Assay Esomeprazole = 3 x 3 = 9 vials.
4. Sample Disposition
Disposition and labeling of releasing-label have to be conducted after reviewing analytical
report and completeness of Batch Production Record.
a. Description have to be performed according to WI-05.06-027.
b. Water Content have to be performed according to WI-05.02-028 or WI-05.02-029.
c. Uniformity of Dosage Unit have to be performed according to WI-05.04-006.
d. pH have to be performed according to WI-05.02-030.
e. Particulate Matter have to be performed according to WI-05.02-020 or WI-05.02-021.
f. Sterility have to be performed according to WI-05.02-084 or WI-05.02-085.
g. Bacterial Endotoxin have to be performed according to WI-05.02-093 or WI-05.02-094.
h. Identification by HPLC and Assay Esomeprazole have to be performed according to
PS&AP No. E-045.
a. For Description of Lyophilized Powder, sample must be a white to off white cake
b. For Uniformity of Dosage Unit of Lyophilized Powder, samples must be in specification
range of :
- Stage I : AV10 ≤ L1%, L1 = 15.0
DVL-VMP-014/02/01NOV2016
- Stage II : AV30 ≤ L1%, and no individual content is less than [1- (0.01)(L2)]M],
nor more than [1+(0.01)(L2)]M], L1 is 15.0 and L2 is 25.0.
c. For Water Content of Lyophilized Powder, samples must be in specification range of
NMT 8.00%.
d. For Sterility of Lyophilized Powder, samples must be sterile.
e. For Bacterial Endotoxin, samples must be in specification range of NMT 2.5 EU/mg
f. For Description of Reconstituted Solution, samples must be a clear and colorless
solution.
g. For pH of Reconstituted Solution, samples must be in specification range of 8.5 – 11.5.
h. For Particulate Matter of Reconstituted Solution, samples must be in specification of:
- Microscopy Method:
≥ 10 µm: NMT 3000/container
- LOPC Method
i. For Identification by HPLC, the retention time of the major peak in the chromatogram
obtained from sample solution corresponds to that in the chromatogram obtained from
standard solution, as obtained in the test for Assay.
j. For assay of Active ingredients:
No Assay Specification
Esomeprazole 36.00 – 44.00 mg/
1
(as Esomeprazole Sodium) 90.0 – 110.0%

Lyophilization Lyophilized Powder
DVL-VMP-014/02/01NOV2016

Description WI-05.06-027 White to off white cake

3 x 2 vials =
2 vials
6 vials
WI-05.02-028
Water Content or NMT 8.00%
WI-05.02-029
- Stage I: AV10
Beginning, ≤L1%
Unifomity of
Middle - Stage II: AV30
Dosage Unit
and End of ≤L1% and no
(Weight 3 x 30 vials
30 vials WI-05.04-006 individual content is
Variation) process = 90 vials
less than [1-(0.01)
L1 = 15.0
(L2)M], nor more
L2 = 25.0
than [1+(0.01)
(L2)M]
WI-05.02-084
3 x 20 vials
Sterility 20 vials or Sterile
= 60 vials
WI-05.02-085
WI-05.02-093
Bacterial 3 x 1 vial = 3
1 vial or NMT 2.5 EU/mg
Endotoxin vials
WI-05.02-094
Reconstituted Solution1)
Clear and colorless

Description WI-05.06-027
solution
3 x 2 vials =
2 vials
6 vials
pH WI-05.02-030 8.5 – 11.5
Beginning, - Microscopy
Middle Method:
and End of ≥ 10 µm: NMT
process 3000/container
WI-05.02-020 ≥ 25 µm: NMT
Particulate 3 x 5 vials =
5 vials or 300/container
Matter2) 15 vials
WI-05.02-021 - LOPC Method
≥ 10 µm: NMT
3000/container
≥ 25 µm: NMT
300/container
The retention time of

the major peak in the
Beginning, chromatogram obtained
Middle from sample solution
Identification by 3 x 3 vials =
Lyophilization 3 vials PS&AP No. E-045 corresponds to that in
HPLC and End of 9 vials
the chromatogram
process obtained from standard
solution, as obtained in
the test for Assay
DVL-VMP-014/02/01NOV2016

Assay
36.0 – 44.0/
Esomeprazole
90.0 – 110.0%
(40 mg/vial)
Note :
NMT : Not More Than
1)
Reconstituted Solution is obtained by mixing Esomeprazole IV Inj 40 mg with 0.9% NaCl Solution.
2)
Choose one of the methods
DVL-VMP-014/02/01NOV2016
Data of Testing Result to Finished Product

by/ Date
Acceptance
Parameter Result
Criteria
Lyophilized Powder
1. Description
White to off white

Beginning, Middle cake
and End of Process
Comments:
2. Uniformity of
Dosage Unit
(Weight Variation) Stage I : AV10 L1%
L1 = 15.0
L2 = 25.0 Stage II: AV30 L1%
and no individual
content is less than
[1-(0.01)(L2)M], nor
Beginning, Middle more than [1+(0.01)
Comments:
and End of Process (L2)M]
3. Water Content
Beginning, Middle NMT 8.00%

and End of Process
Comments:
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
4. Sterility
Beginning, Middle
Sterile
and End of Process
Comments:
5. Bacterial
Endotoxin
Beginning, Middle
and End of Process
NMT 2.5 EU/mg
Comments:
Reconstituted Solution
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
1. Description
Beginning, Middle Clear and colorless

and End of Process solution
Comments:
2. pH
8.5 – 11.5
Beginning, Middle
and End of Process
Comments:
3. Particulate
Matter Microscopy Method:
≥10 µm: NMT
3000/Container
≥25 µm: NMT
300/Container
Beginning, Middle
and End of Process LOPC Method:
≥10 µm: NMT
6000/Container Comments:
≥25 µm: NMT
600/Container
DVL-VMP-014/02/01NOV2016

by/ Date
Acceptance
Parameter Result
Criteria
4. Identification by
HPLC
The retention time
of the major peak in
the chromatogram
obtained from
sample solution
Beginning, Middle corresponds to that
and End of Process in the chromatogram
obtained from
standard solution, as Comments
obtained in the test
for Assay
5. Assay
Esomeprazole
(40 mg/vial)
36.0 – 44.0 mg/

Beginning, Middle 90.0 – 110.0%
and End of Process
Comments
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 11
Documentation
Review Availability, Completeness, Validity, Accuracy and Conformity to GMP of Batch

Production Records/Packaging Direction Records, WI’s, as well as operator training and
qualification
No. Description Doc No. Issued date Conformity
1 Batch Production Record
Operator Training and

2
Qualification Record
3 WI on Line Clearance
4 WI on In-process Control
WI on Intermediate
5
Products & Bulk Products
Comments :
DVL-VMP-014/02/01NOV2016
Attachment 12
Summary, Conclusion and Recommendation
Summary
Test Result
Description Remark
No. Passed Failed
Meets the
01 GMP Compliance V
requirements
Meets the
02 Raw Material Quality V
requirements
Meets the
03 Packaging Material Quality V
requirements
Meets the
04 List of Equipments Used V
requirements
Meets the
05 Analytical Methods and Testing Procedures V
requirements
Meets the
06 Critical Parameters of Process V
requirements
Meets the
07 Environmental Monitoring V
requirements
Sampling and Testing Plan to In-Process of Meets the
08 V
Mixing requirements
Meets the
09 Sampling and Testing Plan to In-Process of Filling V
requirements
Sampling and Testing Plan to In-Process of Meets the
10 v
Finished Product requirements
DVL-VMP-014/02/01NOV2016
Meets the
11 Documentation V
requirements
Meets the
12 Summary, conclusion and recommendation V
requirements
13 Deviation and Discrepancy Report V
Conclusion
Result of 3 batches Esomeprazole IV Inj 40 mg Pilot scale:

Acceptance Batch No.
Result
Criteria T94RM23-01 T94RM23-02 T94RM23-03
Assay average of 36.0 – 44.0 mg
Final Mix (90.0 – 110.0%)
Assay RSD of Final
<5%
Mix
Assay average of 36.0 – 44.0 mg
Finished Goods (90.0 – 110.0%)
Assay RSD of
<5%
Finished Goods
Based on the result, Esomeprazole IV Inj 40 mg batch T94RM23-01, T94RM23-02 and

T94RM23-03 met all specifications for process validation.
Yield of pilot batches
Formula:
w/ validation Sample: w/o validation sample

B B+ C
Batch ¿ x 100 % ¿ Batch ¿ x 100 % ¿
Note:
B : Actual result
Batch Size : 12,500 vials
C : QC Sampling
DVL-VMP-014/02/01NOV2016
Yield w/ Validation Sample Yield w/o Validation Sample

Result
Final Mix Finished Product Final Mix Finished Product
T94RM23-01 93.0% 97.3% 96.0% 99.2%
T94RM23-02 91.7% 97.2% 94.7% 99.1%
T94RM23-03 92.0% 97.2% 95.0% 99.6%
Note:
Detailed calculations for yield are available in Appendix 1.
Yield Specification for final mix : 90.0 – 101.0%
Yield Specification for Finished Product : 90.0 – 100.0%
 w/ = with
 w/o = without
Recommendation
1.The recommended filling speed settings are 00,000 – 00,000 vials/minute.
2.Alternate Source Development (ASD) of Esomeprazole Sodium ex. Metrochem, India is done
to prevent supply issue by replacing the existing source (ex. Esteve, Spain) which has
stopped production for the material.
3.Alternate source of Esomeprazole Sodium as an Active Ingredient met all the specifications
for process validation. It can therefore be implemented for use in commercial batches
after variation registration is approved.
Approved by: Date :
DVL-VMP-014/02/01NOV2016
Attachment 13
Deviation and Discrepancy Report
The following is description of deviation and/or discrepancy to this Process Validation. Use
additional page as necessary.
Reference (Section and Page):
Discrepancy/Deviation:
Resolution:
Acceptable: □ Yes □ No
Approved by: Date :
DVL-VMP-014/02/01NOV2016

Report Esomeprazole IV Inj (Guide Batch 03)

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Document No.

PT DARYA-VARIA LABORATORIA Tbk

Process Validation Report

PT Darya-varia Laboratoria Tbk Citeureup Plant

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 2 of 60

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 3 of 60

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 4 of 60

1.1 Scope of Validation

This process validation report is applicable to conduct process validation of

Change Control No. Issued Date Change

Alternate source addition of Esomeprazole

Manufacturing of Esomeprazole/Esozid IV Inj 40 mg will be conducted with lyophilization

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 5 of 60

Acceptance criteria will depend on the certification that manufacturing process of

 Manufacturing process will be validated by monitoring all critical parameters of

 If the inspection or verification test is not satisfactory, Deviation and Discrepancy

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 6 of 60

Name Title Signature Initial

Nabila Alhaura MTU Pharmacist NAH

7. Change Control Procedures

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Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 8 of 60

Title Name Signature Date

MTU Pharmacist Nabila Alhaura

Validation & Calibration

MTU Head Aprilia Primadawaty

Quality Control Head Dewi Sulistyowati

Production Head Antonius Raino Dymita

Engineering Head Wasana Saputra

Quality Assurance Head Siti Lathifah Noor Amir

Citeureup Plant Division

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 9 of 60

Revision Issued Change Change

00 17-Jun-15 N/A  New Document

01 28-Feb-17 N/A  Initial Production

 Change volume batch size from 27.5 L to

 Changed of product filling volume of

 Alternate source addition of Esomeprazole

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 10 of 60

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 11 of 60

General Manufacturing Process Compliance

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Perform the manufacturing according to Batch Manufacturing Record No.

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Manufacturing Flow Diagram

Mixing Tank o CIP Time

Mixing Tank oWFI

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 15 of 60

STAGE OF EQUIPMENT CRITICAL

TOC ≤ 500 ppb

Total Plate Count < 10 cfu/ 100 mL

o WFI 10% NaOH o Beaker Glass

o WFI oMixing Time

Housing and oIntegrity Test

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 16 of 60

STAGE OF EQUIPMENT CRITICAL

Filter Size 0.2 µm

Integrity Test ≥3,200 mbar

Integrity Test ≥3,200 mbar

Hot Air o Sterilization

Bausch Strobel o Filling Volume

Doc. No. : 058/SLI/VPP/07/22/V/01 Revision No. : 04 Page 17 of 60