Xoxiban 20mg Tab VP

PROCESS VALIDATION PROTOCOL
Document # VP/TAB/PV/051
TITLE: Issue # 01
Effective Date 26-02-2020
XOXIBAN 20mg TABLET Review Date 26-02-2024
(RIVAROXABAN 20mg) Supersede # 00
FILM COATED Page 1 of 13
PREPARED BY: REVIEWED BY: APPROVED BY:
G.M Quality
A.M. QA Sr. QC Manager Sr. QA Manager Sr. Production Manager GM Engineering Operation
TABLE OF CONTENTS
Section Description Page No.

1.0 SCOPE 2
2.0 DOCUMENTATION 2
3.0 VALIDATION APPROACH 2
3.1 PROCESS VALIDATION 2
3.2 VALIDATION STRATEGY 3
4.0 PRODUCT DESCRIPTION 3
5.0 LIST OF MAJOR EQUIPMENT USED IN
4
MANUFACTURING
6.0 PROCESS DETAILS 4
6.1 PROCESS SCALE 4
7.0 PROCESS FLOW DIAGRAM 5
7.1 PROCESS FLOW DIAGRAM Xoxiban 20mg TABLET 5
7.2 MANUFACTURING PROCESS 6-9
8.0 CRITICAL QUALITY ATTRIBUTES 9-10
9.0 PROCESS PARAMETERS TO BE QUALIFIED 10-11
10.0 MANUFACTURING CONDITIONS-
12
REQUIREMENTS AND RESULTS
11.0 PACKAGING 13
11.1 BLISTERING & PACKING 13
12.0 STABILITY STUDIES 13
13.0 ACCEPTANCE CRITERIA 13
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TITLE: Issue # 01
G.M Quality
1.0 SCOPE:
This protocol will document at least the critical steps and parameters of manufacturing process,
i.e. those that may have an impact on the quality of the product.Complete manufacturing
processes, including Granulation, Drying, Blending, Compression, and Coating processes will
be validated.
2.0 DOCUMENTATION:
All batch documents should be in compliance with standard documents.
2.1 Mfg. Directions
2.2 Manufacturing Order
2.3 Standard Operating Procedure
2.4 Standard Control Procedures
2.5 Standard Test Method
2.6 Packaging Order
All of the above stated documents are understood by all responsible persons, as applicable.
All related operating procedures must be in compliance with the product requirement.
3.0 VALIDATION APPROACH:

3.1 Process Validation
This is a new product an approach of concurrent validation with a single lot acceptance
will be adopted. This will be three lot concurrent validation and all three lots will be
subjected to stability studies.
Rationale: Establishing documented evidence with a high degree of assurance, that a
specific process will consistently produce a product meeting its predetermined
specifications and quality characteristics, based on pre-planned protocols, following are
the pre-requisites:
 Equipment, production environment and analytical testing methods – already fully
validated.
 appropriately trained personnel and batch manufacturing documentation prepared after these
critical parameters have been identified, and machine settings, component specifications and
environmental conditions have been determined and specified
 Data within the finally agreed parameters.
– from at least three consecutive batches, giving product of the desired quality may be
considered acceptable.
 Same size batches will be considered for validation.
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G.M Quality
Commercial batch size will be considered.

– Validity of assumptions made should be demonstrated when commercial production
starts.
 Extensive testing at various stages in the manufacturing process _ including on the
final product and its package.
 First three lots of the product will kept for stability studies i.e. accelerated and long
term stability (throughout shelf life).
3.2 VALIDATION STRATEGY:
Focuses on:
 Granulation process
 Drying of granules
 Milling
 Blending
 Compression
 Coating
 Blistering and packing
4.0 PRODUCT DESCRIPTION:

4.1 ACTIVE INGREDIENTS
Each film coated tablet contains Rivaroxaban: 20mg.
4.2 INDICATION
Xoxiban (Rivaroxaban) indicated for:
- Reduction in risk of stroke and systemic embolism in patients with non-
ventricular atrial fibrillation.
- Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).
- Prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip
replacement surgery.
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G.M Quality
5.0 LIST OF MAJOR EQUIPMENTS USED IN MANUFACTURING:

Qualification
S. No. Equipment Description Asset Number
Status
1 Mass mixer 1-01-03-25-0006 Qualified
2 Tablet Compression Machine, BB3B 1-01-03-48-0002 Qualified
3 Thai Coata 1-01-03-32-0001 Qualified
4 China blister machine Alu Alu 1-01-03-02-0003 Qualified
6.0 PROCESS DETAILS:

6.1 PROCESS SCALE
Quantity:
Scale
S. Drug Code Unit of 26.000Kg
mg/tab Material Name
No. No. Measure /100,000
.
Tablets
1 20.00 Rivaroxaban (Micronized) RM-API-0331 Kg 2.000
2 71.00 Avicel PH102 RM-XCP-0105 Kg 7.100
3 49.00 Lactose monohydrate RM-XCP-0047 Kg 4.900
4 71.00 Mannitol RM-XCP-0109 Kg 7.100
5 40.00 Croscarmellose sodium RM-XCP-0125 Kg 4.000
6 4.00 Sodium lauryl sulphate RM-XCP-0074 Kg
0.400
Magnesium Stearate
7 5.00 RM-XCP-0048 Kg
BP/USP 0.500
Tabcoat Opadry (White)
8 - Kg 0.811
TC-117-280000 RM-XCP-0164
Opadry Tabcoat (Yellow)
9 - Kg 0.237
(TC-117-220000) RM-XCP-0166
Compliance to Specification of all (new & already in use) codes used will be checked.
I - Verify the material is received from the approved source.
II - Successful completion of shelf life of the product will confirm the validation of the raw
materials.
7.0 Process Flow Diagram:
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G.M Quality
7.1 Process Flow Diagram of Xoxiban 20mg Tablet
-Rivaroxaban Pass through 40mesh Mass mixer

- Avicel 102
screen in mixer and mix
-Lactose
-Mannitol for 40 minutes
-Crosscarmellose sodium Pass through 40mesh screen in Mass

-Sodium lauryl sulphate Mass mixer
mixer and mix for 40 minutes
-Magnesium stearate Pass through 40mesh screen in Mass

mixer and mix for 5 minutes Mass mixer
Submit sample to QC for Release for Compression

analysis
Compression Compression
Weight /tablet = 260.0mg ± 5% Machine, BB3B
Mix following items for
45min
-Distilled Water
Release for Coating
- Opadry Tabcoat (White)
TC-117-280000 Conventional
- Opadry Tabcoat (Yellow)
TC-117-220000 Coating of Tablets (Film coating) coating pan
Submit sample to QC for

analysis Release for Blistering / Packing China Blister Alu
Alu
Packing 1 x 10’s
7.2 MANUFACTURING PROCESS:

Batch No.1: Mfg. started on: Mfg. completed on:
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G.M Quality
Batch No 2: Mfg. started on: Mfg. completed on:

Batch No.3: Mfg. started on: Mfg. completed on:
Step #01:
Pass the following materials through sieve # 40 and collect in Mass Mixer. Mix for 30minutes
Material Name Quantity
Rivaroxaban 2.000 Kg
Avicel pH 102 7.100 Kg
Lactose 4.900 Kg
Mannitol 7.100 Kg
Step #02:
Pass the following materials through sieve # 40 and collect in Mass Mixer. Mix for 20minutes
Croscarmellose sodium 4.000Kg
Sodium lauryl sulphate 0.400Kg
Step #03:
Pass the following materials through sieve # 40 and collect in blender. Mix for 5minutes
Magnesium stearate 0.500Kg
Step #04:
Collect the blended powder in S.S container and close it tightly. Inform QA for sampling.
Step#. 05:
Weigh the granules and record the yield.
Batch #. Theoretical yield Actual yield % Yield
Step# 06:
Compression
Check compression of tablets with product specifications:
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Parameters Specifications
Compression Machine BB3B
Upper Punch Triangular, slight concave
Lower Punch Triangular, slight concave
Appearance White, triangular, slight biconvex tablets.
Thickness 3.50-4.50mm
Diameter (to be developed)
Hardness 30-60N
Friability NMT 1%
Average Weight 260.00mg ± 5% (247.00mg – 273.00mg)
Disintegration NMT 15 min in Water at 37°C.
Check and record weight after completion of compression.
Batch #. Theoretical yield Actual yield % Yield
Step # 07:
Coating solution preparation
Mix properly the following material in Distilled water in S.S. Container for 45 minutes and filter
through mesh # 100.
Opadry Tabcoat(White) TC-117-280000 0.811Kg
Opadry Tabcoat (Yellow) TC-117-220000 0.237 Kg
Distilled water 5.500Lit.
Step #08:
Close the container tightly and label properly, now the solution is ready for spraying.
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Step #09:
Coating solution application
Equipment Required:
Coating Pan, Pressure Vessel, Spray Guns.
Set up the Coating Pan with spray unit for solution flow rate before loading tablets.
S. No. Parameters Thai Coata
1 No. of Spray Gun 02
2 Distance Spray gun 6 Inch
3 Distance of Gun to Tablet bed 8 Inch
4 Gun nozzle bore size 1.5 mm
Step #10:
Load tablets into Coating Pan and Pre-warm as follows:
S. No. Parameters Thai Coata
1 Pan Speed 02 to 10 rpm
2 Inlet Temp 40 to 75ºC
3 Bed Temp 30 to 55ºC
4 Exhaust air Temp 30 to 55ºC
Step#11:
Apply Sub Coating solution and then Coating solution using the following conditions, with
maintaining agitation throughout spraying.
S. No. Parameters Thia Coata
1 Atomizing Pressure 04 to 08 Bar
2 Solution Flow rate 40-210ml/min
3 Inlet Temp 40 to 75ºC
4 Bed Temp 40 to 50ºC
5 Exhaust air temp 30 to 50ºC
6 Pan Speed 02 to 08 rpm
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Step #12:
On completion of coating run, rotate the pan with jogs of tablets under set condition for 15 minutes,
then switch OFF the hot air, continue to rotate the pan until the exhaust temperature decreases to
30-35C. Ensure that tablets are thoroughly dried after 15 minutes and transfer from the Coating
Pan into polythene lined bag, air tightly close containers and intimate to QA for sampling.
8.0 CRITICAL QUALITY ATTRIBUTES

Critical Quality
How Measured Rationale/Reference
Attribute
Blending:
Assay: Collect sample after blending As per S.T.M.
Rivaroxaban process(.Top, Mid and Bottom of the
blend)
Compression:
Physical characteristics 20 tablets collected each from the As per S.T.M.
(Shape, Color, Marking) beginning, middle and end of
compression process.
Weight variation In‐process control chart used to As per S.T.M.
monitor weight variation.
Hardness , Thickness & In‐process control chart used to As per S.T.M.
Friability of core tablets monitor Hardness, Thickness and
Friability.
Assay: 20 tablets collected each from the top, As per S.T.M.
Rivaroxaban middle and bottom of compression
process.
Disintegration Time 06 tablets collected each from the As per S.T.M.
beginning,
middle and end of compression
process
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Coating
Physical characteristics 20 coated tablets (composite sample) As per S.T.M.

(Appearance, Color, collected from each coating run.
Shape,
Markings)
Inspection of Attributes 100 coated tablets (composite sample) As per S.T.M.
collected from each coating run.
Disintegration Time 18 tablets (composite sample) As per S.T.M.
collected from each coating run.
Coating process & Coating process and parameters noted As per S.T.M.
parameters during each coating run
Assay : 20 tablets collected each from the As per S.T.M.

Rivaroxaban beginning, middle and end of
compression process.
9.0 PROCESS PARAMETERS TO BE QUALIFIED:

9.1 Process Parameters Details
Rationale/
Process
Process Parameter How Monitored Reference
Operating Range
Mxing:
Sieving of Pass through Uniform size As per Mfg. Direction.
- Rivaroxaban 40mesh. Mix for granules.
-Avicel pH 102 40min.
-Lactose
-Mannitol
Sieving of Pass through Uniform size As per Mfg. Direction.
- Crosscarmellose sodium 40mesh. Mix for granules.
-Sodium lauryl sulphate 40min.
B
BBlending
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G.M Quality
Add Magnesium stearate Blend for 5 Uniform size As per Mfg. Direction.
after passing through sieve minutes. material and
#. 40 and blend for 5 min. blending time of
5 minutes.
Compression
Compression of tablets Wt. /tablet = In-process As per Mfg. Direction.
145.00mg ± 5.0% inspection at a
given time
interval.
Coating
Coating solution Mix for 45 Uniform mixing As per Mfg. Direction.
Preparation: minutes and then of coating
Dissolve pass through 100 solution.
- Opadry Tabcoat(White) mesh sieve.
TC-117-280000
- Opadry Tabcoat (Yellow)
TC-117-220000
in Distilled water.
Coating Application : 02-10rpm Check actual As per Mfg. Direction.
Pan speed rpm used
Inlet air temperature 40- 75oC Check actual As per Mfg. Direction.
temperature
used.
Atomizing Pressure 04 - 08 Bar Check actual As per Mfg. Direction.
pressure used
Bed Temp during Coating 30 – 55oC Check actual As per Mfg. Direction.
temperature used
Exhaust temperature during 30 - 55oC 30 - 55oC As per Mfg. Direction.
Coating
Solution Flow Rate. 40-210 ml/min Check actual As per Mfg. Direction.
Flow rate used
10.0 MANUFACTURING CONDITIONS -REQUIREMENT AND RESULTS:
S. No. Section
10.1 Loss on Drying after drying of wet mass :
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G.M Quality
 Moisture content
10.2 Blending :
 Blend uniformity of lubricated bulk granules
10.3 Compression:
 Physical Characteristics of core tablets.
10.4 Compression:
 Average weight and Weight Variation, %Friability, Hardness,
Thickness, Disintegration Test of core tablets.
10.5 Assay of
 Rivaroxaban on Core Tablet (% of L.C. per Tab.)
 Dissolution
10.6 Coating:
 Physical characteristics of coated tablets.
 Inspection of attributes for coated table
 Monitoring of coating parameters.
10.7 Disintegration Test:
 Disintegration Time of coated tablets
10.8  Assay of
 Rivaroxaban on Core Tablet (% of L.C. per Tab.)
 Dissolution of film coated tablet
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G.M Quality
11.0 PACKAGING:
11.1 Blistering and packing
Tablets are blistered by using tablet blistering machine (China blister I /II/III) in
Aluminium Foil Printed Xoxiban 20mg Tablet, 265mm, 20µ, and cold forming printed
aluminium foil 265mm, 150µ, packed in printed cartons as 1 x 10’s pack.
Name of Blistering Blister Sealing
Batch #. Equipment No.
Machine Checks
12.0 STABILITY STUDIES:

All three lots of validation will be kept on stability studies (short term and long term stability), 20
packs from each single lot will be taken for stability studies.
13.0 ACCEPTANCE CRITERIA:

Each validation batch Xoxiban 20mg Tablet will be released for marketing on the basis of
acceptance criteria of product specification limits.
13

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PROCESS VALIDATION PROTOCOL

Section Description Page No.

3.0 VALIDATION APPROACH:

Commercial batch size will be considered.

4.0 PRODUCT DESCRIPTION:

5.0 LIST OF MAJOR EQUIPMENTS USED IN MANUFACTURING:

6.0 PROCESS DETAILS:

7.1 Process Flow Diagram of Xoxiban 20mg Tablet

-Rivaroxaban Pass through 40mesh Mass mixer

-Crosscarmellose sodium Pass through 40mesh screen in Mass

-Magnesium stearate Pass through 40mesh screen in Mass

Submit sample to QC for Release for Compression

Submit sample to QC for

7.2 MANUFACTURING PROCESS:

Batch No 2: Mfg. started on: Mfg. completed on:

8.0 CRITICAL QUALITY ATTRIBUTES

Physical characteristics 20 coated tablets (composite sample) As per S.T.M.

Assay : 20 tablets collected each from the As per S.T.M.

9.0 PROCESS PARAMETERS TO BE QUALIFIED:

12.0 STABILITY STUDIES:

13.0 ACCEPTANCE CRITERIA:

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