Protocol No.

: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 1 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

PROCESS VALIDATION

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 2 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

TABLE OF CONTENTS

1.0 OVERVIEW...............................................................................................................................................
2.0 OBJECTIVE...............................................................................................................................................
3.0 SCOPE........................................................................................................................................................
4.0 RESPONSIBILITY....................................................................................................................................
5.0 REVALIDATION......................................................................................................................................
2.0 PRODUCT DETAILS................................................................................................................................
5.1 2.1 RAW MATERIAL...............................................................................................................................
3.0 LIST OF REFERENCE DOCUMENTS....................................................................................................
2.0 PROCESS VALIDATION PRE- REQUISITE..........................................................................................
4.1 PROCESS QUALIFICATION...................................................................................................................
4.2 RAW MATERIAL ACCEPTANCE..........................................................................................................
4.3 PACKING MATERIAL ACCEPTANCE..................................................................................................
4.4 EQUIPMENT/INSTRUMENT QUALIFICATION..................................................................................
4.5 SUPPORT SYSTEM QUALIFICATION..................................................................................................
4.6 QUALITY SYSTEM..................................................................................................................................
5.0 PROCESS EQUIPMENT / INSTRUMENTS............................................................................................
6.0 MANUFACTURING PROCESS...............................................................................................................
6.1 FLOW CHART OF MANUFACTURING PROCESS..............................................................................
5.2 DESCRIPTION OF MANUFACTURING PROCESS............................................................................
6.0 SAMPLING PLAN..................................................................................................................................
6.1 SAMPLING LOCATIONS FOR OINTMENT / CREAM / MANUFACTURING PLANT..................
7.0 VALIDATION ACCEPTANCE CRITERIA...........................................................................................
8.0 CONCLUSION.........................................................................................................................................
9.0 REPORT...................................................................................................................................................
9.1 ACCEPTANCE CRITERIA.....................................................................................................................
10.0 ABBREVIATIONS AND DEFINITION.................................................................................................

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 3 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

1.0 OVERVIEW

2.0 OBJECTIVE
To validate the manufacturing process CLOTRIMAZOLE as per the Batch
Manufacturing Record to establish documentary evidence that the process will
consistently produce the product, meeting its predetermined In-process and
Finish product specifications by examining three consecutive production
batches.

3.0 SCOPE

This protocol is specific to clotrimazole Cream and is applicable to the three

consecutive batches of clotrimazole Cream to be taken for conducting Concurrent
Validation study at Bellazuri Ltd

4.0 RESPONSIBILITY
Following functional groups shall be responsible for conducting validation study:

Production/Maintenance: Operating and maintaining facilities, equipment,

support system (Water/HVAC) and the process within its predetermined process
parameters and requirements.
Quality Control: Testing and auditing the manufacturing process for compliance
with specifications and requirements.

Quality Assurance: Monitoring the key quality parameters, sampling at various

processing stages. Reviewing and approving the protocol and report. Developing
the site validation plan, to monitor the process parameters and to review the

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 4 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

results.

5.0 REVALIDATION

Revalidation on three consecutive batches must be carried out, if there is:

 Change the batch size.

 Change in Supplier of API.

 Change or replacement of any critical piece of equipment or complete change in

the equipment.

 Change in Manufacturing Process.

 Change in Manufacturing Formulation.

 Change in the Manufacturing Facility.

 Three sequential batches fail to meet product specification.

2.0 PRODUCT DETAILS

Product Name FUNGIGYN

Generic Name CLOTRIMAZOLE CREAM BP 1%W/W
Product Code XXX
A laminated tube having respective over printed details, standard
Description artwork, and standard color scheme and containing white color
cream.
Composition:
Each tube contains:
Label Claim
Clotrimazole 1%W/W

Average Fill weight 20.0 gm + 2%

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 5 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

Shelf Life 2 years

Batch Size 160 kg (8000Tubes)
20 gm is filled in Lami tube, packed in a unit carton with package
Pack Size
insert.

5.1 2.1 RAW MATERIAL

LIST OF STARTING MATERIALS

Sr. Pharmacopoeia
Raw Material Role
No Specification
Active Pharmaceuticals
1.
Clotrimazole BP Active BP

Inactive Pharmaceuticals
2. Ceto Stearyl Alcohol Emulsifying agent BP
3 Methyl hydroxy benzoate preservative BP
4 Propyl hydroxy benzoate preservative BP
5 Propylene Glycol solubilizer BP
6 Potassium Hydroxide Ph adjuster BP
7 Purified water Vehicle BP
8 Ceto macrogol 1000 BP moisturizer BP
9 White soft paraffin Emollient BP
10 Light liquid paraffin Emollient BP

11 Disodium Edetate Chelating agent BP

12 Chlorocresol preservative BP

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 6 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

3.0 LIST OF REFERENCE DOCUMENTS

Sr .No Document Reference

1 Refer to specifications
Specification for clotrimazole BP
folder
2 Specification for chlorocresol
3 Specification for Ceto Stearyl Alcohol
4 Specification for Propylene Glycol
5 Specification for methyl hydroxybenzoate
6 Specification for propyl hydroxy benzoate
7 Specification for Disodium hydrogen phosphate
8 Specification for Ceta macrogol 1000
9 Specification for soft white paraffin
10 Specification for light liquid paraffin
11 Specification for disodium EDTA
12 Specification for purified water BP.

2.0 PROCESS VALIDATION PRE- REQUISITE

Following shall be the pre- requisite for Process Validation of clotrimazole Cream.

4.1 PROCESS QUALIFICATION

4.1.1 All the key process variables are to be identified and their operating ranges to be
established.

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 7 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

4.2 RAW MATERIAL ACCEPTANCE

4.2.1 All the raw materials to be used in the manufacturing shall be procured from
approved vendors.
4.2.2 All the raw materials shall be tested as per respective specifications and STP and
shall meet the specifications laid in the analysis prior to use.

4.3 PACKING MATERIAL ACCEPTANCE

4.3.1 All the primary packing materials and printed packing materials to be used in the
manufacturing shall be procured from approved vendors.
4.3.2 The analytical test reports shall be attached to the final process validation report.

4.4 EQUIPMENT/INSTRUMENT QUALIFICATION

4.4.1 The manufacturing equipment and control instruments to be used for
manufacturing and analysis of the product shall be qualified for IQ, OQ & PQ.
4.4.2 All the instruments used in the process shall be duly calibrated as per the
calibration.

4.5 SUPPORT SYSTEM QUALIFICATION

4.5.1 The support system, i.e., HVAC & Water system shall be qualified for IQ, OQ & PQ.
The environmental conditions should meet the pre-defined acceptance criteria
prior to conducting the process validation study.
4.6 QUALITY SYSTEM
4.6.1 Relevant SOPs shall be in place and training shall be completed on equipment
operation, manufacturing instructions and sampling.

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 8 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

5.0 PROCESS EQUIPMENT / INSTRUMENTS

Sr. No EQUIPMENT NAME EQUIPMENT ID NUMBER

1 Balance bench 20g-150kg BZ/PD/BAL-01

2 Balance bench 50g-300kg BZ/PD/BAL-02

3 PS 360.R2 precision balance BZ/PD/BAL-04

4 WLC 10/A2 10kg balance BZ/PD/BAL-05

5 Applicator Filling machine BZ/PD/UFM-01

6 Mixing vessel XPP 200 BZ/PD/XPP200-01

7 HPLC BZ/QC/HPLC-01

8 AS 310 R2 PLUS analytical balance BZ/PD/BAL-03

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 9 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

6.0 MANUFACTURING PROCESS

6.1 FLOW CHART OF MANUFACTURING PROCESS

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 Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 10 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

5.2 DESCRIPTION OF MANUFACTURING PROCESS

A) STEP A : PREPARATION OF OIL PHASE:

Into wax steam jacket tank take
White Soft Paraffin BP
Liquid Paraffin BP
Heat to melt the waxes for approximately 20 minutes then add.
Ceto Ceta macrogol 1000 BP
Ceto stearyl Alcohol BP
Heat it with occasional stirring to reach the temp. 75°C - 80°C (it takes about 25 to 30 mins)
B) STEP B : PREPARATION OF WATER PHASE:
Collect purified water in 160 kg water steam jacket tank. Heat it to reach the temp.
75°C- 80°C (it takes about 25 to 30 mins.) by passing the steam through outer jacket at 1-2
kg/cm2 pressure.
--Add methyl hydroxy benzoate into manufacturing vessel while stirring.
--Add Di sodium EDTA into manufacturing vessel at continuous stirring.
--Add Chlorocresol BP to the manufacturing vessel at continuous stirring.
--Add propyl hydroxy benzoate to the manufacturing vessel at continuous stirring.
--When the above material dissolve completely Heat the solution up to 70°C to 80°
--Continue stirring and maintain the temperature at 70° - 75°C. Set aside purified
hot water for preparation of ingredients & rinsing all the utensils.
--Adjust the PH of the solution to the range of 4.0 to 7.0 using Disodium
hydrogen phosphate
C) STEP C : PREPARATION OF EMULSION:
Transfer of Oil Phase:
a) Open bottom outlet of wax steam jacket tank & inlet valve of mainstream jacket tank
so that oil is transferred & filtered through 100 mesh sieves fitted in conical filter at

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 11 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

bottom. Rinse the wax steam jacket tank with hot purified water & transfer to mainstream
jacket tank with the help of vacuum.
Continue stirring for 10 mins. at speed no.35 and 70 respectively & then switch on the
homogenizer for 5 mins. to get uniform homogenized cream.
Note.: Before switching on homogenizer, ensure that both the water and oil phase set
temperatures is attained. ensure that the vent valve on the mixing tank is open. Set the
CMX speed at 6000 rpm.
D) STEP D PREPARATION OF ACTIVE INGREDIENTS:
1. Preparation of clotrimazole Solution:
Take Propylene Glycol BP in S.S. Container & heat on hot plate up to 80° to 85°C. Dissolve
0.7kg clotrimazole powder in Propylene Glycol to get a clear solution.
NOTE: It takes about 30 mins. to have a uniform suspension of the active ingredient.

E) STEP E : ADDITION OF ACTIVE INGREDIENTS

Transfer to mainstream jacket tank with continuous stirring. Rinse utensils of Step D (1)
with Propylene Glycol BP 0.02 Kg & then again with purified water & filter while
transferring to mainstream jacket tank. Stir it for 45 mins. & also start cooling water
through jacketed chamber to reach the temp 35°C. (It takes about 45 mins. to reach the
temp. 35°C).
Check pH of the cream (Limit:4.0 to 7.00) and product assay (Limit: 95% to 105% w/w)
F) STEP F : TRANSFER TO HOLDING / STORAGE VESSEL
Discharge the bulk into the S.S holding vessel. Collect samples for chemistry and
microbiology analysis.
G) STEP G: FILLING AND SEALING
Transfer the bulk via the pump into the hopper of the filling machine.
After every 30 minutes, check the weight of the tubes.
At the end of the filling run, withdraw 15 Lami tube composite samples and send them to

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 12 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

QC department for finished product analysis.

Also withdraw a total of 60 Lami tube composite samples for hold time study. From this
give 15 Lami tube each to QC Department after 15, 21, 30 th and 45th day each for
chemical and microbial analysis.
The labeled Lami tube shall be packed as per Packing Instruction. During labeling and
packing, the Lami tube should be checked for cleanliness, sealing and labeling quality and
for batch details coded on the label, carton, and corrugated boxes.

Besides this, the yields at various stages shall be calculated:

After Mixing:
After Filling:
Total yield shall also be calculated:

6.0 SAMPLING PLAN

UNIT SAMPLING POINT SAMPLE SAMPLE CONTROLLED MEASURED
OPERATION QUANTITY CODE PARAMETER RESPONSE
Blending Samples shall be 20 g each S1-A  Blending  Assay
drawn from the from each S1-B time  pH
Manufacturing sampling S1-C
Vessel at intervals location.
of 10min,
20min ,30min as
per the sampling
plan.
IPC Sample 20 gm 20 g S --------  Assay

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 13 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

composite sample  pH
from the sampling
point after
unloading the
material into
Intermediate
Process Container.

Blend After 1,3 7 and 15 2 X 80 gm S2-A, Chemical

Hold-Time days (2 x 20 gm) S2-B, -------- Analysis
Study for S2-C,
chemical S2-D Microbial
analysis Analysis
2 X 80 gm
(2 x 20 gm)
for
microbial
analysis

UNIT SAMPLING SAMPLE SAMPLE CONTROLLED MEASURED

OPERATION POINT QUANTITY CODE PARAMETER RESPONSE

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 14 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

Filling -------- ----- ---- ----  Group

Weight of
10 Empty
Lami tube
(every 30
minutes)
 Group
Weight of
10 Filled
Containers
(every 30
minutes)
 Filled
Weight
(every 30
minutes)
15 Lami tube S3  Finished
Composite Product
Sample for Analysis
Finished Product
Analysis
Filled Lami After 60 Lami tube S4 -------  Chemical
tube Hold 15,21 30 (4 x 15 Lami and
Time Study and 45 tube) Microbial
days Analysis

6.1 SAMPLING LOCATIONS FOR OINTMENT / CREAM / MANUFACTURING

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 15 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

PLANT
After completion of mixing for the defined period, the samples shall be collected
from the bottom of the XPP 200 through a discharge valve.

7.0 VALIDATION ACCEPTANCE CRITERIA

The Process of clotrimazole cream manufacturing stands validated if various critical steps
meet the following acceptance criteria.

 The content of Ceto macrogol, White soft paraffin, paraffin heavy liquid &
dissolved clotrimazole in the Bulk at different layers after defined mixing time
should have Assay in the Range of 95 % to 105% and Relative Standard
Deviation NMT 2%.

 The Average fill weight in the filled Lami tube should not be less than nominal
weight i.e., 20 gm.

 The fill weight variation should be 20.0 gm + 2%, NLT 20.0 gm.

 No leakage shall be observed during sealing quality check.

 Batch coding shall be clear & legible.

 The final yield should not be less than 90 %.

 The final product should meet finished product specifications.

Perform the following in-process checks:

CHECK PARAMETER FREQUENCY

Group Weight of 10 Empty Lami tube (Tare Weight) Every 30 minutes

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 16 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

Group Weight of 10 Filled Lami tube (Gross Weight) Every 30 minutes

Filled Weight (in mgs) (Net Weight) Every 30 minutes

Weight of 10 individual Lami tube Every 2 hours

8.0 CONCLUSION
Statement made for in this protocol on acceptability of manufacturing process meeting
the objective of protocol.

9.0 REPORT
Process validation report shall cover the following:

 Summary Plan of Study

 Acceptance Criteria
 Results, Discussion and Conclusion
 Master Batch Formula Verification and Recommendation

The following attachment shall be referred to in the Process Validation Report:

 Validation Samples Report

 Bulk Analysis Report
 Batch Production Record
 Finished Product Analysis Report

9.1 ACCEPTANCE CRITERIA

PARAMETER
ACCEPTANCE CRITERIA

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 17 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

Average Fill weight 20.0 gm + 2%

Average weight of empty tube 3.7 to 4.0gm

Group Weight of 10 Empty Lami tube NLT 37.0 gm

Average Weight of Filled Lami tube NLT 20 gm

Individual Weight Variation + 2%, NLT 20 gm

10.0 ABBREVIATIONS AND DEFINITION

ABBREVIATED FORM EXTENDED FORM

mg Milligram
gm Gram
Kg Kilogram
ml Milliliter

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 18 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

w/w Weight by weight

RSD Relative Standard Deviation
IP Indian Pharmacopoeia
BP British Pharmacopoeia
QA Quality Assurance
RPM Revolution Per Minute
% Percentage
q.s. Quantity Sufficient
S. No Serial Number
Ref. Reference
o
C Degree Celsius
IQ Installation Qualification
OQ Operation Qualification
PQ Performance Qualification
API Active Pharmaceutical Ingredient

REPORT APPROVAL SUMMARY

PREPARED BY
DATE
Sr. No DESIGNATION NAME SIGNATURE

WAMUKAMA
01 Q.C 03/11/2023
JOSEPHAT

CHECKED BY
Sr. No DESIGNATION NAME SIGNATURE DATE

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Protocol No.: PROCESS VALIDATION
PRODUCT NAME: - FUNGIGYN CREAM
Page 19 of 19
Effective Date: GENERIC NAME: - CLOTRIMAZOLE 1%W/W
23/11/2023 BATCH SIZE: 160kg 8000Tubes

01 PRODUCTION ASHRAF WANDERA 03/11/2023

APPROVED BY

Sr. No DESIGNATION
NAME SIGNATURE DATE

ANGELA
01 Q. MANAGER 03/11/2023
SEMUKUTU

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