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Process Validation Protocol

Product: XXX 60 mg Tablets


Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 1 of 33


XXX 60
Process Validation Protocol

XXX 60 mg Tablets

Reason for amendment Issue Effective date


Prepared by Approved by
number Authorized by
First issue Head of Solids, Quality Control
1 Quality Assurance
01 December 2006
Pharmacist MAnager Manager
Name
Signature
Date
Process Granulation,
Compression,
Coating,
Packaging
in Oral Solid Dose Facility 1
Batch Size 310 000 tablets
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 2 of 33

TABLE OF CONTENTS PAGE


1 Purpose 3
2 Scope 4
3 Responsibilities 7
4 Materials and Equipment (Prerequisites) 12
5 Validation method & Critical Process Parameters 14
6 Process Description 25
7 In process control & QC testing & equipment 28
8 Support documentation 32
9 Validation Acceptance Criteria 32
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 3 of 33

Purpose -1

XXX
60


.
The objective of this Process Validation Protocol is to describe the
procedure to be followed during the validation of the process for the
manufacture of XXX 60 mg Tablets to find all Critical Process
Parameters which can influence on quality of the product..

XXX 60


SOP
.

The objective of the Process Validation is to demonstrate that the


manufacture of XXX 600 mg Tablets is controlled, and to provide
documented evidence that the specified process according to its SOPs
will consistently produce a product which meets its pre-determined
specifications and quality attributes.



.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 4 of 33

The study should also present evidence that challenging the tablet press
speed produces acceptable variation in the physical parameters of the
tablets.

SOP
.
The objective of the Process Validation is to find any really deviations in
SOPs and procedures.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 5 of 33

Scope -2

2-1 :
XXX 60
:
)(



1 .
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 6 of 33

2-2
XXX 60



PV

PV

PV
89- 12
3-1 15
89- 12
3-2 16
89- 12
3-3 17
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 7 of 33

2-3 SOP:
SOP .
SOP SOP


PR WI 081 SOP XXX 1
60 mg
SOP XXX 60 2

SOP XXX 3
60 mg
SOP 4
1

SOP PM 1

SOP PM 2

SOP PM 3

SOP PM V 4

SOP PM 5
BB3B
SOP PM 6

SOP PM 7

SOP 8

SOP 9
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 8 of 33


SOP 10


SOP : 1


SOP 2
SOP 3
SOP 4
) (
QC WI 402 SOP 5

SOP - 6
SOP 7

QC WI 675 SOP XXX 8
)
(
QC WI 406 SOP 9

QC WI 407 SOP 10

2-4 :
1 )(
.

-3 :
3-1 :
) ( .
.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 9 of 33

3-2 :

:




.



QA



GMP

Cleaning
Water
Process Validation AMV Equipment HVAC
Quality
Validation Qualification Validation
Validation



EQ
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 10 of 33

3-3 :
:

IPQC





.

3-4 :

) ( .

3-5 :
) ( .
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 11 of 33

-4 :
)4. PREREQUISITES (Equipment, utilities, materials
)Prerequisites for this validation are that equipment (including testing equipment
and utilities, and materials have been documented and approved.
4-1 :
SOP

.



203864- 100 kg API
2
203665-


Meggle 25 kg
1
204102- 10 kg
3
204183- Wacker 1 kg
1


204102- 6 kg
3
22 L

204102- 20 kg
3
204183- Wacker 2 kg
1
204051- Kirsch Pharma 3 kg
1
203848-
Blenhver 3 kg
2

304455- 156 kg PVC 145


1 mm
HINDALCO 28 kg 137
304608- mm
1
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 12 of 33

: 4-2
4.2 Equipment:
4.2.1 Granulation

No. Equipment Model Made Serial No Qualification


Status
1 Lodige
2 Wet granulator
3 Fluid bed drier
4 Dry Mill
5 Blender

4.2.2 Tablet Press Machine


Qualification
No. Equipment Model Made Serial No
Status
1 Tablet Press BB3B

4.2.3 Tablet Coating Machine


No. Equipment Model Made Serial No Qualification
Status
1 Tab Coater Accela
Cota

4.2.4 Packaging System


No. Equipment Model Made Serial No Qualification
Status
1 Blister Pack
2 Cartoning
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 13 of 33

4-3
4.3 Utilities
No. Equipment Qualification,
Validation, GEP
Status
1 Purified water
2 Industrial Steam
3 Hot & Cold
Drinking Water
4 Compressed Air
5 Vacuum
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 14 of 33

-5
: 5-1

Concurrent Validation will be performed in accordance with the following
procedure:
Three consecutive batches of XXX 60 mg tablets will be manufactured
according to the Method of Manufacture for XXX 60 mg tablets
Critical process parameters will be monitored during the manufacturing
operation of each batch.
Critical process parameters and results associated with the process will be
recorded in the relevant Validation Report.
Where required, samples will be taken during the manufacturing operations
at sampling intervals and sampling locations described in this Process
Validation Protocol, and submitted for in-process control testing and analysis.
Results will be recorded in the Validation Report.
Only identified critical process parameters associated with the specific unit
operations of production will be monitored. This does not in any way
eliminate the need for normal in-process control tests that may be carried
out.
Full batch release will be performed on each batch by the QC laboratory.
These results will be recorded in the In process Analysis Reports.
The monitoring / testing and batch release results of each batch will be
tabulated in the Validation Report for XXX 60 mg tablets.
The tabulated results will be evaluated against the specified validation
acceptance criteria to assess the validation status of the process.
The evaluated results will be recorded in the Validation Report.
Any deviation or abnormality observed during the execution of the protocol
will be documented in the Process Validation Report and Results Records.

Critical Process Parameters 5-2

The process will be considered in its sequential production unit operations.


Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 15 of 33

The following critical parameters for each of these production unit operations
indicated will be monitored, and maintained within the stated ranges.

Mixing and Granulation 5-2-1

Mixing and granulation is carried out using a high shear granulator.


Granulation of this product is essential to ensure uniform distribution of the
active ingredient in the final product.
The critical variable in a high shear granulation process is granule formation:
The particle size distribution of the dried granule will influence the
compression characteristics of the final tablet.
Controlling the following critical parameters can control granule formation:
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 16 of 33

Critical parameters
Quantity of granulating medium
Fluid addition time
Mixing time: Dry mix
Wet mix
Mixer blade speed: Dry mix
Spray mix
Wet mix
Chopper speed: Dry mix
Spray mix
Wet mix
Granulation end-point
Size of screen in wet mill
Wet Mill Speed
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 17 of 33

Drying 2-2 -5

Drying is carried out using a fluidised-bed drier. Drying occurs when the
agglomerated particles are suspended and agitated in a warm air stream
while the granules are maintained in motion.
The critical variable in the drying process is the moisture content of the
dried granule: Moisture content of the granule may influence the physical
characteristics of the final tablet.
Controlling the following critical parameters can control moisture content of
the dried granule:

Critical parameters
Final Loss on Drying
Inlet air temperature
Product temperature end-point

Sampling Plan: To verify that the required moisture content is achieved, one
5 g sample is collected from each sub batch when the product end-point
temperature is attained.

Acceptance criteria: The unit operation is deemed acceptable if each


individual LOD result is within 1.5 to 3.0 % m/m.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 18 of 33

Sizing and sifting / incorporation of 5-2-3


excipients

Particle size reduction and sizing are carried out by passing the material
through a mill / sieve.
The critical variable in the sizing and sifting processes is the particle size
distribution of the sized/sifted material: Particle size of material will influence
its die-filling properties, which will, in turn, influence the weight variation &
content uniformity of the final product.
Controlling the following critical parameters can control particle size
distribution:

Dried Granule and Lubricants:


Critical parameters
Size of the mesh openings of the sieve
Sifting speed
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 19 of 33

Blending 5-2-4

Blending is carried out using a conventional blender.


The efficacy of a blender is highly dependent on the speed of operation.
Operation that is too slow does not produce the desired intense tumbling or
cascading motion, nor does it generate rapid shear rates; rotation that is too
rapid tends to produce a centrifugal force sufficient to hold the powder to the
sides of the mixer and hence reduce efficiency.
The critical variable in the blending process is the blend uniformity: The
objective of the blending operation is to ensure that a maximum degree of
randomness in the arrangement of the individual components of the mix is
attained.
This homogeneous mix of the active and excipients is desired so as to ensure
that there are no areas of high concentration or low concentration of any of
the individual components of the mix that would cause content uniformity
problems in the final product.

Controlling the following critical parameters can control blend uniformity:

Important parameters
Speed of rotation
Blending time

Sampling Plan
To verify that a homogeneous mix is attained after the stated mixing time
and speed,
ten samples (BM 1 10; sample mass) are collected, in triplicate, using a
Model 1 sampling thief (2 cc sampling die), from different locations in the
blender bin as shown in the diagram below;
tests for UOC, assay and identity are performed on each of one set of the
samples collected.

A single sample (TBSA1; 300 g) is collected from the bulk and submitted for:
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 20 of 33

appearance test and


moisture content (KF) and for information only, for
tap density determination,
bulk density determination and
sieve analysis.

Top
Nor
th
Eas
W t
es
Sou
t
th

Middle

Bottom

Acceptance Criteria

Appearance A white to off-white, granular powder.


Identification The HPLC retention time of the drug active conforms to that of
XXX the standard.
Uniformity of All the individual assay results for the ten samples are within 10
content % (absolute) of the mean assay value, and the relative standard
XXX deviation (RSD) for all ten samples assay values is 5.0 %.
Moisture (KF) Not more than 3.5 %.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 21 of 33

Assay
mg XXX per 61.0 % m/m 5 % (58.0 64.1 % m/m)
tablet

Bulk density: 0.5 to 0.7 g/ml


Tap density: 0.6 to 0.8 g/ml
Sieve analysis: For observation only.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 22 of 33

Tablet compression 5-2-5


Tablet compression is carried out using rotary compression machines and
occurs as the heads of the punches pass over the lower and under the upper
pressure rollers.
This causes the punches to penetrate the die to a pre-set depth, compacting
the granule to the thickness of the gap set between the punch surfaces.

The critical variable in tablet compression is tablet uniformity; controlling the


following critical variables can control tablet uniformity:

critical parameters
Speed of operation (Press speed)
Degree of pressure applied by the pressure rollers (measured by tablet
hardness)
Depth of the die filling (measured by tablet mass)
Sampling Plan: To verify that tablet uniformity is achieved and verify the
absence of segregation effects induced during compression, samples (200
tablets) are collected from the start, middle and end of the compression run.
In Process core testing is performed as per the Finished Product Method of
Analysis.
In addition the following tests are also performed: Uniformity of Content,
Friability and Individual Hardness.
Acceptance criteria: The unit operation is deemed to be acceptable if the
results for these three samples are within the following specifications:
Refer Finished Product Method of Analysis for In Process Core testing.
Individual hardness (5 tablets): 180 to 240 N
Friability (20 tablets): Not more than 1.0 % lost after 4 minutes
Content Uniformity (10 tablets): Acceptance value of the 10 units is less than or
equal to L1 % (L1 is 15)
110 109 108

100 3036 100 3036 1003036


:56/2 :56/2 :56/2
()
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 23 of 33

: 56/2 : 56/2 : 56/2



:45/1 :45/1 :45/1
)
: 7/1 : 7/1 : 7/1 (

2/56 2/56 2/56


2/6 2/6 2/6
4 4 5




KN 16.4 KN 16.4 KN 16.4 ) 18KN(
4.8 4.8 4.8

:5 :5 :5
: 5 : 5 : 5
) (
:5/2 :5/2 :5/2

: 9/2 : 9/2 : 9/2

:3 :3 :3
: 3 : 3 : 3


Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 24 of 33

Tablet Coating 5-2-6

Coating of tablet cores is carried out using a perforated coating pan.


The critical variable in the coating process is surface adherence and
uniformity of the coating layer: these variables will influence the appearance
of the final tablet.
Controlling the following critical parameters can control the surface
adherence and uniformity of the coating layer:

Critical Parameters
Distance, angle, and position of the spray gun to tablet bed
Inlet air temperature
Exhaust air temperature
Atomising air pressure
Spray rate
Rotation speed of coating drum
Target weight gain

Sampling Plan: To verify that the required tablet weight increase is achieved,
samples (10 tablets) are collected from the coating drum after 30 minutes
and thereafter every 30 minutes, and at the end of spraying.
The average tablet mass and appearance is determined for each sample.
Acceptance criteria: The unit operation is deemed to be acceptable when the
mean result is within the following specifications:
Average coated tablet mass: 1007.0 mg (976.8 to 1037.2 mg)
i.e. about a 2.4 % increase in tablet mass relative to the
average core tablet mass.
Appearance:A white to off-white film-coated, oblong, biconvex
tablet
with a bisect (breaking line or scored) on one side, and
"A 05" debossed on the other side,
free from cracking,
free from peeling or
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 25 of 33

free from chipping.

Batch Release 5-2-7


To verify the process, samples (200 tablets) are collected after completion of
the manufacturing operation and full batch release testing performed, by the
QC laboratory.
Refer: Finished Product Method of Analysis.

Acceptance criteria

The process is deemed to be acceptable if each of the three batches


conforms to the product specifications and limits indicated above.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 26 of 33

-6 & Process Validation Procedure


Description

6-1 :
1216 1215 1217 XXX 600
mg Tablets.

6-2
:

Quality Risk Management (QRM):



SOP ) 3-2
SOP( XXX 600 mg Tablets
XXX 600 mg Tablets .
: SOP

.

Worst Case
.
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 27 of 33

:
XXX
Microcrystalline cellulose Dry Mixing Vertical granulator
101 Croscarmellose
sodium Hydroxypropyl
cellulose

Granulating medium: Granulation/ wet mill 10 Vertical Granulator /
Purified water mm Wet mill
Sodium lauryl sulfate

Drying Fluid-bed dryer

Sizing 1.5 mm Dry mill

Lactose monohydrate Blending
Croscarmellose sodium Pedestal Blender
Magnesium stearate Blending (Lubrication)
Blend Sampling
Tablet compression Tablet Press

Coating Dispersion Coating Coater
Opadry white Y-1-7000
Purified water
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 28 of 33

:

1217
1216 1215
SOP
OK OK OK


1 1 1 1


10:46 10 10
10
)
(
SOP
OK OK OK

30 30 30 30




30 30 30 30



3 3 3 3
50C 50C 50C
50C

100% 100% 100% 100%
40 43 40 43-40

) -29
29C 30.5C 29C
(31C FBD
14 14 14 14
SOP
OK OK OK

15 15 15
15


10 10 10 10

5 5
5 5

Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 29 of 33

-7 :

In Process Quality Control & QC Testing & Equipment



XXX 600 mg
Tablets .

7-1


Kneading

Bowl
FBD RSD %6

:





:
SOP
IPQC

15
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 30 of 33



7-2 QC


NMT 3% 1
80% should pass sieve No. 14 2
Fines NMT 10%
Angle of repose should be 3
between 25-35 ) (
Bulk density: 0.35-0.45 g/mL 4
Tapped density: 0.50-0.60 g/mL
Compressibility Index: 20-30%
Hausner Ratio(Index): 1.20-1.30
Turret 5



Diameter: 15 0.1 mm Turret 6
Thickness: 5.2 0.1 mm Turret 7
Hardness between: 3-8 kp 8
Weight variation: 250 5% Turret
NMT 1% 9
Turret
NMT 5 minutes 10

Between 95-105% label claim XXX 11
NLT 90% XXX 12
AV NMT 15 XXX 13
Text matter should correspond 14
Batch No., and other checks
should be OK.
NMT 2%, preferably 1%. SOP 15
No pathogenic micro-organism 16
NMT 500 cfu/g
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 31 of 33
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 32 of 33

7-3

No. Equipment Model Made Serial No Calibration
Status
1 Analytical Balance
2 Hardness Tester
3 Friability Tester
4 Disintegration
Tester
5 Dissolution Tester
6 UV
Spectrophotometer
7 HPLC
5 Blister Leak Test
Process Validation Protocol
Product: XXX 60 mg Tablets
Document No. QA PV 101 Facility: Solid Dosage 1
Revision No. 00 Page: 33 of 33

-8 Support Documentation
SOP
XXX 600 mg tablets ) 3-2
SOP (

-9 Validation Acceptance Criteria


XXX 60 mg tablets

) (2-7 .
the specified critical process parameters are met
) (2-7.
the In-Process Control test specifications are met
)(2-7
.
the QC analysis results conform to the product specifications

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