HD THẨM ĐỊNH QUY TRÌNH SẢN XUẤT

VALIDATION PROTOCOL
PROCESS VALIDATION FOR CEFAKID GRANULES
PROTOCOL APPROVAL
Ref. No.: 010012.02/01 Page 1 / 21
Table of Contents
S. No. Content Page No.
1 Objective 3
2 Scope Process Description 3
3 Abbreviations 3
4 Responsibility 4
5 Safety Precautions 5
6 Equipments/ Materials Required for the validation 5
7 Validation Study Plan 7
8 Procedure 10
9 Sampling Plan 16
10 Acceptance Criteria 20
11 Re-Validation 21
12 References 21
1. Objective:
The objective of this proces validation protocol is to establish documented
evidence that the processing for CEFAKID GRANULES will consistency produce
a product, which meets its predetermined specification and quality attributes.
2. Scope Process Description:
The prospective process validation will be performed with qualified equipment in
the Betalactam non-sterile workshop with three consecutive batches of the
product CEFAKID GRANULES.
This process validation (PV) protocol is written in order to document that the
process used in the manufacturing of the product name CEFAKID GRANULES of
batch size: 150.00 kg # 50,000 sachets complies with process parameters
requirement of the Batch Manufacturing Record (BMR) and finished product
specifications.

3. Abbreviations:
• BL - Betalactam
• BMR - Batch Manufacturing Record
• BPR - Batch Packaging Record
• ID No. - Identification Number
• IPC - In-process Control
• HPLC - High Performance Liquid Chromatography
• KF - Karl Fischer
• Mfg. - Manufacturing
• NA - Not Applicable
• NMT - Not More Than
• PE - Polivinyl Ethylene
• PPEs - Personal Protective Equipments
• PV - Process Validation
• PVDC - Polyvinylidene Chloride
• QA - Quality Assurance
• QC - Quality Control
• Q’ty - Quantity
• S. No. - Serial Number
• SOP - Standard Operating Procedure
• SPC - Specifications and Testing Procedure
• Std. - Standard
• IPC - In process control
4. Responsibility:
Department/ Function Responsibility
Research &
Development
To provide the Master Formula Card to be used for the
manufacture of the process batch
To provide technical support during the process validation

activities
To coordinate and implement the process validation
activities
Production of BL Solid
Orals
Execution of BMR and protocol
Providing samples wherever necessary as per the protocol
and BMR
Recording of observation, collection of data and filling of
BMR
Engineering &
Maintenance
To ensure that all the required utilities are working as per
the respective SOPs
To ensure that the related instruments and equipments are
in calibrated and validated status
To ensure that the environmental conditions of all the areas
met the requirements
QC
Testing shall be done as per the sampling plan and
respective specifications
QA
Prepare process validation protocol
Sampling as per the sampling plan (IPC)
Preparation and review of the Validation report, documents
and its compliance to meet the acceptance criteria of the
protocol
5. Safety Precautions:
• Ensure that all clean-rooms and equipments are cleaned completely and
sticked appropriate status labels.

• Ensure that manufacturing areas is maintained under pre-defined air
cleanliness with temperature between 18 – 25
o
C and relative humidity not
more than 55%.
• Ensure that all concerned people involved are trained on all current SOPs/
SPCs and concerned practices in GMP areas during manufacturing process
as well as sampling for testing.
• Ensure that appropriate PPEs (i.e. safety gloves, mask, cap, goggles etc.)
shall be used.
• Checking the electric safety and calibration of instruments.
6. Equipment/ Materials Required for the Validation:
S.
No.
Equipment name ID No.
Qualification
number
Process equipments
Electronic balance DI-600 22041 IOQ-22041
Electronic balance TE 1502S 22040 30111
Milling machine 22002
IQR-L-MX-1
OQR-L-MX-1
PQR-L-MX-1
Vibro sifter GY-450 22029 30011
High speed mixer 22011 30113
Stirring machine 1 22016
IQR-L-KH-1
OQR-L-KH-1
PQR-L-KH-1

Wet granulating machine 22021
IQR-L-XH-1
OQR-L-XH-1
PQR-L-XH-1
Tray dryer 22125 30124
Cubic mixer 1 22017 30104
Metal detecting machine 22027 NA
Vertical sachet packing machine 1 22003 IQR-L-EG-1
OQR-L-EG-1
PQR-L-EG-1
Electronic Balance 22136 30141
Ink-jet printer 22014 IOQ-22014
IPC equipments
Cylinder NA NA
Electronic balance CP224S 22047 IOQ-22047
Leak-test apparatus 22050 IOQ-22050
Digital caliper 22110 NA
QC Laboratory equipments
Analytical Balance
25026 30023
25027 30040
25036 30042
High Performance Liquid Chromatography
25011
IQ.P-K-LC-05
OQ.P-K-LC-05
25012
IQ.P-K-LC-07
OQ.P-K-LC-07
25013

IQ.P-K-LC-08
OQ.P-K-LC-08
Titrator and Karl Fischer 25029 30086
Sieve shaker 25057 30095
7. Validation Study Plan:
7.1 Product information
Product Name CEFAKID granules
API/ Strength Cephalexin 250 mg
Dosage Form Granule
Product Code 50.C45
Batch Size 150.00 kg # 50,000 sachets
Shelf Life 36 months
Category Antibiotic in Cephalosporin group
Label Claim
Each sachet contains: Cephalexin monohydrate equivalent to
cephalexin anhydrous of 250 mg
7.2 Time schedule (approx.)
Batch number Date
7.3 Validation team:
Member Designation
QA department Manager/ officer
R&D department Manager/ officer
Quality control Manager/ officer
Production department Manager/ officer
Engineering department Manager/ officer
Warehouse Manager/ officer
7.4 Manufacturing formula
S.
No.
Raw material

code
Raw material Manufacturer Spec. SPC.No
1 sachet
(mg)
Percent (%)
1 batch (50,000 sachets)
(kg)
TB0C02.DSM
Cephalexin
monohydrate
Spain
In-house
In-house
SPC-RM-046-01
270.00 9.00 13.50 = (2 x 6.75)
Corresp. to Cephalexin
anhydrous)
256.80 8.56 12.84 = (2 x 6.42)
VN4D01.KCP
Sugar milled through
0.8 mm sieve
Vietnam (KCP) EP 6.0 SPC-RM-009-01 1950.00 65.00 97.50 = (2 x 48.75)
NB4A01.AJI Aspartam
Ajinomoto/
Japan
In-house SPC-RM-064-01 40.00 1.33 2.00 = (2 x 1.00)
PH4M01.ROQ Mannitol 60
Roquette/
France
In-house SPC-RM-047-01 700.00 23.33 35.00 = (2 x 17.50)

AN4Q01.UNI Quinolin yellow lake Univar/ England In-house SPC-RM-074-01 0.85 0.03 0.0425 = (2x 0.02125)
MY4K01.ISP PVP K29/32 ISP/ American EP 6.0 SPC-RM-040-01 30.30 1.01 1.515 = (2 x 0.7575)
VN4C01.OPC 96% ethanol Vietnam (OPC) In-house SPC-RM-065-01 NA NA 20.40 = (2 x 10.20)
PH4H01.EXP Apple powder flavour
Expression/
France
In-house SPC-RM-067-01 8.85 0.30 0.4425
Total of filled (Not including solvent)
3 000.00 100 150.00
8. Procedure:
8.1The selected validation approach is prospective validation.
• First three consecutive batches of CEFAKID GRANULES are
manufactured as per the authorized BMR no. 50.C45/M01/03 (for
manufacturing process), the authorized BPR no. 50.C45/P01/03 (for
packaging process) and it is performed validation as per specifications in
protocol.
• QA staff will do the sampling as per given sampling plan. The
samplings will be identified i.e. batch number, stage, the number of sample,
locations and sampling as per the sampling plan (refer section 11).
• The samples will be analyzed by IPC/ QC as per approved testing
method and approved specification.
• Packaging will only be done when capsules comply with all the tests by
QC.
• After satisfactory analytical results, BMR and BPR will be approved by
QA.
• Test results and data generated during the process validation studies
will be complied and reviewed at each stage of manufacturing and defined
process parameters.
8.2The trials will include upper and lower processing conditions that will be encountered
normally in the routine production.

8.3These trials may include worst case conditions but not necessarily simulate the
failure range of the product processing conditions.
8.4A summary report will be prepared on the effect of different variables and final
conclusion will be drawn on the effect of different variables on the processing of
the product.
8.5Manufacturing process and sampling for validation is performed as per the follow
chart
Page 10 / 21
8.6Manufacturing process description
Flow of manufacturing process
• Dispensing
In this stage, dispensing will be carried out as per the BMR and SOP 120003
after line-clearance given by IPC person. Before dispensing, all the
requirement materials with approved status will be verified by IPC, production,
warehouse person.
Dispensed raw materials and intermediate product are transferred to
respective process areas as per material movement plan as per SOP 120003.
• Weighing and Checking
The weight of the materials received from dispensing area will be checked by
IPC, production person against the dispensing labels as per SOP 120003.
• Sifting (all dispensed materials)
Sift Aspartam and sugar, manitol 60 through 24 mesh sieve and contain it in
PE bags
Sift Cephalexin monohydrate through 14 mesh sieve and contain it in PE bags
Check the integrity of sieve before and after use: clean and integrity
• Formulation of paste solution
Pour 10.20 kg 96% ethanol into tank of the stirring mixer. Add PVP K29-32
slowly when stirring.
Stir until the viscous solution become transparent. Stir and put slowly
Quinoline yellow lake mixture, stir until the viscous mixture become yellow.

Stirring time: 10 - 20 minutes.
• High speed mixing
Add sifted-materials in turn to machine: refined sugar, Mannitol 60, Cephalexin
monohydrate, Aspartam. Mix time: 2 + 1 minutes at speed of 1 400 rpm.
After pour slowly paste solution in bowl of high speed mixer. Mix time: 2 + 1
minutes at speed of 1 400 rpm.
• Wet granulating machine
Transfer granules to wet granulating machine. Check the integrity of sieve
2mm after use: integrity.
• Tray dryer
Put stainless steel trays with granules into drying chamber.
Remove ethanol: To install supply fan and exhaust fan at speed of 1400 rpm.
Drying time : 15 minutes.
The 1st drying: To install supply fan and exhaust fan at speed of 1400 rpm.
Drying time : 15 minutes. drying temperature: 32 – 42oC
The 2st drying: To install supply fan and exhaust fan at speed of 1400 rpm.
Drying time : 50-60 minutes. drying temperature: 50-60oC
Cooling: To install supply fan and exhaust fan at speed of 1400 rpm. Cooling
time: 10 minites
• Sizing
Put granules through 10 mesh sieve of machine, collect into separate
containers.
Check the integrity of sieve after use: integrity.
• Final mixing
Add in the order: dried granules of lot 1, Apple powder flavour, dried granules
of lot 2 into bowl of the Cubic mixer. Mixing speed: 25 rpm. Mixing time: 4
phút/ minutes
• Sachet packing
Using vertical sachet packing machine, adjust parameters of machine to meet
stipulated specifications

Before start up of the sachet packing operation, verify and record the
temperature (18 – 25
o
C) and relative humidity (NMT 55%).
8.7Critical process step
• Critical process control variables at each critical manufacturing step and
measured parameters are as follows:
S.
No.
Process
steps
Process
parameter
setting
Rationale Testing
1
Raw material
and packaging
material
NA
Raw material and
packaging material
used are supplied by
approved vendors and
released by QC
NA
2
Dispensing of
raw material
Weighing

operations are
persormed using
calibrated
balances as per
current SOP
Process does not have
variable effects on the
product quality when
defined operating
procedure is followed.
This is performed
according to SOP and
BMR
NA
3
Sifting of raw
materials
Check for any
lumps/ foreign
matter after sifting
Visually check for
the intactness of
sieve before and
after use
Process involves
breaking of
agglomerates and
removal of foreign
materials if any from the
active or excipients.

Sieve integrity
before and after
sifting
4
High speed
mixing
Time and RPM
To demonstrate the
blend uniformity with
binder solusion
Appearance
5 Final mixing
Mixing time and
mixing speed
To demonstrate the
blend uniformity on
completion of
lubrication
Mixing time
Mixing speed
Appearance
Moisture/ Water
content
Distribution
granule size
Bulk/ Tape density
Blend uniformity
S.
No.
Process

steps
Process
parameter
setting
Rationale Testing
6
Sachet
packing
Speed, Vertical
bar temperature,
horizontal bar
temperature,
Glue-pressed
temperature
To demonstrate the
characterization of the
machine parameters
Speed, Vertical
bar temperature,
horizontal bar
temperature,
Glue-pressed
temperature
Appearance
Average mass of
20 empty sachets
Average mass of
granules per
sachet
Average mass of

1 filled sachet
Average mass
Length
Leak test
Identification
Uniformity of
mass
Uniformity of
content
Water content
Dissolution
Assay
9. Sampling Plan:
The sampling plan is defined for a batch as per table below:
9.1 Stage of Final mixing (Granules)
• In-process control:
S. No. Test Item Time Q’ty / sample
Number of
samples
Sampling points
Testing
procedure
1.
Appearance
After completion of
final mixing
60 gram for
each sample
05 As per the figure 1 SOP 020018
2.

Moisture content (LOD)
3.
Bulk/ Tape density
Figure 1: Sampling points
• For QC testing:
S. No. Test Item Time Q’ty / sample No. of Sampling points Testing procedure
Granules level
1
2
5
4
3
samples
1. Distribution granule size
At 4 minutes of final
mixing process
50 gram for each
sample, in triplicate
05 As per the figure 1 STP-010028
2. Appearance
At 4 minutes of final
mixing process
10 gram for each
sample in triplicate
10 As per the figure 2 SPC-IP-062-01
3. Water content
4. Identification
5. Blend uniformity
Figure 2: Sampling points
9.2 Stage of sachet packing

• Done by IPC:
S. No. Test Item Time/ Frequency Sample Q’ty Testing procedure Remarks
1. Appearance During sachet filling stage NA SOP 020018 NA
Granules level
1
2
3
8
9
10
4
5
6
7
BMR No.: 50.C45/P01/03
2.
Uniformity of mass Once 2 hours, start of working day
10 filled
sachets
3.
Sachet length
Starting, middle, end of batch
process stage, start of working
day, or unschedule (if any)
10 filled
sachets
4.
Leak test
Once two hours, start of working
day, whenever change new alu roll

or unschedule (if any)
4 filled sachets
• Done by Production:
S. No. Test Iterm Time/ Frequency Sample Q’ty Testing procedure Remarks
1.
Appearance Every 2 hours
20 filled
sachets
BMR No.: 50.C45/P01/03 NA
2.
Uniformity of mass Every 1 hour
20 filled
sachets
3.
Average mass Every 15 minutes
10 filled
sachets
• For QC testing
S. No. Test Item Time/ Frequency Sample Q’ty
Testing
procedure
Remarks
1.
Characters
Start, middle and end of the stage 40 filled
sachets for
each stage, in
triplicate
SPC-BP-013-01 Three consecutive validation
batches only

2. Identification
3.
Uniformity of mass
4.
Water
5.
Dissolution
6.
Uniformity of content
7.
Assay
10. Acceptance Criteria:
Each validation batch must meet the specifications of CEFAKID GRANULES.
S.
No.
Mfg. Process
Steps
Test Item Acceptance Criteria
1
Final mixing
(Granules)
Appearance
Identical light – yellow granules, no dark spots
and strange coloured trace
Moisture content (LOD) 0.7% - 1.4%
Bulk/ Tape density For information testing
Distribution granule size For information testing
Water content 0.7% - 1.4%
Identification
In the assay, the chromatogram obtained with

test solution shows a peak with the same
retention time as the principal peak in the
chromatogram obtained with reference
solution.
Blend uniformity
• 8.3% (w/w) ± 10.0%; RSD ≤
5.0%
• 90.0% - 110.0%; RSD ≤ 5.0%
2 Sachet packing
Appearance
Rectangle sachet of 3 g, containing spongy
granules, light yellow, dry, not clumping, sweet
flavour.
Uniformity of mass
Average mass of 1 filled sachet ± 5%
Length 72.00 – 75.00 mm
Leak test
Perform for 4 sachets at pressure – 400
mmHg in 10 minutes
Average mass
Average mass of 1 filled sachet ± 1.5%
Identification
In the assay, the chromatogram obtained with
test solution shows a peak with the same
retention time as the principal peak in the
chromatogram obtained with reference
solution.
Uniformity of mass
± 7.5% compared with average mass of
granules.

Water Not more than 5.0%
Dissolution Meet the requirement.
Uniformity of content
• 85 percent to 115 percent of the
average content
• RSD ≤ 5.0%
Assay
Content of Cephalexin (C
16
H
17
N
3
O
4
S) is not
less than 90.0% and not more than 110.0% of
the labelled amount, calculated on average
mass of granules.
• Expanded testing on three batches of CEFAKID GRANULES should
demonstrate reproducible results for the process to be considered
validated.
• Acceptable results on each of the three consecutive batches are needed to
satisfy the validation requirements.
Page 20 / 21
• If possible, control charts for quantitative validation tests will be analysed for
trends and to show satisfactory process control.
• Batches may be dropped from the validation study only if events not related to
the process (e.g. mechanical failure) cause a change in the process. Such
occurrences must be fully documented.

11. Re-Validation:
11.1Process validation will be revalidated, if there is:
• Changes location or site.
• Changes in formula, manufacturing process, source/ specifications of raw
materials/ packing materials, product specification or process control
parameters.
• Changes in sampling plans.
• Changes in equipments, including their location/ critical parts, specifications
and/ or process control parameters in utilities, directly affecting product
quality.
• Changes in approach to validation/ qualification of analytical method, process
validation.
11.2If change in batch size, additional protocol/ addendum shall be prepared, approved
and executed through change control/ deviation procedure.
12.References:
• BMR (50.C45/M01/03) and BPR (50.C45/P01/03) of CEFAKID GRANULES
• SOP 010002 – Change control
• SOP 010011 - Quality Risk Management (QRM)
• SOP 020009 - Instruction for test the disintegration
• SOP 020016 - Instruction for usage of leak-test apparatus
• SOP 020018 - In-process control on manufacturing of betalactam non-sterile
products
• SOP 120003 - Dispensing of raw materials and packing materials of non
sterile betalactam
• SPC-IP-062-02 – Finished granules of CEFAKID GRANULES (process
validation)
• SPC-BP-013-01 – Bulk product of CEFAKID granules
• STP-01014 – Determination of water with Karl Fischer reagent
• STP-01028-Particle-size distribution estimation by analytical sieving
• STP-01003- Test for uniformity of content of single-dose preparations

• STP-01019 – Thin – layer chromatography.
• STP-01001 – Test for uniformity of mass of single-dose preparations
• Validation Master Plan
Page 21 / 21