Prosses Validation Protocol For Enrofolxacine

‫شركة مصانع األدوية البيطرية والزراعية‬
VETERINARY & AGRICULTURAL PRODUCTS MANUFACTURING CO.LTD
Process Validation Protocol
Title: Process Validation Protocol for Enrosol-S Oral Solution (1.0 Lt) HDPE
Revision No: 01
Bottles
Document Number: PVP0004 : Effective Date
Page 1 of 22
For Enrosol-S Oral Solution HDPE Bottles

Batch Size: 1500 Lt~ 1500 Bottle
Pack Size: 1.0 Lt
PROTOCOL APPROVALS FOR USE

Research &Development Department
Preparation Name Job Title Signature Date
&Checking
Prepared by
Checked by
Checkedby(QA)
Departments Approvals
Approvals Name Job Title Signature Date
Approved by
Approved by
Approved by
Approved by
Approved by (Q.A Manager )
Revision No: 01
Bottles
Document Number: PVP0004 Page 2 of 22
Sec. CONTENTS PAGE
1 Glossary. 3
2 Reference Documents. 4
3 Purpose. 5
4 Objective. 5
5 Scope. 5
6 Validation Team and responsibilities. 6
7 Product Information. 7
8 Manufacturing Formula (Master Formula). 8
9 Manufacturing Process Instructions. 9
10 Process critical parameters 11
11 Active raw material. 12
11.1 (Enrofloxacin). 12
12 In-active raw and primary package materials. 12
13 Equipment's Qualifications. 13
14 Analytical Methods for IPC Stage 14
15 Analytical Methods for Bulk Product (After Preparation Stage) 15
16 Finished Product Stage. 16
17 Filling Bottle Stage. 17
18 Bottle Labelling Stage. 17
19 Bottle Shrinking Stage. 17
20 Sampling Location Diagram (Preparation Stage). 18
21 Sampling Levels& Location Table. 19
22 Sampling Plan for all stages. 20
Revision No: 01
Bottles
1.0 Glossary
*QA: Quality Assurance.

* PM: Production Management.
*R&D: Research and Development.
*QC: Quality Control.
*HDPE:High Density Poly Ethylene
*MF: Manufacturing Formula.
*MI: Manufacturing Instructions.
*B.No: Batch Number.
*COA: Certificate of Analysis.
*IQ: Installation Qualification.
*OQ: Operation Qualification.
*PQ: Performance Qualification.
* Max: Maximum.
* Min: Minimum.
Revision No: 01
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2.0 Reference Documents:

Document Number Document Name
Manufacturing Formula.
EN/L/10/153-1 Manufacturing Formula.
Specifications
IPS/47/16 IPC Product Specification.
RPS/1547/16 Released Product Specification.
FPS/547/16 Finished Product Specification.
SPS/1047/16 Shelf Life Specification.
SOP,s
RD-012 ,Version A How To Write and Control Process Validation Protocol and Report SOP.
R&D-003,Version B Product Specification Sheet.
VT-042, Version A Operation Procedure of Uniwin liquid mixing Vessel 1500&2000Lt
VT-008, Version A Operation Procedure of Liquid Mixers (Seitz Afaq)
VT-053, Version A Operating Procedure for Thomason Filling Machine and Capping (6 Nozzle)
VT-025, Version A Operating and Cleaning of Sealing Test Instrument
VT-035, Version A Operation Procedure for AFAQ Shrinking Machine
VT-045, Version B Operation & Cleaning Procedure of Portable liquid mixer
VD-001, Version A General Guideline of Calibration Policy
Methods of Analysis
Refer Table 06 Method of Analysis of Active Raw Material Enrofloxacin.
Refer Table 09 IPC Analytical Method.
Refer Table 10 Method of Analysis for After Preparation Stage (Bulk Stage).
Refer Table 11 Method of Analysis (Finished Good Product).
IQ, OQ, PQ and Calibration
VDQP-004 IQ&OQ Protocol of Uniwin 1500 & 200 Lt Mixer
VDQP-020 PQ Protocol of Uniwin 1500 & 2000 Lt Mixer
VDQP-005 IQ & OQ Protocol of Thomason Filling & Capping Machine
VDQP-025 PQ Protocol for Thomason Filling & Capping Machine
VDQP-013 IO & PQ Protocol of Check Weigher CW Series
VDQP-006 IQ&OQ Protocol of Portable Mixer
VDQP-034 PQ Protocol of Portable Mixer
Table No.:01
3.0 Purpose:
Revision No: 01
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To perform concurrent validation of Enrosol-S Oral Solution 1.0 Lt, manufactured by

VAPCO Industries, to provide documented evidence that a facility equipment and process
do what they purposed to do, based on information generated during actual implementation
of the manufacturing process to show that the process is in a state of control prior to the
request for such evidence.
4.0 Objective:
1.0 To demonstrate that a manufacturing process, operating under defined standard

Condition is capable of consistently producing Enrosol-S Oral Solution 1.0 Lt Bottle
that meets the established product specifications.
2.0 To meet international regulatory standards.
3.0 To define the steps and acceptance criteria for validation process.
5.0 Scope:
Produce three consecutive batches of the Enrosol-S Oral Solution 1.0 Lt Bottle Product
under routine manufacturing process, in to VAPCO manufacturing facility.
6.0 Validation Team and responsibilities:

Revision No: 01
Bottles
Responsibility Designation Department

-To coordinate the entire validation processes with production, QC Manager /Designed R&D
and QA including supervision on the manufacturing of three
consecutive production batches.
-Preparation of validation protocol, MF&MI,
In-process specifications, Packaging
Specifications, analyzing data and test result.
-To review and approve the validation documents
-To prepare the validation protocol
-To approve the process validation protocol
-To review the validation documents Manager / Designed QA
-To checked the process at production area
- Sampling of product for all manufacturing stages
-To review the validation documents Manager / Designed Validation
- To ensure the availability of equipment qualification.
-To review the validation protocol Manager / Designed PM
-Perform manufacturing and packaging procedure
-To review the validation documents
-To review and approve the validation protocol Manager / Designed/Analyst QC
-To review the validation protocol
- Analyzing Samples and test result
Table No.:02
7.0 Product Information:
Product Name: Enrosol-S Oral Solution.

Revision No: 01
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Dosage form: Oral Solution.
Active Ingredient: (Enrofloxacin 100mg)/ml.
Strength: (10%).
Batch Size: 1500 Lt ~ 1500 Bottle
Primary Package: (1.0 Lt) a White High Density Polyethylene

(HDPE)Bottle, Black Polyethylene Screw Cap with
Al. Disk for 1.0 Lt HDPE Bottle
Pack Size: 1.0 Lt Bottle
8.0 Manufacturing Formula (Master Formula).
For active & inactive raw materials

Revision No: 01
Bottles
Theoretical
Code Material Name Quantity Per .Spec.No
Batch/Kg
18..1.500 1500 RM/0018/15
Purified Water #
16.3.265 45.0 RM/0021/16
Potassium Hydroxide
18.1.045 Carboxy Methyl Cellulose Na 1.5 RM/0022/16
10.1.112 Enrofloxacin 150 RM/0023/16
16.1.065 Ethyl Alcohol (Ethanol 99.9%) 15.0 RM/0024/16
16.2.027 Basonyl-Red Dye 0.06 RM/0025/16
Table No.:03
up to 1500 lt #
:Manufacturing Process Instructions 9.0
.Current Enrosol-S 1.0 Lt Oral Solution MF and MI are attached for batches subjected to validation
Step Materials Preparation Procedure Equipment

Revision No: 01
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Weighing &Dispensing
1 Active material & Inactive material Balances at Weighing Booth
At clean area
2 Load 50% of the First portion of
Uniwin 1500/2000 Lt Mixing Vessel
Load & )V/1471/14(/)V/1470/14(
Purified Water
Lowara Portable Pump (V/1330/11)
3 Uniwin 1500/2000 Lt Mixing Vessel
+ Potassium Hydroxide Mixing (1)
)V/1471/14(/)V/1470/14(
%of Purified Water 50 )Completely Dissolved(
+Enrofloxacin Mixing (2)
)V/1471/14(/)V/1470/14(
Mixed (1) Material )Completely Dissolved(
Keep the solution covered until use ))Solution A
)V/1471/14(/)V/1470/14(
6 Load 25% of the second portion of Lt Holding Tank 600
Load
Purified Water )V/890/05(
7 Lt Holding Tank 600
+Carboxy Methyl Cellulose Mixing (3)
Portable Mixer & )V/890/05(
%of Purified Water 25 )CompletelyDissolved(
(V/021/77)
8 Lt Holding Tank 600
Keep the solution covered until use ))Solution B
)V/890/05(
9 Ethyl Alcohol (Ethanol 99.9%) Load Lt SS Container 20
10 Basonyl Red Dye + Ethyl Alcohol Mixing (4)
Lt SS Container& SS Road 20
(Ethanol 99.9%) )CompletelyDissolved(
11 Keep the solution covered until use ) Solution C) Mixed 4 Lt SS Container 20
Mixing (5) )V/1471/14(/)V/1470/14(
Add Solution B to the Solution A
)CompletelyMiscible( &
Lowara Portable Pump (V/1330/11)
+ Add Solution C (Mixed 4) Mixing (6)
)V/1471/14(/)V/1470/14(
Mixed (5) Material )Completely Miscible(
14 Third portion of Purified Water
Uniwin 1500/2000 Lt Mixing Vessel
(Complete the volume up to total Mixing (7)
)V/1471/14(/)V/1470/14(
volume) adding to Mixed (6) )Completely Homogenous(
Material
Step
Materials Preparation Procedure Equipment
Contact QA for Sampling for IPC &QC Lab

15
Revision No: 01
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Transfer
Transferring
16 Mixed (7) Material in to Storage
Mixed (7)
Afaq 2650 Lt Storage Tank
Tank
17 Mixed (7) Material+(HDPE Bottle) Bottle Filling Thomason Filling & Capping
+Screw Cap Capping & Machine V/1450/14
18 Automate Induction Sealer
Filled Capped Bottles Induction Sealing
V/477/99
19 Labelling
Enrosol-S 1.0 Lt Oral Solution
Stick Printed Label onto Labelling Machine V/409/96
Filled Bottle
nude Bottle
20 Enrosol-S 1.0 Lt Oral Solution Filled Shrinking
Shrinking Machine
Labelled Bottle V/803/04
21 )Contact QA for Sampling for QC Lab Start up, Middle, End) (Finished Product Stage)
22 Pack Enrosol-S 1.0 Lt Oral Solution Comarme Cartoner Machine

Cartooning
Filled Shrink Bottle V/1159/08
23 Filled Cartons With Enrosol-S 1.0 Lt March Printing Machine
Printing of the Carton
Oral Solution Filled Shrink Bottle V/1161/08
24 Printed Filled Cartons With Enrosol-
Signode Strapping Machine
S1.0 Lt Oral Solution Filled Shrink Strapping Carton
V/609/02
Bottle
25 Transfer the Carton to the storage in the finished Product Warehouse under Storage Condition until Export (Internal &
.External)
Table No.:04
:Process critical parameters 10.0
The critical parameters to be tested and their effect on the finished product are summarized in
the following table:
Critical variable to be cheeked Parameter related to Variable Step description Step
Revision No: 01
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No.
Speed
rpm & min. Mixing (1) 3
Time
Speed
Time
Speed
Time
Speed
Time
Speed
Time
Speed
Time
Speed
rpm & min. Time Mixing (7) 14
Bottle/ min.(Capacity) Filling Speed
Filling
(Lt) Filling Volume for 6 Nozzles 17
Bottle/min Capping Speed
°C Induction Sealing Temperature Induction Sealing 18
Bottle/min Speed Labeling
19
Proper Labeling Check Proper Labeling
rpm & min Speed
°C Temperature Shrinking 20
Proper Shrinking
Proper Shrinking
(Quality Shrink)
Proper closing and Printing Proper closing and Printing(Printing Cartooning &Printing
Inspect every 60 min (Visual) Quality)
22 & 23
Step 22&23
Proper strapping Strapping the Carton
Proper strapping 24
Inspect every 60 min (Visual) Step 24
Table No.:05
11.0 Active raw material:
11.1(Enrofloxacin)
Active material batch/batches will be used in the manufactured batch (Enrofloxacin)
Revision No: 01
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Active Name :(Enrofloxacin) _ Cat .No: 10.1.112
Test Method No Test
BP2014 Description, Appearance, Color

AM/048 Identification
TM/009 Loss on drying
BP2014 Solubility in Water
BP2014 Solubility in methylene chloride
BP2014 Solubility in methanol
AM/048 Assay
Table No.:06
12.0 In-active raw materials and primary package materials:
All in-active and primary package materials batches used in the manufactured batch
Spec.No./revision Cat .NO Material
RM/0018/15 18.1.500 Purified Water
RM/0021/16 16.3.265 Potassium Hydroxide
RM/0022/16 18.1.045
Carboxy Methyl Cellulose Na
RM/0024/16 16.1.056 Ethyl Alcohol (Ethanol 99.9%)
RM/0025/16 16.2.027 Basonyl-Red Dye
White High Density

PM/0005/15 01.5.113.2
Polyethylene (HDPE) Bottle 1.0Lt
PM/0006/15 01.5.271.5 Black Polyethylene Screw Cap for Bottle 1.0 Lt
Table No.:07
13.0 Equipment’s Qualifications
The qualification/validation status of each equipment's in each stage
VAPCO ID No. Machines Names

Revision No: 01
Bottles
V/1471/14
Uniwin 1500&2000 Lt Mixing Vessel
(V/021/77)
Portable Mixer
(V/1330/11)
Lowara Portable Pump
V/890/05
600 Lt Holding Tank
V/159/88
500 Lt Holding Tank
V/855/05
Afaq 2650 Lt Storage Tank
ST-005
Non-Viscous Liquid Sampler ST-005
V/1450/14
Thomason Filling &Capping Machine
V/938/06
Check Weigher
V/477/99
Automate Induction Sealer
V/409/96
Labeling Machine
V/803/04
Shrinking Machine
V/477/99
Automate Induction Sealer
V/1161/08
March Printing Machine
V/1159/08
Comarme Cartoner Machine
V/609/02
Signode Strapping Machine
Table No.:08
14.0 Analytical Methods for IPC Stages:
All analytical methods used for in-process testing, bulk intermediate testing, have been found to
be suitable; used reference methods code numbers
Revision No: 01
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Acceptance Criteria Method Test
RD/AM/083 Description
A red clear liquid
Appearance and Color
1000 ± 2% RD/AM/072 Fill Volume (ml)
(1.0375 – 1.0475) RD/AM/076 Density (gm./ml) at 20ºC
(7.25 – 9.25) RD/AM/079 pH of (1.0 ml/ 2.0 Lt tap water)
Miscible RD/AM/082 Miscibility with water
RD/AM/081
( 1.363 – 1.393) Refractive Index at 25ºC
Complies RD/AM/143 Sealing test (Integrity Test)
Table No.:09
15.0Analytical Methods After Preparation Stage (Bulk Stage):
All analytical methods used for bulk Product testing have been found to be suitable; used
reference methods code numbers
Revision No: 01
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A red clear liquid
RD/AM/081
The Retention time of the major
peak in the chromatogram of the
assay preparation corresponds to RD/AM/122 Identification of (Enrofloxacin)
that of the standard preparation
(96.0 – 104.0 ) % of labeled Assay for Enrofloxacin
amount of Enrofloxacin RD/AM/122 Theoretical Conc of Enrofloxacin is (10.0%)
Table No.:10
:Finished Product Stage 16.0
:Release result for the batch subjected to process validation
A red clear liquid
Revision No: 01
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RD/AM/081
Acceptance Limit ≤10^2 Absence of Microbial Limit TAMC (CFU/ml)
RD/AM/092
Escherichia Coli
Microbial Limit TYMC (CFU/ml)
Acceptance Limit ≤10^1 RD/AM/092
The Retention time of the major peak
in the chromatogram of the assay
RD/AM/122 Identification of (Enrofloxacin)
preparation corresponds to that of the
standard preparation
(95.0 – 105.0 )% of labeled amount Assay for Enrofloxacin
RD/AM/122
of Enrofloxacin Theoretical Conc of Enrofloxacin is (10.0%)
Related Substances
N.M.T 0.1
RD/AM/122 Single Impurities (%)
N.M.T 0.5
Total Impurities (%)
Packing Information
Sheet,QF.094
Complies Primary and Secondary Packaging Material
Revision .B, and BPR-
VT/123/AAP
Table No.:11
17.0 Filling Bottle Stage:
Test Method Number Acceptance criteria

SOP QA-035, BPR
Physical Appearance of Bottle Clean, No Damage
–VT/123/AAP
Filling Weight of Bottle RD/AM/072 Lt ± 2.0 % (980-1020) ml 1.0
Sealed Bottle
Capping Sealing Integrity Test RD/AM/143
Table No.:12
Revision No: 01
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18.0 Bottle Labeling Stage:
Test Method Number Acceptance criteria

Physical Appearance of Label BPR –VT/123/AAP Clean,No Damaged
Quality of printing on Label BPR –VT/123/AAP Clear Clean Printing
Table No.:13
19.0 Bottle Shrinking Stage:
Test Acceptance criteria Method Number
Physical Appearance of Shrinking Clean,No Damaged BPR –VT/123/AAP
Table No.:14
20.0 Sampling Locations Diagram (Preparation Stage):
(Preparation Area)
1.0 Take Upper and Middle samples (1.0 Lt) by using Non-Viscous Liquid Sampler S-005
thief.
2.0 Take the Bottom sample (1.0 Lt) directly inside the bottle of the sample from the pipe
inside the Mixing Vessel, by circulation of the bulk product (by use the pump) between
the circulation pipes and the Mixing Vessel after starting circulation for 5 minutes;
because the thief will not reach the Bottom Location of the vessel properly.
Revision No: 01
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1 Upper
2
Middle
3
Bottom
Discharge
Valve
Diagram No.: 01
Sampling Levels & Locations Table 21.0
Sample
Level SampleLocation and Direction
ID No
Upper 1 Upper
Middle 2 Middle
Bottom 3 Bottom
Table No.:15
Revision No: 01
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22.0 Sampling Plan for all Stages:
Sample
Process Step Test Required Sample Size
Frequency
Description Level Quantity
Mixing
Stage Filling Volume (ml)
Upper 1.0 Lt
(Bulk Stage) After Preparation
Density (gm./ml) at 20ºC (Once)
Mixed (7)
Material Middle 1.0 Lt
pH of (1.0 ml/2 Lt tap water)
Revision No: 01
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Miscibility with water
Refractive Index at 25ºC

Identification of Enrofloxacin Bottom 1.0 Lt
Assay for Enrofloxacin
For Bottle physical tests (As IPC)
Start-up ( at the
Physical Appearance of Bottle beginning of process Bottles 10
,
Initial (after 25% of
the batch) Bottles 10
Sealing Test (integrity Test) , Physical Test
Filling Stage Middle (after 50% of

the batch) 30 Bottles
, (5 Bottles for each
Filling Volume End (after 75 % of Nozzles)
the batch)
Bottles 10
Primary Packaging Material Physical Test
Table No.:16-1
Sample
Process Step Test Required Sample Size & Level
Frequency
For Bottle physical & Chemical tests
)As Finished Product(
Description Initial
Filling Bottle Stage Appearance and
Color 6 Bottles (One bottle form
each Nozzle)
Filling Volume (ml)
Density (gm./ml) at ,
Revision No: 01
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20ºC
pH of (1.0 ml/2 Lt
tap water)
Miscibility with
water
Refractive Index at
25ºC
Microbial limit
Bottles (One bottle form 6
TAMC (CFU/ml) each Nozzle)
Microbial limit
TYMC (CFU/ml)
Identification of
Enrofloxacin
Assay for Enrofloxacin

Bottles (One bottle form 6
Related Substances for each Nozzle)
Enrofloxacin Middle
Primary and Secondary
Packaging Material
Table No.:16-2
Sample
Process Step Test Required Sample Size & Level
Frequency
Physical Appearance of Initial
Label
Labeling
Middle Bottles 10
(Label stick on the Bottle )
Quality of overprinting
on the Label End
Initial
Shrinking
)Shrink surrounds the Bottle( Physical Appearance of Bottles 10
Middle
Shrink
End
Revision No: 01
Bottles
Table No.:16-3

Prosses Validation Protocol For Enrofolxacine

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‫شركة مصانع األدوية البيطرية والزراعية‬

VETERINARY & AGRICULTURAL PRODUCTS MANUFACTURING CO.LTD

Process Validation Protocol

Process Validation Protocol

For Enrosol-S Oral Solution HDPE Bottles

Pack Size: 1.0 Lt

PROTOCOL APPROVALS FOR USE

Process Validation Protocol

Sec. CONTENTS PAGE

Process Validation Protocol

*QA: Quality Assurance.

Process Validation Protocol

2.0 Reference Documents:

Process Validation Protocol

To perform concurrent validation of Enrosol-S Oral Solution 1.0 Lt, manufactured by

1.0 To demonstrate that a manufacturing process, operating under defined standard

6.0 Validation Team and responsibilities:

Process Validation Protocol

Responsibility Designation Department

7.0 Product Information:

Product Name: Enrosol-S Oral Solution.

Process Validation Protocol

Dosage form: Oral Solution.

Active Ingredient: (Enrofloxacin 100mg)/ml.

Batch Size: 1500 Lt ~ 1500 Bottle

Primary Package: (1.0 Lt) a White High Density Polyethylene

Pack Size: 1.0 Lt Bottle

8.0 Manufacturing Formula (Master Formula).

For active & inactive raw materials

Process Validation Protocol

18.1.045 Carboxy Methyl Cellulose Na 1.5 RM/0022/16

10.1.112 Enrofloxacin 150 RM/0023/16

16.1.065 Ethyl Alcohol (Ethanol 99.9%) 15.0 RM/0024/16

16.2.027 Basonyl-Red Dye 0.06 RM/0025/16

:Manufacturing Process Instructions 9.0

Step Materials Preparation Procedure Equipment

Process Validation Protocol

Contact QA for Sampling for IPC &QC Lab

Process Validation Protocol

22 Pack Enrosol-S 1.0 Lt Oral Solution Comarme Cartoner Machine

:Process critical parameters 10.0

Process Validation Protocol

Process Validation Protocol

Active Name :(Enrofloxacin) _ Cat .No: 10.1.112

Test Method No Test

BP2014 Description, Appearance, Color

12.0 In-active raw materials and primary package materials:

RM/0018/15 18.1.500 Purified Water

RM/0021/16 16.3.265 Potassium Hydroxide

RM/0025/16 16.2.027 Basonyl-Red Dye

White High Density

PM/0006/15 01.5.271.5 Black Polyethylene Screw Cap for Bottle 1.0 Lt

The qualification/validation status of each equipment's in each stage

VAPCO ID No. Machines Names

Process Validation Protocol

14.0 Analytical Methods for IPC Stages:

Process Validation Protocol

Acceptance Criteria Method Test

(1.0375 – 1.0475) RD/AM/076 Density (gm./ml) at 20ºC

(7.25 – 9.25) RD/AM/079 pH of (1.0 ml/ 2.0 Lt tap water)

Miscible RD/AM/082 Miscibility with water

Complies RD/AM/143 Sealing test (Integrity Test)