PROCESS VALIDATION PROTOCOL FOR CIPROFLOXACIN HYDROCHLORIDE EYE DROPS

BP 0.3% (5 ml)

PROCESS VALIDATION PROTOCOL

FOR

CIPROFLOXACIN HYDROCHLORIDE

EYE DROPS BP 0.3% (5 ml)

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BP 0.3% (5 ml)

PROTOCOL CONTENTS

S.No. TITLE PAGE

No.
1.0 PROTOCOL PRE APPROVAL 3
2.0 OBJECTIVE 4
3.0 SCOPE 4
4.0 RESPONSIBILITY 4-5
5.0 VALIDATION APPROACH 6
6.0 REASON FOR VALIDATION 6
7.0 REASON FOR RE-VALIDATION 6
8.0 PRE-REQUISITE 7
8.1 TRAINING DETAILS 7
8.2 PRODUCT INFORMATION 7
8.3 ENVIRONMENTAL MONITORING 8
8.4 MANUFACTURING PROCESS INSTRUCTION 8-9
8.5 MANUFACTURING FORMULA 9-10
8.6 BATCH DETAILS 10
8.7 EQUIPMENT QUALIFICATION VERIFICATION 11
9.0 MANUFACTURING PROCEDURE 12
10.0 PROCESS FLOW DIAGRAM 13
11.0 DETERMINATION OF CRITICAL PROCESS PARAMETER 14-15
12.0 SAMPLING AND ANALYSIS PLAN 16-17
13.0 SAMPLING LOCATIONS 18
14.0 ACCEPTANCE CRITERIA 19-20
15.0 CONTINUOUS PROCESS VERIFICATION 21
16.0 DEVIATIONS 21
17.0 VALIDATION REPORT 21
18.0 CONCLUSION 21
19.0 REFERENCE DOCUMENTS 21
20.0 LIST OF ATTACHMENTS 22
21.0 ABBREVIATIONS 22
22.0 REVISION HISTORY 22

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1.0 PROTOCOL APPROVAL

PREPARED BY:
DESIGNATION NAME SIGNATURE DATE
OFFICER/EXECUTIVE
(QUALITY ASSURANCE)

REVIEWED BY:
DESIGNATION NAME SIGNATURE DATE
EXECUTIVE/MANAGER
(QUALITY ASSURANCE)
HEAD
(QUALITY CONTROL)
HEAD
(MICROBIOLOGY)
HEAD
(PRODUCTION)
HEAD
(ENGINEERING)

APPROVED BY:
DESIGNATION NAME SIGNATURE DATE
HEAD
(QUALITY ASSURANCE)

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2.0 OBJECTIVE:

 The objective of this protocol is to validate the manufacturing process of Ciprofloxacin

Hydrochloride Eye Drops BP 0.3% (5ml) using qualified facilities, equipment & utilities by
evaluating the consecutive batches being manufactured at the Three Piece Line.
 This study shall be conducted for the generation of sufficient data to establish documentary
evidence that the manufacturing process including dispensing, CIP/SIP, bulk preparing, filtration,
filling, sealing, visual inspection and packing process is suitable and appropriate for its intended
purpose and validated process shall consistently meet the predefined specifications and quality
attributes of the finished product.

3.0 SCOPE:

 The scope of this protocol is to validate the manufacturing process of Ciprofloxacin

Hydrochloride Eye Drops BP 0.3% (5ml) manufactured at Three Piece Line.
 Type of validation: Concurrent Validation

4.0 RESPONSIBILITY:

DEPARTMENT RESPONSIBILITIES
1. Responsible to prepare, review and approved process validation protocol.
2. To co-ordinate with cross functional teams to support the process validation
execution and also responsible to monitor the execution of process validation.
Quality 3. Ensure that the facility/equipment’s/instruments and utilities conform to the
Assurance validated/calibrated state prior to the execution of process validation.
4. To review the trends/statistical evaluation for Critical Process Parameters (CPP)/
Critical Quality Attributes (CQA) for every product manufactured at the site.
1. To perform Process validation sampling as per sampling plan and submit them to
Quality Control Department.
IPQA 2. To monitor, verify and record critical process attributes.
3. To record and report any deviation either planned or unplanned happened during
batch manufacturing.
1. Responsible to review process validation protocol.
2. To analyze the samples as per sampling plan during process validation and to
QC maintain the records of the test results followed by the reporting of the results.
3. Review of analytical data & submission of analytical results to QA.

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DEPARTMENT RESPONSIBILITIES
1. Responsible to review process validation protocol.
2. Responsible to collect sample as per process validation protocol.
Microbiology 3. To analyze the samples as per sampling plan during process validation and to
maintain the records of the test results followed by the reporting of the results.
4. Review & submission of results to QA.

1. Responsible to review process validation protocol.

2. Ensure that the current effective version of SOP’s, Batch Records etc. are
implemented and Concerned Personnel are trained.
Production 3. Prior to execution of process validation batch to ensure that facility / equipment /
instruments & utilities are in validated / calibrated state.
3. Execution of process validation and collection of routine in-process samples as
defined in the batch manufacturing record.

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5.0 VALIDATION APPROACH:

Validation shall be carried out in three consecutive batches with prospective approach as new product is
introduced to the facility. Study shall be carried out in two phases
 Review of documents.
 Manufacturing of batches.
Review of documents shall include
 Standard Operating & cleaning Procedures & Qualification and Validation status of equipment and
system.
 Manufacturing Process & BMR.
 Standard Testing Procedure.
 Raw material, packing material, in-process, finished product specifications.

6.0 REASON FOR VALIDATION:

 New Product manufactured at Three Piece Vial Line.

7.0 REASON FOR REVALIDATION:

 Any major change in the manufacturing process which may affect the quality of the product.
 Any change in the batch size.
 Any change in the batch formula.
 Change in manufacturing site.
 Any modification in any critical equipment.
 Any major modification in the related utility system.
 Any change in the specification and/or change in the source of active pharmaceutical ingredient
(API).

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8.0 PRE-REQUISITE:

8.1 TRAINING DETAILS:

 The validation team shall be approved by Head-QA

 All the personnel involved in the manufacturing and Packing of Validation Batches, Sampling
and Testing of Validation Samples should be appropriately trained both in their job related
activities and on the process validation protocol by Head-QA.

8.2 PRODUCT INFORMATION:

GENERIC NAME : Ciprofloxacin Hydrochloride Eye Drops BP 0.3%

LABEL CLAIM : Composition:

Ciprofloxacin Hydrochloride BP
Equivalent to Ciprofloxacin..............................% w/v
Benzalkonium Chloride BP..................................% w/v
(As Preservative)
Sterile aqueous vehicle...............................q.s.
PACK SIZE : LDPE, White 5 ml

BATCH SIZE : 100 L / 19607 Nos.

MANUFACTURING LICENSE No. : ……………..

SHELF LIFE : 36 Months

MARKET : Export

DOSAGE FORM : Eye Drops

DESCRIPTION : A Clear colorless solution free from foreign particulate

matter filled in 5 ml white bottles.
STORAGE CONDITION : Do not store above 25°C. Store in the original
packaging. Do not refrigerate or freeze.

MANFACTURING LOCATION:

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8.3 ENVIRONMENT MONITORING:

All environment parameters of critical area as listed shall be verified during execution of the process
validation study.
 Passive air sampling/Settle plate monitoring
 Active air sampling/Volumetric air sampling
 Surface monitoring
 Personnel monitoring
 Non-viable particle monitoring
 Pressure differential monitoring
 Temperature & Relative humidity monitoring

8.4 MANUFACTURING PROCESS INSTRUCTIONS:

 Manufacturing process: Sequential steps in manufacturing process shall be followed as per the
approved current BMR. Process parameters during each unit operation shall be monitored to
demonstrate that product meets the acceptance criteria.
 Raw material: Raw materials to be used in the manufacturing shall be procured from the approved
vendor and shall meet all the specifications in the analysis prior to use. All the raw materials shall
have valid certification from quality control lab before use for manufacturing. Containers used in the
dispensing of raw materials should be clean and dry. After dispensing of API, it should be stored in
air tight container.
 Primary Packing Materials: Primary packing materials being used in the manufacturing shall be
procured from the approved vendor and shall meet the laid down specification in the analysis prior to
use.
 Secondary & Tertiary Packing Material: Secondary and Tertiary packing materials being used in
the packaging process shall be procured from the approved vendor and shall meet the laid down
specification in the analysis prior to use.
 Bulk Preparing: Temperature of bulk solution is to be maintained during entire batch
manufacturing process. Bulk solution hold in SS 316 L mixing vessel should not exceed 12 hours
before filtration and filtered bulk solution hold in SS 316 L holding vessel should not exceed 24
hours before final filtration.
 Filtration: Pre-integrity test and post integrity test of 0.2 µ filter shall be done with Bubble Point
Test at 20°C to 25°C. Bulk solution filtration and filling should not exceed 24 hours.

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 Visual inspection of bottles for any defect like Dirty Vial, Mould defect, Broken Ratchet, surface
particles, Improper Sealing, improper fixing of cap & vial without cap etc. shall be performed after
capping.

8.5 MANUFACTURING FORMULA:

RAW MATERIALS:
Theoretical
Material Manufacturer Label
S.No. Ingredients Specifications Quantity Unit
Code Name Claim
(For 100 L)
1. Ciprofloxacin
BP 0.3% w/v 0.364* Kg
Hydrochloride
Benzalkonium
2. 0.006 %
Chloride 10% w/v IH 0.063** Kg
w/v**
Solution
3. Mannitol BP --- 0.820 Kg
4. Glacial acetic acid BP --- 0.900 L
5. Sodium acetate
USP --- 0.300 Kg
anhydrous
6. Disodium Edetate BP --- 0.050 Kg
7. Sodium Hydroxide BP --- 0.150# Kg
8. Hydrochloric acid BP --- 0.030# L
9. Water for Injection BP --- q.s. L

Note 1: *Material has been calculated with considering the Assay; NLT 98.0% (OAB) & Water Content
NMT: 6.7%.
Note 2: **This label claim of Benzalkonium Chloride and quantity has been calculated with considering
the Assay NLT 9.5% w/v of BKC solution. BKC solution to be dispensed in Kg with respect to
weight/ml.
Note 3: # For pH adjustment only.

PRIMARY PACKING MATERIALS:

S.No. Material Name of Material Manufacturer Function Theoretical Unit
Code Name Quantity
(For 100 Liters /
19607 Vials)
HPME- Bottle, LDPE, Primary
1. 19607 Nos.
00051 White 5ml Packing Material
HPME- Nozzle, Primary
2. 19607 Nos.
00052 LDPE, Natural 5ml Packing Material
HPME- Caps HDPE, White, Primary
3. 19607 Nos.
00053 20mm Packing Material
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8.6 BATCH DETAILS:

Standard Batch
Batch No. Manufacturing Date Expiry Date Shelf Life
Size
36 months$
36 months$
36 months$
Batch details such as batch number, manufacturing date and expiry date shall be recorded during
protocol execution.
$ Shelf life is provisional and shall be ascertained based on real time stability data.

8.7 EQUIPMENT QUALIFICATION VERIFICATION:

Ensure all equipment’s to be used for the manufacturing must be qualified as per Qualification acceptance
criteria. The reference Qualification Documents shall be verified and mentioned in the Process Validation
Report. The list of major equipment’s used for manufacturing of Ciprofloxacin Hydrochloride Eye Drops
BP 0.3% (5 ml) in Three Piece line mentioned below:

S.No. Name of Equipment/Machine Make Equipment ID

1. Mobile Mixing Vessel

2. Holding Vessel
3. Filling Machine
4. Buffer vessel
5. LAF for three-piece line
6. Dynamic Pass Box
7. Dynamic Pass Box
8. Dynamic Pass Box
9. Dynamic Pass Box
10. Dynamic Pass Box
11. Static Pass Box
12. LAF For Filtration Room
13. Autoclave
14. Checkweigher

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9.0 MANUFACTURING PROCEDURE:

Dispensing, bulk preparation, filtration, filling & screw capping and visual inspection shall be carried out as
per the approved batch manufacturing record. All respective process parameters shall be evaluated as
specified in this protocol.
After each stage of process like bulk preparation, filtration, aseptic filling, the samples shall be tested.
Test Results and data generated during the process validation study shall be compiled and reviewed at each
stage of manufacturing.
Warehouse shall issue the primary packing materials to production department based on the batch record.

Machine parts shall be sterilized in Autoclave Bung Processor as per the pre-validated loading pattern.
After sterilization machine parts shall be unloaded in sterile material unloading area and aseptically
transferred to the filling room through mobile LAF and Assemble the accessories aseptically on filling
machine as per respective SOP.
Perform the CIP, SIP, of mobile mixing vessel and holding vessel along with product transfer line.
Process validation batch of Ciprofloxacin Hydrochloride Eye Drops BP 0.3% (5ml) with a batch size of
100.00 L will be manufactured as per the approved BMR.
After completion batch manufacturing activity, bulk solution is passed through the 0.2 µ filter from mobile
mixing vessel to holding vessel and record the filtration activity in BMR.
Then bulk solution shall be filtered through 0.2 µ filter installed before the buffer vessel.

Perform the filter integrity test for 0.2 µm filters before & after filtration.
The filling machine shall fill the solution in to 5 ml bottles through the manifold, filling pump & filling
needles.
After completion of the batch capping activity, reconcile all materials, yield are calculated and recorded in
the batch record.
Capped bottles are transferred to visual inspection and inspect the bottles as per respective SOP.

After visual inspection good bottles shall be transferred to packing department.

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10.0 PROCESS FLOW DIAGRAM:

Requisition for BMR & BPR

RM/PM Requisition issue Slip

Dispensing / Issuance of RM/PM in stores

Check Materials as per Requisition cum Issue Slip for both RM/PM

Materials from Stores to Production with BMR/BPR file

Raw Materials transfer to Manufacturing Area

Collect Water for injection in Mobile

Mixing Vessel

Send the Sample

to QC for Analysis

Add all the Ingredients Step-wise with continuous stirring as per

Manufacturing Process

Check the Initial pH

of Bulk Solution

Make-up the
Required Volume of Bulk Solution

Check the final pH of Bulk Solution

Sample is withdrawn by QA &

Send to QC for Analysis

Bulk Release for Filling & other Processing Bulk Solution filter through 1.0µ (Pre) + 0.2µ
(Primary) + 0.2µ (Secondary) filter

Sterilized LDPE vials,

Nozzles& Screw caps
from Packing Material Filling and screw

Store capping Bulk Solution

Send for Packaging

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11.0 DETERMINATON OF CRITICAL PROCESS PARAMETERS (but not limited):

Critical/
Process Steps Process Parameters Rationale Assessment Criteria
Non critical
Temperature, RH &
 Temperature Balance Verification is
 Temperature: NMT 25°C
 RH % critical and shall be
Dispensing Critical  RH: NMT 55%
 Balance maintained as per API
 Should be Complies
Verification and raw material
requirement.
 Sterilization time: NLT 30
Sterilization time,
Mins.
Sterilization
Sterilization  Sterilization time  Sterilization temperature for
Temperature is critical
of  Sterilization Critical m/c part: NLT 121.4o C
and shall be maintained
Equipment’s temperature  Sterilization temperature for
as per Sterility
mobile mixing vessel &
requirement.
holding vessel: NLT 122o C

Temperature and pH is
 Load Cell  Should be Zero
critical for stability of
Verification  Temperature: 30°C to 40°C
formulation.
Preparation of  Temperature  Stirring Speed: 200 RPM to
Stirrer speed should be Critical
bulk solution  pH 1440 RPM
maintained to ensure
 Stirrer speed  pH: 4.0 to 5.0
complete dissolution of
 Volume makeup  100 L
API and excipients.
 Sartopore- 2
 Filter type
 Sartorius
 Make
Filtration is most critical  0.2 µ
 Filter pore size
Filtration step to maintain the Critical  ≥ 3172 mbar
 Filter integrity
sterility of the product  ≤ 5000 mbar
 Filtration pressure
 NMT 2.5 kg
 Filtration Time
 Total Filtration Time

 Filling Speed
Aseptic filling
 Filling machine Fill volume and filling  80 to 150 vials/min
and Screw
speed challenge test speed is critical for Critical  5.05 to 5.15 ml
Capping of
 Fill Volume content uniformity.  Leak test shall be passed
vials
verification

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Critical/
Process Steps Process Parameters Rationale Assessment Criteria
Non critical
 Bottle, Nozzle &
Capping integrity
 Torque should be pass
Torque Test  Capping integrity Cap should be full tight Critical
within specified limit
 Machine Speed During Bottle Labeling  200 to 300 ampoules/min
Labelling all respective parameters
 Label printing Non-Critical  Label printing quality &
Machine need to be checked for
quality Quality Expects text matter shall be readable
Visual  Critical, major, Removal of defective  Visual inspection shall be
Critical
inspection minor defects Vials done as per respective SOP

11.1 HOLD TIME OF COMPONENT:

 Cleaned & sterilized component/garments shall be used within the recommended hold time of
respective components and shall be stored under LAF unit.
 Hold time shall be considered from the process end time i.e. cleaning & sterilization upto the uses of
components.
 Recommended hold time of various component at different stages is mentioned below.

Recommended Hold
S.No. Location Stage Component
Time
1. Mobile Mixing Vessel 24 Hours
2. After Cleaning Holding Vessel 24 Hours
3. m/c Parts 24 Hours
4. Three Piece Line Sterile Garments 48 Hours
5. Mobile Mixing Vessel 24 Hours
6. After Sterilization
Holding Vessel 24 Hours
7. m/c Parts 24 Hours

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12.0 SAMPLING AND ANALYSIS PLAN:

Collect the samples at various intervals at different operations as per the Sampling Plan mentioned below.
Location of
STAGE Test to be performed Sample size Responsibility
Collection
Description
Clarity
Mobile Mixing Vessel 100 ML
pH
Conductivity
Description
Cleaning of Clarity QA/QC &
Holding Vessel 100 ML
Equipment’s pH Production
Conductivity
Description
Clarity
m/c Parts 100 ML
pH
Conductivity
Description
QA/QC &
pH 100 ML
Production
Water for Injection Before batch mixing Conductivity
QA/Micro &
BET 10 ML
Production
Description
Bulk Mixing after 15
pH 50 ML
min. (Top)
Assay
Description
Bulk Mixing after 15
pH 50 ML
min. (Bottom)
Assay
Description QA/QC &
Preparation of
Production
Bulk Solution at pH
700 RPM Weight per ml
Colour Index 100 ML
Bulk Sample before
Filtration Assay
Preservative Content
Osmolarity
QA/Micro &
Bioburden 100 ML
Production
Filtration of Bulk Bulk sample after QA/Micro &
Sterility 100 ML
Solution filtration Production

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Location of
STAGE Test to be performed Sample size Responsibility
Collection
Nitrogen gas from Initial, Middle, End of QA/Micro &
Sterility 1000 Ltr.
user point filling Production
Pre sterilized empty
Initial, Middle and End 20 Nos. from QA/Micro &
vial, Dropper, Sterility
of filling Stage each stage. Production
Screw caps
Description
pH (Acidity)
Average filled volume
Uniformity of filled 56 Nos. from QA/QC &
Filling & Screw Initial, Middle and volume each stage Production
Capping End Particulate Contamination
Assay
Preservative Content
20 Nos. from QA/Micro &
Sterility
each stage Production
Description
Identification
Average filled volume
Uniformity of filled
volume
Osmolarity QA/QC &
pH (Acidity) 56 Nos. Production
Finished Sample Finish Stage
Related Substances
Particulate Contamination
Assay
Preservative Content
QA/Micro &
Sterility 20 Nos.
Production

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13.0 SAMPLING LOCATIONS:

MIXING VESSEL:

T Top Layer

Composite

B Bottom Layer

T = Top Layer
B = Bottom Layer
T + B = Composite (Bulk Sample before filtration)

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14.0 ACCEPTANCE CRITERIA:

S.No. Stage Test Acceptance criteria

Description Clear Colourless Liquid.

Clarity Should be clear

1. Cleaning of
equipment’s
pH 5.0 to 7.0

Conductivity NMT 1.3 µS/cm

Description Clear Colourless Liquid.

pH 5.0 to 7.0
2. Water for
Injection
Conductivity NMT 1.3 µS/cm

BET NMT 0.25 EU/ml

3. Nitrogen
Sterility Should be sterile after 14 days of incubation.
Gas
Pre
sterilized
4. empty vial Sterility Should be sterile after 14 days of incubation.
Dropper,
Screw caps

Description A Clear colorless solution.

pH 4.0 to 5.0

Weight per ml 0.995 to 1.050 g/ml

Colour Index NMT 0.200 AU

5. Bulk Mixing Osmolarity 260mOsmol/kg to 340 mOsmol/kg
Assay: Each ml contains:
Ciprofloxacin Hydrochloride BP 0.291 % w/v to 0.321 % w/v
eq. to Ciprofloxacin 0.3 %w/v (97.0 % to 107.0 % of label claim)
Preservative Content:
Benzalkonium Chloride BP 0.00480% w/v to 0.00720% w/v
(80.0% to 120.0% of label claim)
0.006 % w/v

6. Filling and Description A clear colorless solution free from foreign

Sealing particulate matter filled in 5 ml white bottles.

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S.No. Stage Test Acceptance criteria

Identification
The retention time of the principal peak in the
A. By HPLC chromatogram obtained with solution (1) should
(Diode array detector) be similar to that of the peak in the
chromatogram obtained with solution (2).
The retention time of the major peak of the
B. By HPLC sample solution should be corresponds to that of
(Benzalkonium Chloride) the standard solution obtained as directed in the
assay.
Average filled volume Not Less Than 5 ml

Uniformity of filled volume 4.55 ml to 5.45 ml

Osmolarity 260 mOsmol/kg to 340mOsmol/kg

pH (Acidity) 4.0 to 5.0

Related Substance
Impurity C NMT-0.40 %
Impurity E NMT-0.30 %
Any other secondary Impurity NMT- 0.20 %
Sum of all secondary Impurity NMT-0.70 %

Test for Sterility Should comply test of sterility.

Particulate Contamination

Visible particles: Should be free from visible particles

(i) ≥ 10 micron - NMT 1000 particles/ml
For sub visible particles: (ii) ≥ 25 micron – NMT 100 particles/ml

Assay: Each ml contains:

Ciprofloxacin Hydrochloride BP 0.285 % w/v to 0.330 % w/v
eq. to Ciprofloxacin 0.3 %w/v (95.0 % to 110.0 % of label claim)
Preservative Content:
Benzalkonium Chloride BP For- Information
0.006 % w/v

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15.0 CONTINUOUS PROCESS VERIFICATION:

Continuous Process Verification will be carried out for continuous monitoring of manufacturing
process both Critical Quality Attributes & Critical Process Parameter as per SOP.

16.0 DEVIATIONS:
All protocol deviation, non-conformances and out of specification results obtained shall be
investigated in accordance with corresponding SOP’s and documented in the validation report.

17.0 VALIDATION REPORT:

A Validation Report shall be prepared as per the sampling and analysis plan mentioned in this
Protocol by Quality Assurance Department. This Report shall be pre-approved by all functional heads
of all the concerned departments. Validation data shall be recorded by Quality Assurance Department
in the controlled copy of the pre-approved Process Validation Report. This Process Validation Report
shall be reviewed and then post-approved by all functional heads of all the concerned departments.

18.0 CONCLUSION:
Validation data shall be written on Process Validation Report, clearly stating the achievement or
Non-compliance of the acceptance criteria, effect of the deviations made during the validation and
in Case of failure, investigation carried out and their findings.

19.0 REFERENCE DOCUMENTS:

19.1 Relevant Specifications and Standard Testing Procedures
19.2 Relevant Standard Operating Procedures
19.3 Relevant Qualification Documents
19.4 British Pharmacopoeia

20.0 LIST OF ATTACHMENTS:

The relevant following documents to be attached with the Validation Report:
1. Records for all critical parameters with graphical representation, where applicable.
2. Relevant Sterilization Charts
3. Raw Data of Validation Testing.

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4. Certificate of Analysis of API.

5. Certificate of Analysis of Finished Product.

21.0 ABBREVIATIONS:
API : Active Pharmaceutical
Ingredient IP : Indian Pharmacopoeia
BMR : Batch Manufacturing Record
BPR : Batch Packing Record
GMP : Good Manufacturing Practice
IPQA : In-process Quality Assurance
NLT/NMT : Not Less Than/ Not More
Than SOP : Standard Operating Procedure
STP : Standard Testing Procedure
w/v : Weight by volume
BET : Bacterial Endotoxins Test
CIP : Clean in Place
SIP : Sterilization in Place

22.0 REVISION HISTORY:

Revision Change Control Detail of Reason for Effective Date Updated By
No. No. Changes Change

00 NA New Protocol

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