Juvia Protocol 50-1000

PROCESS VALIDATION PROTOCOL
Document # VP/TAB/PV/046
TITLE: Issue # 01
Effective Date 03-09-2019
JUVIA-M PLUS TABLET 50/1000 mg Review Date 03-09-2023
(SITAGLIPTIN + METFORMIN HCl ) Supersede # 00
FILM COATED Page 1 of 16
REVIEWED BY:
PREPARED BY: APPROVED BY:
Sr. Officer QA Sr. Manager Q.C Sr. Manager Q.A Sr. Production Manager GM Engineering
G.M Quality 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
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 4-5
7.0 PROCESS FLOW DIAGRAM 5
7.1 PROCESS FLOW DIAGRAM OF Juvia-M Plus 5-6
Tablet 50/1000mg
7.2 MANUFACTURING PROCESS 7-10
8.0 CRITICAL QUALITY ATTRIBUTES 11-12
9.0 PROCESS PARAMETERS TO BE QUALIFIED 12-14
10.0 MANUFACTURING CONDITIONS- 15
REQUIREMENTS AND RESULTS
11.0 PACKAGING 16
11.1 BLISTERING & PACKING 16
12.0 STABILITY STUDIES 16
13.0 ACCEPTANCE CRITERIA 16
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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.
i) Mfg. Directions
ii) Manufacturing Order
iii) Standard Operating Procedure
iv) Standard Control Procedures
v) Standard Test Method
vi) 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.
Rationale: As per change proposal number HP/CPRF-016/19, the formulation,
average weight of tablet and batch size of the product is now going to revised
i.e. 184.800Kg. Initially three lots will be manufactured using this batch size and
direction, therefore it has been planned to take this product on concurrent
validation with single lot acceptance plan.
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 preplanned 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
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 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.
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 Sitagliptin as monohydrate …. 50mg and
Metformin HCl USP ……1000mg
4.2 INDICATION: Juvia-M Plus is indicated as an adjunct to diet and exercise to
improve glycemic control in patients inadequately controlled on their maximum
tolerated dose of Metformin HCl alone or in those already being treated with the
combination of Sitagliptin plus Metformin.
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5.0 LIST OF MAJOR EQUIPMENTS USED IN MANUFACTURING:

Sr.No Equipment Description Asset Number Qualification
. Status
1. Mass mixer 1-01-03-25-0006 Qualified
2. Fitz Mill with 12 mesh screen 1-01-03-28-0001 Qualified
3. Tray dryer 1-01-03-34-0001 Qualified
4 Double Cone Blender 1-01-03-27-0005 Qualified
6. Tablet Compression 1-01-03-48-0002 Qualified
Machine,BB3B
7. China coata 1-01-03-32-0001 Qualified
8. China blister machine Alu Alu 1-01-03-02-0003 Qualified
6.0 PROCESS DETAILS:

6.1 PROCESS SCALE
Sr. Scale Drug Name Drug Code Unit of Quantity:
No. mg/tab No. Measure 184.800Kg /150000
Tablets
1. Metformin HCl Kg
500.000 RM-API-0102 150.000
BP/USP
2 Sitagliptin Kg
65.000 Phosphate RM-API-0103 9.750
Monohydrate
4 59.000 PVPK-30 RM-XCP-0055 Kg 8.850
5 Pregelatinized Kg
100.000 RM-XCP-0071 15.000
Starch
8 8.000 Magnesium RM-XCP-0048 Kg
1.200
Stearate BP/USP
9. - Distilled water RM-XCP-0183 Lits. Q.S
10. Opadry Tabcoat Kg
- White RM-XCP-0164 5.625
(TC-117-280000)
11. Insta Coat Aqua Kg
- Green RM-XCP-0151 1.686
(A02R20089)
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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:

7.1 Process Flow Diagram of Juvia–M Plus Tab 50/1000mg
- Metformin Hcl Pass through 12mesh

- Sitagliptin Phosphate Mass mixer
screen in Mass mixer
-
and mix for 20 minutes
Prepare PVP paste Granulate with step 2 and mix for 10 Mass mixer
by dissolving Minutes or till proper wet is
-PVP K30 obtained
-Distilled Water
Collect in S.S Tray Dry the granules for Tray Dryer

8 hours. At 600C
-Pre-gelatinized Add pre-gelatinized starch by passing 16 mesh screen

starch through 16mesh sieve. Mix for 10
minutes.
-Magnesium Stearate Add Magnesium stearate by passing 40 mesh screen

through 40mesh sieve. Mix for 5
minutes.
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Blended granules transfer to

Submit sample to
Polyethylene lined Plastic Containers.
Q.C. for analysis
Release for Compression
Submit sample to QC
for analysis Compression Compression
Weight /tablet =1232.000mg Machine,BB3B
Mix following items in
Distilled Water (45 min)
-Tabcoat opadry (white) TC- Release for Coating
117-280000
- INSTA COAT AQUA GREEN
(A02R20089)
Coating of Tablets (Film coating) China Coata
Submit sample to
Submit sample
Q.C. for to QC
analysis
for analysis
Release for Blistering / Packing China Blister Alu Alu
Packing 1 X 10’S
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7.2 Manufacturing process:

Batch No.1: Mfg. started on: Mfg. completed on:
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 # 16 and collect in blender. Mix for 20 minutes.
Material Name Quantity
Metformin HCL 150.000Kg
Sitagliptin 9.750Kg
Step #02:
Prepare granulating solution by dissolving PVP K30 in Distilled water to obtain clear
solution.
Povidon K-30 8.850Kg
Distilled water ____Lit.
Step #03:
Add granulating solution in step # 1& mix for 10 minutes, or till proper wet mass is
obtained. (In order to obtain proper wet mass use additional distilled water if required. Mix
for 10 minutes.
Quantity of additional Distilled Water used _____Liters.
Step #04:
Dry the granules at 60°C for ___ hours or till moisture remains NMT 2.0-2.5%
Actual moisture: ________%
TOP MIDDLE BOTTOM
Sample COMPOSITE
Locatio Location Location MEAN LIMIT
Time %
n% % %
60 Minutes Less Than
120 Minutes 4.0%
180 Minutes
240 Minutes
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720 Minutes
Conclusion
Performed
By
Verified By
Step #05:
Pass the dried granules of step # 4 through 16 mesh screen and transfer in blender, and
then add following material passing through 16 mesh screen and blend for 10 minutes.
Pre-gelatinized starch 15.000Kg
Then add the following material through sieve # 40 in Blender and blend for 5 minutes.
Magnesium stearate 1.200Kg
Step #06:
Collect granules in polythene line container and tightly closed it. Weigh the granules and
record the yield. Inform QA for sampling.
S. Assay (%)
Assay (%)
No Location Metformin Acceptance Criteria
Sitagliptin
. HCL
1 Top Sitagliptin:
2 Middle Metformin HCL:
3 Bottom
4 Composite
Step #07:
Weigh the blended powder mix and record the yield.
Batch #. Theoretical yield Actual yield % Yield
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Step# 09: Compression

Check compression of tablets with product specifications:
Parameters Specifications
Compression Machine BB3B
Upper Punch Oblong, slight concave
Lower Punch Oblong, slight concave
Appearance White, oblong, slight biconvex tablets.
Thickness 7.00-8.00mm
Length 19.50mm
Hardness 100-140N
Friability NMT 1%
Average Weight 1232.00mg ± 5% (1170.40mg – 1293.60mg)
Disintegration NMT 15 min in Water at 37°C.
Check and record weight after completion of compression.

Batch #. Theoretical yield Actual yield % Yield
Step # 9:
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(Yellow) TC-117-220000 5.625Kg
Instacoat Aqua Green (A02r20089) 1.686Kg
Distilled water 7.00Lit.
Step #10:
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.
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S. No. Parameters China Coata

1 No. of Spray Gun 04
2 Distance Spray gun 6 Inch
3 Distance of Gun to Tablet bed 8 Inch
4 Gun nozzle bore size 1.5 mm
Step #11:
Load tablets into Coating Pan and Pre-warm as follows:
1 Pan Speed 02 to 08 rpm
2 Inlet Temp 70 to 80°C
3 Bed Temp 45 to 55°C
4 Exhaust air Temp 40 to 50°C
Step#12:
Apply Sub Coating solution and then Coating solution using the following conditions, with
maintaining agitation throughout spraying.
1 Atomizing Pressure 03 to 06 Bar
100 to
2 Solution Flow rate
150mL/min
3 Inlet Temp 3 to 6 rpm
4 Bed Temp 70 to 80°C
5 Exhaust air temp 45 to 55°C
6 Pan Speed 40 to 50°C
Step #13:
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.
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8.0 CRITICAL QUALITY ATTRIBUTES:

Critical Quality Attribute How Measured Rationale/Reference
Blending:
Assay : Collect sample after
Sitagliptin (As phosphate blending process(.Top Mid
monohydrate) and Bottom of the blend)
Metformin HCl
Compression:
Physical characteristics 20 tablets collected each
(Shape, Color, Marking) from the beginning, middle
and end of Compression
Process.
Weight variation In‐process control chart
used
to monitor weight
variation.
Hardness , Thickness & In‐process control chart
Friability of core tablets used
to monitor Hardness,
Thickness and Friability.
Assay : 20 tablets collected each
from the beginning, middle
and end of compression
process.
Disintegration Time 06 tablets collected each
from the beginning,
middle and end of
compression process
COATING
Physical characteristics 20 coated tablets
(Appearance, Color, Shape, (composite sample)
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Markings) collected from each coating

run.
Inspection of Attributes 100 coated tablets
(composite sample)
collected from each coating
run.
Disintegration Time 18 tablets (composite
sample) collected from
each coating run.
Coating process & parameters Coating process and
parameters noted during
each coating run
Assay : 20 tablets collected each
Sitagliptin(As phosphate from the beginning, middle
monohydrate) and end of compression
Metformin HCl process.
9.0 PROCESS PARAMETERS TO BE QUALIFIED:

9.1 Process Parameters Details:
Process Process Operating How Monitored Rationale/
Parameter Range Reference
WET GRANULATION:
Sieving of Pass through 16 Uniform size As per Mfg.
- - Metformin HCl mesh granules Direction
- Sitagliptin
Phosphate
- Dissolve PVP K- Mixing until clear Check the clarity As per Mfg.
30 in distilled solution is obtained of the solution Direction
water
- Mix PVPK-30 Mixing for 10 Check for mass of As per Mfg.
solution together minutes till a proper suitable Direction
and granulate it wet mass is formed consistency
with Step 1 till
proper wet mass is
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obtained
Dry wet mass in Load wet mass into Check for uniform As per process
Tray Dryer Tray Dryer size of granules requirement
Drying Time For ___ hrs. or Moisture content As per process
Moisture content is 2.0-2.5%. requirement
Less than 2.0-2.5%
Sieving of Dried By using 16 mesh Uniform size of As per process
Granules sieve. granules requirement
BLENDING
After drying and Blend for 10 Uniform size As per Mfg.
sieving. Add minutes. material and Direction.
Pre-gelatinized blending time of 10
starch minutes.
After sieving
through 16 mesh
screen in blender
Add Blend for 05 Uniform size As per Mfg.

Magnesium minutes. material and Direction.
Stearate blending time of 05
After sieving minutes.
through 40 mesh
screen in blender
Compression:
Compression of Wt. /tablet = In-process As per Mfg.
tablets 1230mg ± 5.0% inspection at a Direction.
given time interval.
Coating
Coating solution Mix for 45 minutes Uniform mixing of As per Mfg.
Preparation: and then pass coating solution. Direction.
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Dissolve : through 100 mesh

- Insta Coat Aqua sieve.
Green
(A02R20089)
- Tabcoat Opa Dry
(white) TC-117-
280000 in Distilled
water
Coating Application 02-10rpm Check actual rpm As per Mfg.
Pan speed used Direction.
Inlet air 70- 80oC Check actual As per Mfg.
temperature temperature used. Direction.
Atomizing Pressure 04 - 08 Bar Check actual As per Mfg.
pressure used Direction.
Bed Temp during 30 - 50oC Check actual As per Mfg.
Coating temperature used Direction.
Exhaust 30 - 50oC 30 - 50oC As per Mfg.
temperature during Direction.
Coating
Solution Flow Rate. 100-150 ml/min Check actual Flow As per Mfg.
rate used Direction.
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10.0 MANUFACTURING CONDITIONS -REQUIREMENT AND RESULTS:

Sr. Section
No.
10.1 Loss on Drying after drying of wet mass :
 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)
 Sitagliptin(As phosphate monohydrate) and Metformin HCl
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
 Sitagliptin(As phosphate monohydrate) and Metformin HCl
on Coated Tablet (% of L.C. per Tab.).
 Dissolution of film coated tablet
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11.0 BLISTERING AND PACKAGING:

11.1 Blistering and packing
Tablets are blistered by using tablet blistering machine (China blister) in
Aluminium Foil Printed, Juvia-M Plus 50/1000mg Tablet, 185mm, 20µ, and cold
forming printed aluminium foil 185mm, 150µ, packed in printed cartons as 1 x
10’s pack.
Name of Blistering Equipment Blister Sealing
Batch #.
Machine No. 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 Juvia-M Plus 50/1000mg Tablet will be released for marketing on
the basis of acceptance criteria of product specification limits.
16

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PROCESS VALIDATION PROTOCOL

3.0 VALIDATION APPROACH:

 Data within the finally agreed parameters.

3.2 VALIDATION STRATEGY:

4.0 PRODUCT DESCRIPTION:

5.0 LIST OF MAJOR EQUIPMENTS USED IN MANUFACTURING:

6.0 PROCESS DETAILS:

7.0 PROCESS FLOW DIAGRAM:

- Metformin Hcl Pass through 12mesh

Collect in S.S Tray Dry the granules for Tray Dryer

-Pre-gelatinized Add pre-gelatinized starch by passing 16 mesh screen

-Magnesium Stearate Add Magnesium stearate by passing 40 mesh screen

Blended granules transfer to

Release for Compression

7.2 Manufacturing process:

Step# 09: Compression

Check and record weight after completion of compression.

S. No. Parameters China Coata

8.0 CRITICAL QUALITY ATTRIBUTES:

Markings) collected from each coating

9.0 PROCESS PARAMETERS TO BE QUALIFIED:

Add Blend for 05 Uniform size As per Mfg.

Dissolve : through 100 mesh

10.0 MANUFACTURING CONDITIONS -REQUIREMENT AND RESULTS:

11.0 BLISTERING AND PACKAGING:

12.0 STABILITY STUDIES:

13.0 ACCEPTANCE CRITERIA:

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