Process Validation Protocol of

Ciprofloxacin Tablets（500mg）

（500mg）
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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1. Protocol Approval:

Signing of this approval page of Process Validation Protocol No. ……………1 indicates
agreement with the Process Validation approach described in this document. Any
modifications to the Process Validation will be prepared and approved as an addendum.

Process validation protocol prepared by

Department Name Signature Date

Process validation protocol approved by

Department Name Signature Date

Production dept.

Quality Assurance

Engineering dept.
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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The List of Validation Team

Name Department Position

2. Objective:

The objective of this protocol is to define the tests, procedures and acceptance criteria that are important
to establish documented evidence which provides a high degree of assurance that the manufacturing
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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process chosen for Ciprofloxacin Tablet （ 500mg ） will consistently produce a product meeting its
predetermined specifications and quality characteristics. This will establish the:

 Control variables to be monitored for routine production batches

 In process and finished product specification

 % yield at critical stages of manufacturing process

Suitability of equipments / area and operators

3. Scope:

This protocol shall be applicable for first three consecutive commercial scale batches
manufactured with specific batch size & equipments and operating parameters for the
Tablet.
4. Validation Approach:
The validation approach shall be prospective and following things shall be reviewed:

a. Review the qualification documents of equipments and related utility

systems which shall be employed for the manufacturing of batch.
b. Review the calibration record of instruments used in validation.
c. Review the master formula records.
d. Review the specification and analytical procedures of raw materials and
packing materials.
e. Review the specification and analytical procedures for in-process &
finished products.
5. Reason for Validation:
New product in the manufacturing facility
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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6. Revalidation:

Revalidation shall be done in case of following cases:

a. Any major change in the manufacturing process which may affect the
quality of the product.
b. Any change in the batch size
c. Any change in the batch formula
d. Change in manufacturing site
e. Any modification in any critical equipment
f. Any major modification in the related utility system
g. Any change in the specification and/or change in the source of active
pharmaceutical ingredient (API)
h. Any change in primary packaging material.

7. Responsibilities:

a. Quality Assurance shall be responsible for:

i. Of the data compiled, review of deviations (if any), monitoring the process as per
the process parameters and for withdrawal of validation samples.
ii. Review of facility, equipment
iii. Report, review and its approval.
b. Production shall be responsible for:
i. To execute the batches as per the batch production record and process validation
protocol. qualification and utility validation reports.
ii. cGMP compliance during manufacturing process, review and evaluation of the
data/results generated during validation process.
iii. Preparation, approval and training of validation protocol, review
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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iv. Preparation of process validation summary

v. Compilation of data related to manufacturing area and furnishing the same for
review.
vi. Review of protocol and summary report.
c. Quality Control shall be responsible for:
i. Raw material and packing material analysis
ii. In process and finished product samples analysis as per the sampling plan.
iii. Collection and review of in process and finished product analysis data.
iv. Submission of data /results to QA for review and evaluation.
d. R&D shall be responsible for
i. It is the responsibility of R and D to prepare validation protocols and identify
critical process parameters
ii. Participate in the validation process as a team member

8. Reference Documents:

SOP name File Version number Effective date Conform or not

Yes□No□

Yes□No□

Yes□No□

Yes□No□

Yes□No□

Yes□No□
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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SOP name File Version number Effective date Conform or not

Yes□No□

Yes□No□

Yes□No□

Yes□No□

Yes□No□

Yes□No□

Yes□No□
Conclusion：

Checked by： Date：________________

Reviewed by： Date：_______________

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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9. The Process Flowchart of Ciprofloxacin Tablet（500mg）

Raw Material

Crushing & Sieving

Weighing & Dispensing

Starch
Granulating

Drying

Microcrystalline cellulose PH102 、

Milling Magnesium stearate 、 Sodium
carboxymethyl starch 、 Silicon
Dioxide
Intermediates Inspection
Batch Blending

Intermediates Inspection Tablet Pressing

Thin film coating

powder
Coating 薄膜包衣粉
Intermediates Inspection

Aluminum Foil
Blister Packaging
& PVC

External Package
Material 料
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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External Packaging
Finished Product Inspection

Finished Product Release Grade D area

9.1 Process Description

Overview
Tablet production takes place in OSD line. The manufacturing process consists of wet
granulation of the active ingredient with diluent using a binder solution. The excipients are
added subsequently. Then the wet granules are transfer to a fluidized bed dryer for drying
which will be milled and sieved for dry blending operation. The dried granules are
transferred to a tumbler mixer where all the reaming ingredients are to be added. The
lubricated granules are then transferred to a compression cubicles where tablet are
compressed with their appropriate dyes and punch set. During compression, tablet will be
inspected for their appearance, weight, disintegration, friability and hardness. The
compressed tablet are then to be film coated and transferred to a coating department
where. Finally, they’re packed into boxes, together with packaging leaflet, marked with the
batch number and expiry date, as detailed in the below Process

S/N Process Description

1 Weighing APIs and Excipients should be tested according to its specifications,
and only approved materials can enter weighing rooms. Weighing is
performed in a separated area under Laminar Air Flow (LAF) with
Class D background.
2 Binder Solution Disperse to dissolve the require amount of the binder
Preparation
3 Granulation Add binder solution slowly to the dry mix in RMG with appropriate
impeller and chopper speed until to get desired granules.
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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4 Filtration The solution is filtered through a 0,22 µm filter (filter sterilization)

when leaving the reactor towards the filling machine. This filter should
be integrity testes before and after each usage.
5 Drying and Dry wet mass at inlet temperature 50oC ± 10oC till desired LOD is achieved.
sizing Sift the dried granules through #20 S.S. sieves. Mill the retentions through
multimill using 1.5 mm screen at low speed. Repeat the cycle until to ensure that
whole granules passed through #20 S.S. sieve.
6 Dry blending Add the require amount of excipient ……… and finally lubricate the granule
and lubrication
7 Compression Before compression of the mixed constituents, the production
pharmacist/ section head assures the proper set-up of the tablet
compression machine and toolings. Following is compression of
ingredients using 16.4x8mm oval shape punches and dies. At this
stage, in-process quality control tests are diligently performed for the
following parameters.
1. Weight and appearance of tablet
2. Friability
3. thickness
4. Disintegration time

8 Coating Prepare the required amount of film coating polymer, plasticizer and
the solvent. Then Film coat the tablet using a perforated pan coated
9 Labelling Labelling is performed manually that imprints the batch number and
expiry date on the label.
The parameters that can influence the labelling process are:
Label – The correctness of the label placement is essential to the
identification of the product, influencing its quality.
Batch & Expiry date printing – The correctness of the printing will
allow the correct traceability of the batch.
10 Packaging Packaging is performed manually by placing the ampoules in boxes
which is re enforced with a nest to accommodate the ampoules. The
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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box is printed with batch details and patient information leaflet is

inserted inside.

9.1. Quality Risk Assessment

The FMEA method was used to perform the qualitative risk assessment, which could
identify the Critical quality Attributes (CQAs) that have the greatest chance of causing
product failure, i.e., not meeting the QTPP (Quality Target Product Profile). The first step
in the risk assessment was to systematically gather up all the possible factors that could
influence product quality. To identify these factors, we reviewed the literature, our past
experiences, and data collected during the initial formulation development studies
described above. These factors were organized hierarchically using an Ishikawa or
“fishbone” diagram The parameters outlined in the Ishikawa chart aided in the
identification of the failure modes (i.e., the ways or modes by which a system, process
step, or piece of equipment might fail).

Using FMEA, the modes of failure can be prioritized for risk management purposes
according to the seriousness of their consequences (effects), how frequently they occur and
how easily they can be detected. From this information, the variables (CQAs) that need to
be further studied and controlled can be identified.

Applying the failure mode effect analysis to identify potential failure modes, and score for
the risk severity (SEV), occurrence probability (OCC), and detection probability (DET) on
a 10-point scale, that is to say, score from the lowest point to the highest point from
1,2,3,4,5,6,7,8,9 to10 points, as shown in Table 1, Table 2 and Table 3.
Table 1: Risk Severity (SEV) Scoring System (10-Point Scale)

Result The severity of the result Score

The failure mode that happens with or without warning, affects the
Critical safety of operators and machines or violates relevant laws and
regulations, and their severity. 9.-10
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Cause great damage to the production line, and may result in partial or
total scrapping of the product, failure of the main function or
High
degraded work of the product or system, and customer dissatisfaction 7.-8
(including the subsequent operation and the end user).
。
Cause small damage to the production line, and may result in
Medium scrapping of some products (without the need to pick out) or rework
of 100% products. Make customers feel inconvenient or dissatisfied. 5.-6

Cause small damage to the production line, and may require picking
Low out of the products, and reworking of some products. Half to most of
customers can detect these defects. 3.-4
。
Cause minor damage to the production line, and reworking of some
products. However, few customers can detect the defect or the defect
Minor
will not influence the products. Customers can hardly detect the 1.-2
defect.

Table 2: Risk Occurrence Probability (OCC) Scoring System (10-point Scale)

The
occurrence
The occurrence possibility of failure Examples Score
probability of
failure

Very high: nearly impossible to

Occur very frequently
avoid failure ≥1/3 9.-10

High: failure occurs repeatedly Occur every day

≥1/20 7.-8

Medium: failure occurs occasionally ≥1/2000 Occur monthly 5.-6

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Occurs every few

Low: failure occurs rarely
≥1/10000 months 3.-4

Extremely minor: failures nearly Only occurred once

≤1/150000 1.-2

Table 3: Risk Detection Possibility (DET) Scoring System (10-point Scale)

Detection The possibility of detecting defects by process control before

Score
Possibility they occur.

Extremely There is no effective method at all or current method is nearly

impossible impossible to detect any failure mode
or minor 9.-10

Low Failure modes are less likely to be detected with the current
possibility method. 7.-8

Medium Failure modes are moderately likely to be detected with the

possibility current method. 5.-6

High Failure modes are highly likely to be detected with the current
possibility method. 3.-4

Very high Failure modes are extremely likely to be or can certainly be 1.-2
possibility or detected with the current method, and the detection method is
almost reliable.
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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certainly 。

The risk assessment formula is:

RPN (Risk Priority Number (risk level)) = S × O × D.

When the RPN value is higher than 60, the process are considered critical and
corresponding measures must be adopted.

Table: 4 Quality risk analysis of Tablet manufacturing operations with respect to patient
risk by failure mode effects analysis

Potential
Failure Impact of cause or Detection or
Unit OP S O D RPN
mode change route of control method
failure
Dry mixing Poor
CU 5 1 Yes 1 5
time monitoring
Wet Mixing Hardness, Operator’s
5 1 Yes 1 5
Wet time dissolution error
Granulation Operator’s
CU,
error
RMG rpm Hardness, 5 Yes 1 5
equipment
dissolution
failure
Operator’s
Poor granule error
FBD drying Drying time 5 2 Yes 2 20
quality equipment
failure
Drying Poor granule 5 Operator’s 2 Yes 2 20
temperature quality error
equipment
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Potential
Failure Impact of cause or Detection or
Unit OP S O D RPN
mode change route of control method
failure
failure
Particle size,
Milling Operator’s
Milling hardness, 5 5 Yes / Carr index 1 25
speed error
flow problem
Blending Poor
CU 5 3 NIR 4 60
time monitoring
Operator’s
Blender error,
Blending CU 5 3 NIR 1 15
speed equipment
failure
Poor air
Humidity CU 3 1 NIR/hygrometer 1 3
handling
CU and Poor air
Humidity 3 3 Hygrometer 3 27
hardness handling
Disintegration,
Compressio Hardness, Poor
3 3 dissolution, 3 27
n force dissolution granulations
Tableting hardness tester
Operator’s
Compressio error,
CU 5 5 NIR/HPLC 4 100
n speed equipment
failure
Operator
Disintegration,
Dissolution, error, poor
Hopper level 5 5 dissolution, 5 125
hardness developmen
hardness tester
t
Poor
Vendor Disintegration,
Dissolution, developmen
Raw Material grade 4 5 dissolution, 4 80
hardness t, operator
differences hardness tester
error
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Potential
Failure Impact of cause or Detection or
Unit OP S O D RPN
mode change route of control method
failure
Different Physical Physical Visual
4 3 3 36
sources properties variation inspection
CU,
Material Malvern/
Particle size dissolution, 5 3 4 60
variation hardness tester
hardness

10.Product Details:

Product Name

Generic Name
Shelf life
Storage condition
Label claim

Overage (if any)

Batch size
Packing instruction

a. Raw Materials Detail

S/N In-Put Description Quantity per Quantity per Batches

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ampoule

b. Packing Material Detail

S/N Description

1 Type I ampoule
2 Label
3 Primary box
4 Leaflet
5 Transport cartoon

10.1. Confirmation of Major Raw Materials and its Suppliers

The raw material and packing materials suppliers should be form approved suppliers list
a. . Raw Materials
Name of raw Material Approved by QA or
Item code suppliers Materials
materials grade not

Yes□No□
Yes□No□
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Name of raw Material Approved by QA or

Item code suppliers Materials
materials grade not

Yes□No□
Yes□No□
Yes□No□
Yes□No□
Deviation Description and disposal

Criteria: All Raw materials suppliers must be listed in the approved vendors list
Conclusion：

Checked by： Date：_____________________

Reviewed by： Date：_____________________
b. Packaging Materials
Name of packing materials Item code Name of supplier Approved by QA or not

Pvc/pvdc
Yes□ No□

Aluminum foil Yes□ No□

Label
Yes□ No□
Leaflet
Yes□ No□
Box
Yes□ No□
Carton
Yes□ No□

Deviation Description and

disposal:

Conclusion：
Checked by： Date：__________________
Reviewed by： Date：__________________
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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10.2. Quality confirmation of each raw materials used for validation

a. The Confirmation of Raw Materials

The testing result must comply with the quality standard of raw materials.

Name of Raw Quality Testing

Supplier Conform or not
Materials Standard QCR No. Result
batch No.

Yes□ No□
Yes□ No□
Yes□ No□
Yes□ No□
Yes□ No□
Yes□ No□
Conclusion：

Checked b： Date：___________________
Reviewed by： Date：___________________

c. Packing Materials.
The testing result must comply with the quality standard of packing materials.

Name of packing materials Item code Name of supplier Approved by QA or not

Pvc/pvdc
Yes□No□

Aluminum foil

Label
Yes□No□
Leaflet
Yes□No□
Box
Yes□No□
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Name of packing materials Item code Name of supplier Approved by QA or not

Carton
Yes□No□

Deviation Description and

disposal:

Conclusion：
Checked by Date：___________________
Reviewed by： Date：___________________

11. Qualification of Production Equipment and Measuring Apparatus

11.1. Production Equipment

Prior to validation ensure that the performance of all production equipment meet the
requirements of production process which can make the manufacturing operation system
effectively implemented.

Equipment Equipme Applying Date of check Confirmation

Conform or not
Name nt No. station & approval Report No.

Dust-free yes □no □

IQ：
Pulverization & yes □no □
feeding OQ：
yes □no □
integrated PQ：
machine
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Equipment Equipme Applying Date of check Confirmation

Conform or not
Name nt No. station & approval Report No.

Wet type IQ： yes □no □

granulator OQ： yes □no □
PQ： yes □no □

IQ： yes □no □

OQ： yes □no □
PQ： yes □no □

Fluid bed dryer

IQ： yes □no □

OQ： yes □no □
PQ： yes □no □

Double-cone IQ： yes □no □

blender OQ： yes □no □
PQ： yes □no □
IQ： yes □no □
tablet press
OQ： yes □no □
PQ： yes □no □

perforated IQ： yes □no □

coating machine OQ： yes □no □
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Equipment Equipme Applying Date of check Confirmation

Conform or not
Name nt No. station & approval Report No.

PQ： yes □no □

Blister IQ： yes □no □

packaging
machine OQ： yes □no □
PQ： yes □no □

Box packaging IQ： yes □no □

machine OQ： yes □no □
PQ： yes □no □

11.2. Calibration of Measuring Devices

Before process validation, confirmed that all the measuring apparatus have been calibrated and in their
valid period, and the performance of all measuring apparatus should meet the requirements of
production process which can make the manufacturing operation system effectively implemented.

Equipment Apparatus Applying Cal. Due Cal. Certificate

Cal. Date Conform or not
Name No. Station Date No.\

Digital yes□no□
weighing
yes□no□
Scale
yes□no□

Temperature yes□no□
Sensor
yes□no□

yes□no□
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Equipment Apparatus Applying Cal. Due Cal. Certificate

Cal. Date Conform or not
Name No. Station Date No.\

yes□no□

Conclusion:

Checked by： Date：

Reviewed by： Date：

12. The Confirmation of utility system Validation

Prior to the process validation, conform the validation of the production environment and public system
and conform whether to comply with the requirements.

Approval
Report No. Conform or not
Validated Items Date

HVAC validation yes□no□

PW system validation yes□no□

The validation of air compression system yes□no□

The cleaning and disinfecting effect of yes□no□

protective garments

The cleaning effect of containers yes□no□

The cleaning effect of sanitary fittings yes□no□

The way of entering clean area for men yes□no□

 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Deviation Description and disposal:

Conclusion:

Checked by： Date：

Reviewed by： Date

13. The Confirmation of Training

Prior to the process validation, train the operators, managers and the QC personnel about the operating
practice and GMP management document, and assess the effectiveness of training.

Training Contents Trainee File Version No. Pass Rate(%)

The SOP of weigh and

preparation station

The SOP of pulverization and

sieving station

The SOP of granulation and

drying station

The SOP of blending station

The SOP of tableting station

The SOP of coating station

The SOP of blister packaging

station
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Training Contents Trainee File Version No. Pass Rate(%)

The SOP of external packaging

station

The SOP of dust-free

pulverization & feeding integrated
machine

The SOP of lifter

The SOP of wet type granulator

The SOP of fluid bed dryer

The SOP of rotary milling

machine

The SOP of double-cone blender

The SOP of tablet press

The SOP of perforated coating

machine

The SOP of blister packaging

machine

The clean SOP of lifter

The clean SOP of wet type

granulator

The clean SOP of fluid bed dryer

The clean SOP of rotary milling

machine

The inspection SOP of the

intermediates of Ciprofloxacin
Tablet（500mg）
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Training Contents Trainee File Version No. Pass Rate(%)

The inspection SOP of the

finished products of Ciprofloxacin
Tablet（500mg）

The quality standard of the

intermediates of Ciprofloxacin
Tablet（500mg）

The quality standard of the

finished products of Ciprofloxacin
Tablet（500mg）

The process planning of

Ciprofloxacin Tablet（500mg）

The validation scheme of the

process of Ciprofloxacin
Tablet（500mg）

*Remark Pass rate (%) refers that all trainee must pass the training test by 100% mark

Conclusion:

Checked by Date：：

Reviewed by： Date：：

13. The Process Validation

13.1. Major Equipment Used for Validation the in the Process of Production

Serial Equipment Equipme Equipment Capacity Qty. Confirmation Result

Number Name nt No. Specification
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Electronic 1000kg
1 1
Balance 100kg

Wet Type
2 Granulator 1

Fluid bed
3 1 1. cleaned or
dryer
not, cleaned
Rotary
4 milling 1 2.The OQ of
machine equipment
includes:
blender
5 Double- 1 3.the
cone calibration
qualification
of equipment
6 Tablet Press 1 includes:

Coating
7 machine 1

Blister
8 packaging 1
machine

Conclusion:

Checked by：： Date：

Reviewed by：： Date：

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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13. 2. The Process Validation

Process parameters and quality standard of all stations, including weighing, preparation, crushing,
sieving , granulation, drying, blending, tableting, coating, blister packaging and the external packaging
will be evaluated . The control parameters of key process should be marked out by the bold italics with
under lines.

13.2.1. Sifting & Sieving Station

13.2.1.1. Acceptance Criteria for sifting and sieving

11.2.1.1.2. The quality conformation of sifting & sieving

The test data of validated batches shall comply with the requirements of control standard.

Controlled Items

Batch Samples
No. No. Conclusion
Appearance Yield of
Foreign Matter
Granulation

1#

2#

3#

1#

2#

3#

1#

2#

3#

Deviation description and disposal:

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Conclusion:

Collected by： Date：

Reviewed by： Date：

11.2.2. Weighing & Dispensing Station

11.2.2.1 Weighing

The whole weighing process should be confirmed.。

Weighing data Reviewed data

Name of Raw Supplier QCR No.
Batch No. Batch Qty.
Materials Batch No. container Material Material
Weight container
net net
Weight
weight weight

Ciprofloxacin
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Weighing data Reviewed data

Name of Raw Supplier QCR No.
Batch No. Batch Qty.
Materials Batch No. container Material Material
Weight container
net net
Weight
weight weight

xxxxxxxx
xxxxxxxxxx

Silicon Dioxide

Magnesium
stearate

Reviewed by
Weighed by
Reviewed by
Weighed by

Deviation Description and

disposal:

13.2.2.2 Quality of raw materials

The quality of raw materials should be confirmed before weighing process.

Name of Raw
Assay Moisture
Materials
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Ciprofloxacin

xxxxxxxx
xxxxxxxxxx

xxxxxxxxx

xxxxxxxx

Silicon Dioxide

Magnesium stearate

Conclusion:

Collected by Date：

Reviewed by： Date：

13.2.3. Granulation & FBD Drying

13.2.3.1. Process parameters and products quality in the granulation station

11.2.3.2.1. The confirmation of control of process parameters

Control Parameters Control Standard Batch No. Deviate or not

Drying Time 5min yes□no□

 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Dry-mixed time

Wet mixing time 3min yes□no□

Total Granulation yes□no□

8min
Time

Impeller Speed 50～145r/min yes□no□

Chopper Speed 切 1000～2000 r/min yes□no□

FBD Drying Inlet yes□no□

60-70℃
Temperature

FBD drying Outlet yes□no□

Temperature

Drying Time yes□no□

50min

Mesh number of yes□no□

sieve 20 meshes

Deviation description and disposal:

Conclusion:

Collected by： Date：

Reviewed by： Date：

13.2.3.2.2. Granulation Process parameters/ Process Acceptance criteria

Controlled Items Control Standard

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Moisture ≤2%

Yield of Granulation 94%≤Yield≤102%

13.2.3.2.3. The quality confirmation of granulation and drying

The test data of validated batches meet the requirements with the range of control standard

Batch Controlled Items

Samples No. Conclusion
No. Moisture Yield of Granulation

1#

2#

3#

1#

2#

3#

1#

2#

3#

Deviation description and disposal:

Conclusion:

Collected by Date：

Reviewed by：： Date：

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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13.2.1. Critical Process Sampling plan, test parameters, acceptance limits

13.2.1.1Blend sampling
13.2. 1.1. Sampling method
Blend uniformity samples should be taken directly from the blender just before unloading the blend. If it
is not possible to perform sampling from blend then sample may be taken from the container after
unloading. Two samples should be taken from each sampling location. Thieving method or ('thief')
samplers is used. The method relies on dipping a 316 stainless steel road in the blend and retrieves a
powder amount as stipulated in the sampling plan by using a capturing device which comprises three
separate sample chambers. The sample chamber(s) can be opened and closed by an operator via controls
at the top end of the device as shown in the figure below.

13.2.1.2. Sampling Plan Diagram

Using a Double Cone Blender , blend for 20, 25 and 30 minutes and collect the sample
from 10 locations as shown in the figure. The sample size after 3 minutes lubrication shall
be between 90.25mg to 99.75mg. All samples shall be collected in PE bags. Collect
samples in two sets. One set of sample is taken for analysis and other set is kept as a
reserve sample. In case of failure results of one set use the reserve sample set for analysis,
otherwise, discard the reserved sample set.
Double cone blender sampling location:
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Left Middle Right

Top Top Top
Center Center-Top Center
Bottom Center-Bottom Bottom
Bottom

Table: Acceptance criteria for critical in process controls and sampling plan:

Testes Approximate
Critical Process Sampling To be sample
Process variables frequencies performed size Acceptance criteria
Mixing Blending 20,25& 30 uniformity 3X10 samples 100±15% RSD NMT 5%
time min of content and at each time
RSD interval 90.25
mg to 99.75mg
in poly bag
Compression At three At different Description 20 Tablets White to off white
different speeds Colored round uncoated

machine biconvex tablet plain surface

speed on both sides.

Weight 40 Tablets RSD nmt 5%
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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variation
Hardness 6 Tablets As per FPP specifications
Thickness 40 Tablets As per FPP specifications
Disintegration As per FPP specifications
time 6 Tablets
Friability 20 Tablets As per FPP specifications
Dissolution 3x12 Tablets RSD nmt 5%

Content RSD nmt 5%

Hopper Full hopper Weight RSD nmt 5%

study at approximately variation 40 Tablets

maximum middle hopper Hardness 6 Tablets As per FPP specifications

speed and near end Thickness 40 Tablets As per FPP specifications

hopper Disintegration As per FPP specifications
time 6 Tablets
Friability 20 Tablets As per FPP specifications
Dissolution 3x12 Tablets RSD nmt 5%
Content RSD nmt 5%
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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13.2.4. Dry Blending Validation

13.2.4.1. The confirmation of dispensed material amount for dry blending

Dispensed
Batch No. Name of Raw Materials Standard Qty. Deviate or not
Qty. Incoming No.
（kg）

xxxxxxxxxxxxxx yes□no□

xxxxxxxxxxxxx yes□no□

Silicon Dioxide yes□no□

Magnesium stearate yes□no□

xxxxxxxxxxxxxx yes□no□

yes□no□
xxxxxxxxxxxxx

Silicon Dioxide yes□no□

Magnesium stearate yes□no□

xxxxxxxxxxxxxx yes□no□

xxxxxxxxxxxxx yes□no□

Silicon Dioxide yes□no□

Magnesium stearate yes□no□

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Dispensed
Batch No. Name of Raw Materials Standard Qty. Deviate or not
Qty. Incoming No.
（kg）

xxxxxxxxxxxxxx yes□no□

xxxxxxxxxxxxx yes□no□

Silicon Dioxide yes□no□

Deviation description and disposal:

Conclusion:

Collected by： Date：

Reviewed by： Date：

13.2.4.2. The confirmation of process parameters and quality standard of blending

13.2.4.2.1. The confirmation of Control of process parameters

Control parameters Control standard Batch No. Deviate or not

Blending rate yes□no□

20min yes□no□
Blending time
25 min yes□no□

30 min yes□no□

Deviation description and disposal:

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Conclusion:

Collected by Date：

Reviewed by： Date：

13.2.4.2. Mixing Validation Record

1. Product Detail

Batch no Batch size Mfg date Exp date

2. Equipment Detail

Equipment name ID Capacity Calibration

Double cone Blender Calibrated for
volume

3. Critical Process Controls Checks & Acceptance Limits

a. Mixing time
b. Uniformity of content (95- 105% and RSD ( ≤5%)
c. Powder micromeritics
 Bulk density ,sieve analysis,
 Compressibility index,
 water content (LOD),
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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4. Observation
Table 1: The content uniformity results of xxxxxxxx in the blend after 20, 25 and 30
minutes of blending Batches batch no. ……….., ………….& ….

Samplin % of …………………… using USP HPLC method

g Batch no Batch No.1 Batch No.2 Batch No.2

Locatio Blending 20 30mi 20 30mi

20 min 25min 30min 25min 25min
ns time min n min n

Left Top
Center
Bottom
Top
Center-
Top
Middle
Center-
Bottom
Bottom
Top
Right Center
Bottom
Composite
Avg.
SDV
RSD (≤5%)
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Table 2: The physical parameters of the blend for three batches are as follows
Parameters Batch 1 Batch 3 Batch 3
W Wt. Wt. Wt. Wt. Wt. Wt. Wt.
t. Cumula (gm) retai Cumulative (gm) retain Cumulative
Sieve Wt.
( tive ned ed
Aperture retai
g O- U- O- U- O- U-
(mm ned
m siz siz size size size size

) e e
2000
Particle size
850
distribution
600
425
250
180
150
125
Receiver
Bulk volume of
granules
( VBulk ) of 100 g
(ml)
Tapped volume
of granules
( VTapped) of
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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100g(ml)
Bulk density

Tapped density

Compressibility
index
(Carr's Index)
LOD

5. Meet acceptance criteria :YES√ / NO

6. Conclusion:
The physical characteristics of …….. powder for compression is well acceptable as per the
predetermined specification at all the intervals of blending as shown by the samples
analyzed , mixing for xxx to xxminutes results show more closer homogeneity of ……
active distribution with other excipients of blend.
The blending time of xxx toxx minutes is concluded validated blending time at mixer
medium RPM for xxxxxxx tablet blending, when the process is performed in Double cone
Blender for a commercial batch size of …. tablets. Bulk density and Particle size
distribution of the lubricated blend was uniform among three batches indicates that the
sifting and blending process has proved to be consistent among the Commercial batches.

13.2.4.3. Compression Validation

1. Product Detail

Batch no Batch size Mfg date Exp date

 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

Document No: Title: Issue No. Page No.

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........................
........................
........................

2. Equipment detail

Equipment name Id Capacity Calibration

3. Critical Process controls checks & acceptance limits (at three machine speed)
 Weight variation
 Hardness
 Thickness
 Disintegration time
 Thickness
 Friability
 Dissolution

4. Observation
Table 3: Assay of ........................ in ........................ tablets compressed at different
speeds 15, 18, 21 RPM for the Batch no ........................, ........................&........................

% of ........................
Batch No ........................ ........................ ........................
M/C 15 18 21 15 18 21 15 18 21
 Company Name:

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Speed RPM RPM RPM RPM RPM RPM RPM RPM RPM
1
2

AVG

SD

RSD %

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The Assay of the three batches with all three M/C speed were within
the limit.

Table 4: Dissolution of ........................ tablets compressed at different speeds 15, 18, 21

RPM for the batch no. ........................, ........................&........................

The % of ........................ release after 30min using USP Dissolution method (Paddle, RMP 50).
NLT 80% (Q)
Batch ........................ ........................ ........................
No.
M/C 15RPM 18RPM 21RPM 15RPM 18RPM 21RP 15RPM 18RP 21RP
speed M M M
( RP
M)
1
2
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3
4
5
6
Avg.
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The Dissolution at three different m/c speeds were within the
limit

Table 5: Disintegration of ........................ tablets compressed at different speeds 15,

18, 21RPM for the batch no. ........................, ........................ & ........................

Disintegration time (second)

Batch ........................ ........................ ........................
No.
M/C 15RP 18RP 21RP 15RP 18RP 21RP 15RP 18RP 21RP
speed M M M M M M M M M
( RP
M)
1
2
3
 Company Name:

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4
5
6
Ave.

SD

RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The disintegration time of compression at three different
M/C speeds were within the limit.
Table 6: Friability of (three sets of 20 tablets) ........................ tablets compressed at
different speeds 15, 18, 21 RPM for the batch
no. ........................, ........................&........................
% of FIRIABILITY
Batch ........................ ........................ ........................
No.
M/C 15RP 18RP 21RP 15RP 18RP 21RP 15RP 18RP 21RP
Speed M M M M M M M M M
(RPM
)
1 0.25 0.35 0.32 0.19 0.27 0.28 0.38 0.32 0.29
2 0.31 0.24 0.36 0.28 0.19 0.35 0.33 0.27 0.19
3 0.29 0.26 0.28 0.24 0.36 0.31 0.35 0.19 0.31
Avg. 0.28 0.28 0.32 0.24 0.27 0.31 0.35 0.26 0.26
 Company Name:

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SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The friability during compression at three different machine speeds
(15, 18 & 21) RPM were within the limit.

Table 7: Hardness of ........................ tablets compressed at different speeds 15, 18, 21

RPM for the batch no. ........................, ........................ & ........................
HARDNESS (kpa )
Batch No. ........................ ........................ ........................
M/C Speed 15RPM 18RP 21RP 15RP 18RP 21RP 15RP 18RP 21RP
(RPM) M M M M M M M M
1
2
3
4
5
6
Avg.
SD
RSD
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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 Meet acceptance criteria: YES (√) / NO

 Conclusion: The hardnessduring compression at three different machine speeds
(15,18 & 21)RPM were within the limit.

Table 8: Weight Variation of ........................ tablets compressed at different speeds 15,

18, 21RPM for the batch no. ........................, ........................ & ........................
Weight Variation of ........................ tablet 95 ±5%
Batch ........................ ........................ ........................
No.
Speed( 15 RPM 18 21 15 18 21 15 RPM 18 21 RPM
RPM) RPM RPM RPM RPM RP RPM
M
1
2
3
4
5
6
7
8
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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9
10
11
12
13
14
15
16
17
18
19
20
Avg.
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The weight variation of compression at three different M/C speeds 15,
18 and 21 were within the limit.
5. Conclusion:
The compression was carried out between the speed limits and physical parameters of the
tablets were studied at this speed. The parameters checked included appearance, individual
weight variation, group weight variation, hardness of tablet, tablet friability and tablet
disintegration time and dissolution.
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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The parameters are well within the limits of acceptance criteria at the speeds studied.
Hence the compression stage of ........................ is consistent and reproducible when the
compression was carried out at the speeds of 15, 18, 21 rpm of the turret.
Content uniformity and dissolution of compressed tablets of all three speeds of
compression stage are found to be uniform and well within the limits of acceptance
criteria.

13.2.4.4. HOPPER Level Study Validation STUDY

1. Batch Detail
Batch no Batch size Mfg date Exp date

2. Equipment detail

Equipment name ID Capacity Calibration

3. Critical Process controls checks & acceptance limits (at Full hopper, middle hopper
and near end hopper)
 Weight variation
 Hardness
 Thickness
 Disintegration time
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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 Thickness
 Friability
 Dissolution
 Content
4. Observation
Table 9: Dissolution of ........................ ........................ in the full, lower &optimum of
compressed tablet batch no. ........................, ........................ & ........................
% of ........................ release.
Batch No. ........................ ........................ ........................
Hopper
Fill
volume Lower Half Full Lower Half Full Lower Half Full
1
2
3
4
5
6
Avg.
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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 Conclusion: The dissolution of the three batches with all three hopper fill
volumes were within the limit.

Table 10: Assay of ........................ tablets compressed at lower, Optimum and Full
hopper volume of compressed tablet batch no. ........................, ........................
& ........................

% of ........................
Batch
........................ ........................ ........................
No.
Hopper
fill Lower Half Full Lower Half Full Lower Half Full
Volume
1
2
3
Avg
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The Assay of the three batches with all three hopper fill volumes
were within the limit.
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Table 11: Disintegration of ........................ tablets compressed at lower, optimum and

full hopper volume for the batch no. ........................, ........................ & ........................

Disintegration time(seconds)
Batch ........................ ........................ ........................
No.
Hopper Lower middle Full Lower middle Full Lower middle Full
fill
Volume
1
2
3
4
5
6
Avg.
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The DT during compression at three different hopper fill volume were
within the limit.
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Table 12: Friability of (three sets of 20 tablets) ........................ tablets compressed at

lower, Optimum and Full hopper volume for the batch
no. ........................, ........................ & ........................
% of Friability (NMT 1%)
Batch ........................ ........................ ........................
No.
Hopper Lower Middl Full Lower Middle Full Lower Middl Full
Volume e e
1
2
3
Avg.
SD
RSD

 Meet acceptance criteria: YES (√) / NO

 Conclusion: The friability during compression at three different hopper fill volume
were within the limit.
Table 13: Hardness of ........................ tablets compressed at different at lower,
Optimum and Full hopper volume for the batch no. ........................, ........................
& ........................

HARDNESS (kpa )
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Batch No. ........................ ........................ ........................

Hopper Lower Optimu Full Lower Optim Full Lower Optimu Full
fill volume m um m
1
2
3
4
5
6
Avg.

 Meet acceptance criteria: YES(√) / NO

 Conclusion: The hardness of tablets compressed at different hopper fill volume
was within the limit.
Table 14: Weight Variation of ........................ tablets compressed at lower, Optimum
and Full hopper volume for the batch no. ........................, ........................ & .................
Weight Variation of ........................ tablet 95 ± 5%
Batch No. ........................ ........................ ........................
hopper Lower Optimu Full Lowe Optimu Full Lowe Optimu Full
fill m r m r m
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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volume
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Avg.
SD
RSD
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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 Meet acceptance criteria :YES√ / NO

 Conclusion: Hopper study was carried out for full hopper, half hopper
(optimum) and near end hopper to establish the segregation of the blend during
compression.

Content uniformity and dissolution of........................ (........................)

compressed tablets of all three hopper volumes condition of compression are
found to be uniform and well within the limits of acceptance criteria.

13.2.4.5. Coating Station Validation

13.2.6.5.1 The confirmation of process parameters
Batch Number
Control Parameters Control Standard Deviate or not

1-2r/min yes□ no□

Rotary rate of
coating pot

Inlet Temperature Above 85℃ yes□ no□

 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Above 65℃ yes□ no□

Outlet Temperature

Temperature of yes□ no□

40-45℃
tablet bed

Temperature of yes□ no□

tablet bed in 35-40℃
spraying process

Deviation description and disposal:

Conclusion:

Collected by： Date：

Reviewed by： Date：

13.2.4.5. 2. Coating Acceptance Criteria

Controlled Items Control Standard

Round appearance, complete and polishing tablet,

Appearance color consistency

Dissolution No less than 80% of the stated amount.

Completeness rate of tablets ＞99%

Yield of coated tablets 包衣片收率 99%≤Yield≤100%

13.2.4.5.3 The Confirmation of Coating Quality

The test data of validated batches meet the requirements with the range of control standard.
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Controlled Items

Completeness Yield of coated Conclusion

Appearance Dissolution
Batch No. rate of tablets tablets

Conclusion:：

Collected by：： Date：

Reviewed by：： Date：

14. Environmental Monitoring Data of the Clean Area Used to Produce the Validated
Batches

Serial Production Confirmation

Monitoring Items Acceptable Standards Result
No. Lot Number Method

1 Temperature Temperature:18-26℃ HVAC

Humidity 温度：18-26℃； ）
2
check and
3 confirm the
Differential Humidity:45-65%；
monitoring data
Pressure
湿度：45-65%； according to the
monitoring
regulation of
Cleanliness
Differential Pressure HVAC and clean
 Company Name:

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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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: More than 10Pa between area.

different clean area; more
than 5Pa between two
adjacent clean area.
Deviation description and disposal:

Conclusion:

Collected by： Date：

Reviewed by： Date：

15. Finished Products Analysis Report

Take samples for the three above-mentioned batches according to the sampling method of the finished
products xxxxxxxxxx Tablet（xxxxmg）. These samples will be tested in the light of the pharmacopoeia
criterion of xxxxxx The test data of the finished products of xxxxxxx
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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Detecting Items Standard (BP/USP/ IH) Batch No.

Assay
90.0~110.0%

of the stated amount

There is the maximum

Ultraviolet-visible absorption at the

spectrophotometry wavelength of 276nm

Identification

The retention time of

HPLC main peak of solution for
test should be consistent
with that of reference.

Related substance If there is impurity peak

in chromatogram of t

Dissolution rate
not less than 80%
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Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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There should not be more

than two tablets which
Weight Variation (the limit of weight
over the limit of weight
variation is 7.5%)
variation and none of
tablets can be more than
doubled.

The specification and disposal about the outlier and deviation: no deviation.

Conclusion:

Collected by： Date：

Reviewed by： Date：

16. Stability:

If acceptance criteria at all the stages of 3 batches are satisfied, the process to be
accepted as validated for manufacturing the product at site, EPHARM. The
Validation batches shall be introduced for complete stability studies as per stability
protocol.

17. Deviations:

Any deviation from the protocol related to manufacturing process, raw materials,
equipment used, sampling, in-process controls and analytical methods should be
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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authorized and documented in the batch manufacturing record as well as the

validation report.
Deviations from the signed and approved methodology, procedure or expected
versus actual results will be recorded on the deviation log book and categorized as
critical and non-critical. Minor changes such as typographical errors require a
comment only and do not require deviations
Critical deviations are those where the actual results do not agree with the
expected results and failure to do so result in compromise of the system and/or data
integrity. Each deviation should be referenced to the test section and must be
approved by Quality Assurance. A deviation must be raised for all critical
deviations and referenced.

Non-critical deviations are those where the actual results do not agree with the expected
results and failure to do so is caused by a misunderstanding of the requirement, function, or
procedure. Additionally, non-critical deviations do not compromise the system. Each
deviation should be referenced to the test section and must be approved by Quality
Assurance. A deviation is not required for non-critical deviations. The manufacturing
procedure cannot be considered valid for use until all critical deviations have been
resolved.

18. The Cycle of Re-Validation

If there happened some major changes about the production process, the major production equipment or
the main raw materials, they should be re-validated. Generally, the validation should be held every five
years.
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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19. The Result and Assessment to the Validation

19.1. The Result and Assessment of the Validation Team

Signed by (the head man of the Validation team)：

Date：

19.2． The Result and Assessment of the General Superintendent in Charge of Validation

Singed by (the general superintendent of Validation)：

Date：
 Company Name:

የኢትዮጵያመድኃኒትፋብሪካአ·ማ·
Ethiopian Pharmaceuticals Manufacturing Sh. Co.

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20. Annex

20.1The Batch Production Record of xxxxxxxxxxxxxxxT ablet（500mg）