Bimatoprost PDR

PHARMACEUTICAL DEVELOPMENT REPORT
Name of Product Bimatoprost Ophthalmic Solution 0.01%
PDR No. MRC/BI1/PDR/2020/003/00
Issue Date
Version No. 00
Supersedes -
PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 1 of 81

Bimatoprost Ophthalmic Solution 0.01%
Approval Sheet
This development report is Prepared, Reviewed and Approved by as under:
Name
Designation
Prepared by
Signature
Date
Name
Designation
Reviewed by
Signature
Date
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Designation
Approved by
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Date

Contents
1. Executive Summary..................................................................................................10-11
2. Analysis of Reference Listed Drug Product...................................................................11
3. Clinical Pharmacology....................................................................................................11
3.1 Mechanism of Action................................................................................................11-12
3.2 Pharmacokinetics............................................................................................................12
3.3 Pharmacodynamics....................................................................................................12-13
4. Physicochemical characterization:............................................................................13-14
5. How Supplied.................................................................................................................14
6. Reference pack characterization................................................................................15-17
7. Composition....................................................................................................................17
8. Quality Target Product Profile (QTPP) for the ANDA product...............................17-19
9. Quality Attributes of Bimatoprost Opthalmic Solution 0.01%.................................20-26
10. Components of Drug Product.........................................................................................27
10.1 Drug Substance......................................................................................................27
10.2 General information...........................................................................................27
10.3 Physicochemical properties..........................................................................27-28
10.4 Biological properties..........................................................................................28
10.5 Solubility profile................................................................................................28
10.6 Related substances / Impurities..........................................................................29
10.7 Packing and Storage condition...........................................................................29
11. Chemical stability in solid state and in solution.............................................................29
11.1 Initial Risk Assessment of Drug Substance Attributes.................................30-31
11.2 Justification for the initial risk assessment of drug substance attributes......32-34
11.3 Excipients...............................................................................................................35
11.4 Selection of Excipients.................................................................................35-36
12. Drug product...................................................................................................................36
12.1 Formulation development.............................................................................36-37
13. Process Selection............................................................................................................37
14. Initial Risk Assessment of Process parameters..............................................................38
14.1 Justification for the initial risk assessment of process parameters:..................39-43
15. Formulation Development Study....................................................................................44
16. Prototype formulation:....................................................................................................44
16.1 Effect of Temperature.......................................................................................45-46
16.2 Effect of Light..................................................................................................46-48
16.3 Effect of Purging Gas.......................................................................................48-51
16.4 Effect of pH......................................................................................................51-61

16.5 Stability Batches…………………………………………………………………………………………………... 61-68
16.6 Hold time study/ Compatibility study with SS316L vessel..............................68-71
16.7 Filter compatibility study.................................................................................72-74
16.8 Tubing compatibility study...............................................................................74-78
16.9 Antimicrobial effectiveness testing.......................................................................79
16.10 Excursion study................................................................................................80-84
16.11 Photostability study..........................................................................................85-86
17. Brief Manufacturing Process and Flow Diagram.........................................................120
18. Manufacturing process flow chart for Phenylephrine HCl Ophthalmic solution, USP 2.5% & 10% 123

List of Tables
Table : Physicochemical characterization of the RLD Bimatoprost ophthalmic solution 0.01 %

..................................................................................................................................................13
Table 2: Pack Characterization of Bimatoprost ophthalmic solution 0.01%..........................15
Table 3: Composition of Bimatoprost Ophthalmic Solution 0.01%.......................................17
Table 4: Quality Target Product Profile (QTPP) of Bimatoprost Ophthalmic solution,
0.01%........................................................................................................................................17
Table 5: Critical Quality Attributes (CQAs) of Bimatoprost Ophthalmic solution 0.01%
………………………………………………………………………………………………..20-
25
Table 6: General information of Bimatoprost..........................................................................27
Table 7: Physicochemical properties of Bimatoprost.........................................................27-28
Table 8: Biological properties of Bimatoprost.........................................................................28
Table 9: Solubility Profile of Bimatoprost...............................................................................28
Table 10: Related substances / Impurities................................................................................29
Table 11: Degradation study results for Related Substance of Bimatoprost……………… 30
Table 12: Assay data of Bimatoprost.......................................................................................31
Table 13: Overview of Relative Risk Ranking System...........................................................31
Table 15: Initial risk assessment of the drug substance attributes...........................................31
Table 16: Justification for the initial risk assessment of the drug substance attributes...........33
Table 17: List of excipients and their respective suppliers......................................................36
Table 18: Formulation selected as per process development...................................................38
Table 19: Initial risk assessment of the process parameters....................................................39
Table 20: Justification for the initial risk assessment of the process parameters.....................40
Table 21: Prototype formulation..............................................................................................45
Table 22: Results of hygroscopic study...................................................................................46
Table 23: Analytical results of hygroscopic study on Related Substance...............................46
Table 24: Batch details of Effect of Temperature study..........................................................47
Table 25: Analytical results of Effect of Temperature study at 25ºC, PL/011/028A..............47
Table 26: Analytical results of Effect of Temperature study at 60ºC, PH1/PL/025/105........48
Table 27: Analytical results of Effect of Temperature study at 60ºC, PH2/VP/013/184........49
Table 28: Batch details of Effect of Light study......................................................................50
Table 29: Analytical results of Effect of Monochromatic light, PL/011/028A.......................50
Table 30: Analytical results of Effect of Monochromatic light, PH2/VP/013/129 (Invert)....52
Table 31: Analytical results of Effect of Monochromatic light, PH2/VP/013/129 (Upright). 53
Table 32: Analytical results of Effect of Normal light, PH1/VP/013/117...............................53

Table 33: Batch details of Effect of Gas study........................................................................54

Table 34: Analytical results of Effect of Nitrogen Gas study- PL/011/028A.........................55
Table 35: Analytical results of Effect of Oxygen Gas study, PH1/VP/013/113.....................56
Table 36: Analytical results of Effect of Carbon Dioxide Gas study, PL/011/109..................57
Table 37: Analytical results of Effect of Air study, PH1/PL/025/050.....................................57
Table 38: Analytical results of Effect of Oxygen Gas study, PH2/VP/013/179......................59
Table 39: Analytical results of Effect of Nitrogen Gas study, PH2/VP/013/129 (Invert).......61
Table 40: Analytical results of Effect of Nitrogen Gas study, PH2/VP/013/129 (Upright)....61
Table 41: Batch details of Effect of pH study..........................................................................63
Table 42: Analytical results of Effect of 4.0 pH study, PL/011/039A....................................63
Table 43: Analytical results of Effect of 5.0 pH study, PL/011/039B.....................................64
Table 44: Analytical results of Effect of 5.8 pH study, PL/011/028A.....................................65
Table 45: Analytical results of Effect of 6.5 pH study, PH1/PL/011/178A............................67
Table 46: Analytical results of Effect of 7.5 pH study, PL/011/028B.....................................70
Table 47: Analytical results of Effect of 4.0 pH study, PH2/VP/030/050...............................70
Table 48: Analytical results of Effect of 6.5 pH study, PH2/PL/025/173...............................72
Table 49: Analytical results of Effect of 7.0 pH study, PH2/VP/030/055...............................73
Table 50: Batch details of Sterilization process feasibility study............................................81
Table 51: Analytical results of Sterilization process feasibility study.....................................81
Table 52: Batch details of Hold time study of 2.5%...............................................................82
Table 53: Batch details of Hold time study of 10%.................................................................83
Table 54: Analytical results of Hold Time study of 2.5% (Before Filtration - SS316L vessel)84
Table 55: Analytical results of Hold Time study of 2.5% (After Filtration - SS316L vessel) 84
Table 56: Analytical results of Hold Time study of 2.5% (After Filtration - Glass Bottle)....85
Table 57: Analytical results of Hold Time study of 10% (Before Filtration - SS vessel).......86
Table 58: Analytical results of Hold Time study of 10% (After Filtration - SS vessel)..........87
Table 59: Analytical results of Hold Time study of 10% (After Filtration - Glass Bottle).....87
Table 60: Batch details of Filter compatibility study of 2.5%.................................................88
Table 61: Batch details of Filter compatibility study of 10%..................................................89
Table 62 : Analytical results of Filter compatibility study of 2.5%.........................................89
Table 63: Analytical results of Filter compatibility study of 10%...........................................90
Table 64: Batch details of Tubing compatibility study for 2.5%.............................................91
Table 65: Batch details of Tubing compatibility study for 10%..............................................92
Table 66: Analytical results of Tubing compatibility study (Dynamic - Platinum cured silicone)
..................................................................................................................................................93

Table 67: Analytical results of Tubing compatibility study (Static - Platinum cured silicone)94
Table 68: Analytical results of Tubing compatibility study (Dynamic - Pharmapure)............95
Table 69: Analytical results of Tubing compatibility study (Static - Pharmapure).................95
Table 70: Analytical results of Tubing compatibility study (Dynamic – Platinum cured
silicone)....................................................................................................................................96
Table 71: Analytical results of Tubing compatibility study (Static – Platinum cured silicone)97
Table 72: Analytical results of Tubing compatibility study (Dynamic– Platinum cured silicone)
..................................................................................................................................................98
Table 73: Analytical results of Tubing compatibility study (Static – Platinum cured silicone)98
Table 74: Batch details of Gasket compatibility study for 2.5%...........................................100
Table 75: Batch details of Gasket compatibility study for 10%............................................100
Table 76: Analytical results of Gasket compatibility study (Platinum cured Silicone).........100
Table 77: Analytical results of Gasket compatibility study (PTFE)......................................101
Table 78: Analytical results of Gasket compatibility study (Platinum cured Silicone).........102
Table 79: Analytical results of Gasket compatibility study (PTFE)......................................102
Table 80: Batch Details of the Effect of packaging material sterilization.............................103
Table 81: Analytical results of Packaging material sterilization PH1/PL/011/173A............104
Table 82: Analytical results of Packaging material sterilization PH1/PL/011/173B.............104
Table 83: Analytical results of Packaging material sterilization PH1/PL/025/040A (Invert)105
Table 84: Analytical results of Packaging material sterilization PH1/PL/025/040A (Upright)
................................................................................................................................................106
Table 85: Analytical results of Packaging material sterilization PH1/PL/025/040B (Invert)107
Table 86: Analytical results of Packaging material sterilization PH1/PL/025/040B (Upright)
................................................................................................................................................108
Table 87: Analytical results of Packaging material sterilization PH1/VP/013/109A (Upright)
................................................................................................................................................108
Table 88: Analytical results of Packaging material sterilization PH1/VP/013/109A (Invert)109
Table 89: Analytical results of Packaging material sterilization PH1/VP/013/109B............110
Table 90: Batch details of Antimicrobial effectiveness testing.............................................111
Table 91: Analytical results of Antimicrobial effectiveness study........................................111
Table 92: Batch details of Thermal cycling study/ Thermal excursion study.......................112
Table 93: Analytical results of study PH1/VP/013/121 (15 mL Pack)..................................112
Table 94: Analytical results of study PH1/VP/013/125 (2 mL Pack)....................................113
Table 95: Analytical results of study PH2/VP/013/184 (5mL Pack).....................................115
Table 96: Batch details of Photostability study......................................................................116

Table 97: Analytical results of Photostability study PH1/VP/013/121 (15 mL Pack)...........116

Table 98: Analytical results of Photostability study PH1/VP/013/125 (2 mL Pack).............118
Table 99: Analytical results of Photostability study PH2/PL/025/058 (5 mL Pack).............119
Table 100: Manufacturing process flow chart for Phenylephrine HCl Ophthalmic solution 124
List of Figures
Figure 1: Flow chart for Process Selection..............................................................................38

Figure 2: Flow Diagram of Manufacturing Process...............................................................123

Executive Summary
The pharmaceutical development report summarizes the development of Bimatoprost
Ophthalmic Solution 0.01%. Bimatoprost is indicated for the reduction of elevated
intraocular pressure in patients with open angle glaucoma or ocular hypertension.
Quality by Design (QbD) approach was used to develop generic Bimatoprost Ophthalmic
solution that is therapeutically equivalent to the innovator. Initially, the quality target
product profile (QTPP) was defined based on the properties of the drug substance,
characterization of the innovator product, and consideration of the innovator label and
intended patient population.
Identification of critical quality attributes (CQAs) was based on the severity of harm to the
patient (safety and efficacy) resulting from failure to meet that quality attribute of the drug
product. Our investigation during pharmaceutical development focused on those CQAs
that could be impacted by a realistic change to the drug product formulation or
manufacturing process. For generic Bimatoprost Ophthalmic solution, these CQAs
included Description, Assay, pH, Content of Preservative, Related Substances, and
Sterility.
Bimatoprost IH API was sourced from Chemo, which has a US- DMF having DMF
number: 16918
Risk assessment was used throughout development to identify potentially high risk
formulation and process variables to determine which studies were necessary to achieve
product and process understanding in order to develop a control strategy. Each risk
assessment was then updated after development to capture the reduced level of risk based
on improved product and process understanding.
The excipients used in the generic formulation are similar to the RLD both qualitatively
and quantitatively, i.e. Q1/Q2 equivalent as per Control Correspondence for (2.5mL) is
06665, (5mL) is 06665 and (7.5mL) is 06665. Excipient grade selection was based on
literature and reference listed drug package insert leaflet.
The process involved in the development of Bimatoprost ophthalmic solution is simple and
it is optimized systematically to develop a robust process.
Critical Process Parameters (CPPs) are the parameters whose variability have an impact on
a CQA and therefore should be monitored or controlled to ensure the process produces the

desired quality. Our investigation during pharmaceutical development focused on those

CPPs that could lead to a realistic potential change to the stability, safety and efficacy of
the drug product.
Finally, the proposed control strategy that includes the material attributes and process
parameters identified as potentially high risk variables during the initial risk assessments.
The control strategy also includes in-process controls and finished product specifications.
The process shall be monitored during the lifecycle of the product and additional
knowledge gained shall be utilized to make adjustments to the control strategy as
appropriate.
Analysis of Reference Listed Drug Product

RLD details mentioned in electronic version of orange book are provided below:
Applicant Holder : Allergan,Inc.
NDA Number: 022184
Proprietary Name: LUMIGAN
Active Ingredient: Bimatoprost
Strength: 0.01%
Reference Listed Drug: Yes
Reference Standard: Yes
Dosage Form: Solution/ Drops
Route of Administration: Ophthalmic
RLD Approval Date: Aug 8, 2010 (as per Orange Book)
Bimatoprost ophthalmic solution 0.01% listed under Marketing category NDA and has the
Application number 022184.
As per patient information leaflet available, clinical pharmacology of Bimatoprost ophthalmic
solution is as follows:
Clinical Pharmacology
The RLD Bimatoprost ophthalmic solution 0.01% manufactured by Allergan, Inc is
indicated for the reduction of elevated intraocular pressure in patients with open angle
glaucoma or ocular hypertension.

3.1 Mechanism of Action

Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin
with ocular hypotensive activity. It selectively mimics the effects of naturally occurring
substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in
humans by increasing outflow of aqueous humor through both the trabecular meshwork and
uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss.
The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field
loss.
3.2 Pharmacokinetics
Absorption: After one drop of bimatoprost ophthalmic solution 0.01% was administered
once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked
within 10 minutes after dosing and were below the lower limit of detection (0.025 mg/mL)
in most subjects within 1.5 hours after dosing. Mean Cmax and AUC0-24hr values were
similar on days 7 and 14 at approximately 0.08 mg/mL and 0.09 mg•hr/mL, respectively
indicating that steady state was reached during the first week of ocular dosing. There was no
significant systemic drug accumulation over time.
Distribution: Bimatoprost is moderately distributed into body tissues with a steady-state
volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the
plasma. Approximately 12% of bimatoprost remains unbound in human plasma.
Metabolism: Bimatoprost is the major circulating species in the blood once it reaches the
systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-
deethylation and glucuronidation to form a diverse variety of metabolites.
Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to
six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 mg/mL
and decreased rapidly with an elimination half-life of approximately 45 minutes. The total
blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was
excreted in the urine while 25% of the dose was recovered in the feces.
3.3 Pharmacodynamics:
Primary pharmacodynamics
Mechanism of action: Bimatoprost is a synthetic structural analog of prostaglandin F2α.
Drug activity related to proposed indication:
Prostamides such as bimatoprost are believed to lower intraocular pressure by increasing the
outflow of aqueous humor via both the trabecular meshwork and uveoscleral routes. The

sponsor has conducted a number of studies to investigate the endogenous formation of

prostamides and the role that they may play in controlling IOP via interaction with the
prostamide-sensitive receptors. Studies in feline iris suggest the presence of separate
populations of prostamide-sensitive receptors and prostanoid FP receptors. Additional
studies in dogs and mice provide evidence regarding the novelty of bimatoprost-sensitive
receptors.
New Evidence Supporting the Existence of Unique Prostamide Receptors: Bimatoprost
and Prostaglandin F2α Selectively Stimulate Calcium Signaling in Different Cat Iris
Sphincter Cells (BIO-03-404)
Summary: Although bimatoprost and prostaglandin (PG) F2α have similar potency to
stimulate contractile responses in isolated cat iris sphincter tissue, more selective studies
indicate that the 2 compounds act at different receptors. Confocal microscopic imaging of
digested cat iris sphincter tissues showed that bimatoprost and PG F2α induced calcium
signaling in different cells within the same preparation. Regardless of the order of exposure,
the two compounds always acted on different populations of cells without overlap. PF F2α
potently induced calcium signaling in HEK cells transfected with the feline or human FP
receptor and human dermal fibroblasts that contain natural FP receptors and bimatoprost did
not, providing further evidence that the compounds act at different receptors.
Secondary pharmacodynamics
In addition to its direct action on prostamide-sensitive receptors, some data from monkeys
suggests that chronic bimatoprost treatment is associated with remodeling and
morphological changes that increase aqueous outflow by the trabecular and uveoscleral
routes.
4. Physicochemical characterization
The physicochemical characterization of the RLD Bimatoprost ophthalmic solution 0.01%
is summarized in below table .
Table 1: Physicochemical characterization of the RLD Bimatoprost ophthalmic solution 0.01
%
Product Name Bimatoprost ophthalmic solution 0.01%
Manufacturer Allergan, Inc.

Batch. No 07887 E85611 99084
Pack 2.5 mL 5 mL 7.5 mL

Expiry Date Feb- 2021 Mar-2021 Aug- 2020

Test Parameters Results
Clear Colorless Clear Colorless Clear Colorless
Description
solution solution solution
Identification -
The retention time of the
bimatoprost peak of
sample solution Complies Complies Complies
corresponds to that of the
reference/working
standard solution as
obtained in the assay.
pH 7.16 7.25 7.13
Osmolality (mOsmol/kg) 295 301 291
Assay
Bimatoprost
101.0 98.6 100.5
(mg/mL,%)
Content of Benzalkonium
101.0 99.1 100.5
Chloride
Organic impurities (wt%, By HPLC)
15 (R) – Isomer 0.047 0.18 0.045
5,6-trans Bimatoprost 0.055 0.14 0.051
Any unspecified Impurity 0.057 0.038 0.054
Total Impurities 0.33 0.46 0.24
th
*Testing date- 8 May 2019
ND: Not detected
5. How Supplied
Bimatoprost Ophthalmic Solution 0.01% is supplied sterile in opaque white low density
polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in
following sizes:
2.5 mL fill in a 5mL container …………………….NDC 0023-3205-03
5 mL fill in a 10 mL container ……………………NDC 0023-3205-05
7.5 mL fill in a 10mL container ……………………NDC 0023-3205-08
Store at 2°- 25°C (36° to 77°F).

6. Reference pack characterization

Table 2: Pack Characterization of Bimatoprost ophthalmic solution 0.01%
Product name Bimatoprost ophthalmic solution 0.01%

Manufacturer/Innovator Allergan,Inc
Dosage form Sterile Ophthalmic Solution
Single/ Multi dose Multidose
Label Claim Each mL contains: Bimatoprost 0.1mg/mL
NDC Number 0023-3205-03 0023-3205-08

Market USA
Container-Vial (Primary)
Type (Moulded/
White opaque round LDPE bottle
Tubular)
Fill Volume 2 .5mL 7.5 mL
Color Opaque white
Over flow capacity
7.6ml 12.6 mL
(OFC)
Neck size (Outer
13.09 mm 13.08 mm
diameter)
Body diameter 20.10 mm 24.84 mm
Total height 39.83 mm 44.02 mm
Head Space 67.1 %V/V 40.48% V/V
Wall Thickness 0.564 – 0.652mm 0.540 – 0.642 mm
Weight of empty 2.57 g 3.36 g
Closure
Type of Closure Turquoise Tampered Closure
Color Turquoise
MOC (Material of
PS
construction)
Closure Height 18.86 mm 18.87 mm
Outer diameter of
18.14 mm 18.10 mm
Closure
Total Weight of Closure 1.094 g 1.088 g
Special Feature Bottle is recived in opended condition
Nozzle
Nozzle Description LDPE Nozzle White
Nozzle Height 16.40 mm 16.40 mm
Drop Weight ( Average
0.0248g with product 0.0248g with product
10 Drops)
Nozzle Diameter 9.34 mm 9.94 mm
Nozzle Flange Diameter 11.39 mm 11.40 mm
MOC LDPE
Weight Of Nozzle 0.42 g 0.41 g
Special feature NA

Label
Size (L X H) 75 X 20 mm (LXH) 90 X 20 mm (LXH)
Over printing details LOT: 07887 LOT: 99084
(Lot/ Exp) EXP: 02/2021 EXP: 08/2020
Laminated/ Varnished Varnished Paper Label
Barcode 1D Barcode 1D Barcode
Number of colors CMYK Combo Colors CMYK Combo Colors
Storage condition details Store at 2° - 25°C (36° - 77°F)
Secondary Pack
Carton Printed White Back Board both side Tuck-in carton
MOC FBB white back board
Dimensions 31 X 30 X 70
30 X 30 X 70 mm (LXWXH)
(L X W X H) mm (LXWXH)
Laminated/ Varnished Aqua Varnished
Grammage of Board 315 g/m2 315 g/m2
1D Barcode (0023-3205-
03) 1D Barcode (0023-3205-08)
Barcode 2D Barcode 2D Barcode (GTIN00300233205082
(GTIN00300233205037 SN (100000189248))
SN (100006643530)
Literature
Size (L X W) 570 X 179 mm 570 X 179 mm
Type of Paper Printed Bible Paper
Grammage of Paper 40 g/m2
Final Fold Size
115X 25 mm 115 X 25 mm
(L X W)
7. Composition
In response to Q1,Q2 submitted to FDA and on the basis of RLD labelling and literature,
Table lists the composition of Bimatoprost Ophthalmic solution 0.01% is listed below
Table 3: Composition of Bimatoprost Ophthalmic Solution 0.01%
Bimatoprost ophthalmic solution
S.No Pharmacopoeia Quantity
Component Function
l Status (mg/mL)
Active Pharmaceutical
1. Bimatoprost IH 0.1 mg
Ingredient
2. Boric Acid NF Buffering agent 8.1 mg
3. Sodium Borate NF Buffering agent 4.95 mg
4. Glycerin USP Tonicity Agent 9.9 mg
Benzalkonium
5. NF Preservative 0.2 mg
Chloride
6. Hydrochloric Acid NF pH adjusting agent q.s.

7. Sodium Hydroxide NF pH adjusting agent q.s.

8. Water for Injection USP Vehicle q.s. to 1 mL
*pH will comply with USP monograph limit of 7.0-7.2
q.s. quantity sufficient
8. Quality Target Product Profile (QTPP) for the ANDA product

QTTP( Table number 4) were identified after evaluation of physiochemical
characterisation of RLD and collecting information for Packager insert leaflet(PIL).
Table 4: Quality Target Product Profile (QTPP) of Bimatoprost Ophthalmic solution, 0.01%
QTPP Elements Target Justification
Pharmaceutical equivalence
Dosage form Ophthalmic solution
requirement: Same dosage form.
Dosage design Ophthalmic solution
requirement: Same dosage design.
Route of administration Drop Solution requirement: Same Route of
Administration.
Dosage strength 0.01%
requirement: Same strengths.
0.01% - 2.5 mL,5 mL Pharmaceutical equivalence
Fill Volume
& 7.5 mL requirement: same fill volume.
Therapeutically Bioequivalence requirement needed
Pharmacokinetics
equivalent to RLD to ensure rapid onset and efficacy.
At least 24 months
Equivalent to or better than RLD
Stability shelf-life at room
shelf-life.
temperature
Description
Identification
pH
Osmolality
Foreign matter
Water loss Meeting the same compendial or
Particulate matter other applicable (Quality) standards
Minimum Fill
Drug product quality attributes Assay (identity, assay, purity and quality
Preservative content (as per ICH and USP general
Related Substances
Residual solvents chapters).
Sterility
Antimicrobial
Effectiveness Testing
Weight per mL

Container Closure
Integrity
Container closure Suitable container closure system to
system qualified as achieve the target shelf-life and to
Container closure system
suitable for the drug ensure product integrity during
product. shipping.
Administration/Concurrence
Similar to RLD Same labelling as RLD
with labelling
Alternative methods of
None None
administration
Based on QTPP and available literature on the drug substance / drug product, prior experience,
published regulatory guidelines and quality parameters related to Ophthalmic solution, an
assessment of Critical Quality Attributes (CQAs) was done in relation to the envisaged drug
product.

9. Quality Attributes of Bimatoprost Ophthalmic solution, 0.01%

The quality attributes along with justifications are discussed in below table. The table also indicates which attributes were classified as
drug product critical quality attributes (CQAs).
Table 5: Critical Quality Attributes (CQAs) of Bimatoprost Ophthalmic solution 0.01%

Quality Attributes of the Drug Is this a
Target Justification
Product CQA?
Description of a product is an indirect
measurement of quality of the product. Any
change in color may be an indication of
degradation which needs to be supported by
other attributes like potency and impurities.
Clear, colorless solution in a three piece This CQA can be effectively controlled by the
Description Yes
bottle with turquoise cap. quality management system and will be
monitored in drug product release.
Formulation and process variables do not
impact identity. Therefore, this CQA will not
be discussed during formulation and process
development.
Identification (HPLC) HPLC: The retention time of the principal Yes* Though identification shall be effectively
peak in the chromatogram of the sample controlled by the quality management system
solution corresponds to the principal peak and shall be monitored at drug product release.
in the chromatograms of the Therefore, this CQA shall not be discussed

working/reference standard solution as

obtained under assay method.
UV: The UV spectrum of the major peak
of the sample solution corresponds to that
of the standard solution, as obtained in the
assay.
HPLC (For Benzalkonium Chloride): The during formulation and process development.
retention time of the principal peak in
chromatogram of the sample solution
corresponds to the principal peak in the
chromatograms of the working/reference
standard solution as obtained under assay
method.
pH of solution has direct effect on stability of
finished product and patient acceptability. As
per regulatory requirement, the generic
ophthalmic product need to have qualitatively
Ph 6.8- 7.8 Yes
and quantitatively same amount of active and
inactive ingredient as used by RLD, however
to establish the safe range of pH, it is still
considered as critical.
Osmolality 240 to 350 mOsmol/kg Yes Osmolality is critical to maintain the tonicity
of the eye. Therefore, this quality attribute is

critical to product safety.

The formulation doesn’t contain polymer
Viscosity To be Establish No
hence viscosity is not critical for the product.
Color Value
The formulation is colorless solution, hence
Absorbance To be Establish No absorbance value is not critical for the
product.
Light Transmittance (%)
At 600.0 To be Establish Light transmission not directly link to the
No potency of the drug product hence Light
At 650.0 To be Establish Transmittance not considered as a critical
The presence of particulate matter in
ophthalmic solution can result in severe
Diameter ≥ 10µm; No. of Particles: 50/mL
Particulate matter ( By light consequences, such as stinging on instillation
Diameter ≥ 25µm; No. of Particles: 5/mL Yes
obscuration method) and conjunctival sensitization may occur.
Diameter ≥ 50µm; No. of Particles: 2/mL
Hence, it is considered to be a critical quality
attribute and would be monitored closely.
Fill Volume is an important parameter that
For 2.5 mL: Not less than 2.5 mL
ensures the accurate deliverable volume/dose
Minimum Fill For 5 mL: Not less than 5.0 mL Yes
of the formulation. Hence, it is considered to
For 7.5 mL : Not less than 7.5 mL
be a critical quality attribute.
Formulation and process variables may affect
1. In Process: 95- 105%
the assay of the drug product, which can affect
Assay 2. Release: 95-105% Yes
the safety and efficacy. Thus, assay shall be
3. Shelf Life : 90- 110%
evaluated throughout product and process

development.
Formulation and process variables may affect
the preservative content. Preservative content
1. In process: 80-120%
variability will affect antimicrobial
Preservative content 2. Release: 80-120% Yes
effectiveness of the drug product. Hence, the
3. Shelf life: 70-120%
same shall be evaluated throughout the
product and process development.
Related Substances Release: Yes Degradation products can impact safety and
1. 5466RC01(15-Epi-Bimatoprost) – must be controlled based on ICH requirements
NMT 0.50% or RS characterization. Formulation and
2. 5466RC02(5,6 Trans process variables shall impact degradation
Bimatoprost) – NMT 0.50% products. Therefore, degradation products
3. Any unspecified degradation shall be assessed during product and process
product- NMT 0.1% development.
4. Total impurities- NMT 1.0%
Shelf Life:
5. 5466RC01(15-Epi-Bimatoprost) –
NMT 1.0%
6. 5466RC02(5,6 Trans
Bimatoprost) – NMT 1.0%

7. Any unspecified degradation

product- NMT 0.1%
8. Total impurities- NMT 2.5%
Pharmacopoeial requirement as this will affect

the safety and efficacy of the product. It shall
be controlled through environmental
conditions and process parameters by the
Sterility Should comply as per USP <71> Yes*
quality management system and shall be
monitored at drug product release. Therefore,
this CQA shall not be discussed during
formulation and process development..
The drug product contains preservative which
is essential for product safety during use once
opened. However, the preservative content in
Antimicrobial Effectiveness
Should comply as per USP <51> No the formulation is in line with that of the RLD
Testing
and the same shall be monitored during the
shelf life of the product. Hence, it is not a
critical quality attribute.
Container Closure Integrity Method need to be confirm No Container Closure Integrity is essential to
ensure the quality of the drug product in the
Container closure system. During product
development, the Container Closure system
shall be thoroughly evaluated and therefore

shall not impact the safety and efficacy of the

drug product.
Loss of water is recommended for aqueous
based products packed in semi permeable
plastic container. Similar container is used for
packing in ophthalmic solution USP. The
container selected is meeting USP
requirements for plastic materials including
Water Loss Not more than 5% No
test for water vapor transmission rate and
hence loss of water shall be monitored during
accelerated stability study to verify the
containing functioning but this test parameter
is not considered as critical as it is not related
to formulation or process variability.
*Formulation and process variables are unlikely to impact the CQA. Therefore the CQA will not be investigated and discussed in detail in subsequent risk assessment and pharmaceutical
development. However, the CQA remain a target element of the drug product profile and are addressed accordingly.
For this product Description, Identification, pH, Osmolality, Particulate matter, Assay, Sterility, Preservative content and Related substances
were identified as the subset of CQAs that have the potential to be impacted by the formulation and/or process variables and, therefore, shall be
investigated and discussed in detail in subsequent formulation and process development studies.
On the other hand, CQAs including Anti-Microbial Effectiveness Testing, Color value, Light Transmittance, Water Loss and Container
Closure Integrity test which are unlikely to be impacted by formulation and/or process variables shall not be discussed in detail in the
pharmaceutical development report. However, these CQAs are still target elements of the QTPP and are ensured through a good pharmaceutical
quality system and control strategy.


Components of Drug Product

10.1 Drug Substance: The information of Drug substance is taken from the DMF(Drug
Master file) of Bimatoprost.
10.2 General information
Table 6: General information of Bimatoprost
Characteristics Properties
Name Bimatoprost
(5z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-
phenyl-1- pentenyl]cyclopentyl]-N-ethyl-5-heptenamide
Chemical Name Or
(5Z,9α,11α,13E,15S) -9,11,15-trihydroxy-17-phenyl-18,19,20-
trinorprosta-5,13-dienoicacidethylamide
CAS No. 155206-00-1
Molecular formula C25H37NO4
Molecular Weight 415.6
Molecular Structure
Pharmacopoeial Status In-house

Storage Condition
10.3 Physicochemical properties

Table 7: Physicochemical properties of Bimatoprost
Characteristics Properties
Physical form White or almost white crystalline powder.
Melting Point [°C] 70ºC – 80 ºC
This polymorphic form is well characterized by XPRD,
DSC, IR , and melting point.
XPRD, IR , melting point , DSC of Bimatoprost
crystalline form A obtained by Industriale Chimica (Batch
L05866) is described below:
1) XRPD Analysis ( X-Ray Powder diffraction)
(equipment: APD 2000 Ital Stuctures
diffractometer; obtaining technique: at 25°C using like X
Polymorphism ray source tube CuKα 40 kV, 30mA, λ=1.5406 Å).
2) IR Analysis (recorded in KBr; equipment: Shimadzu FT
IR 8.300).
3) Melting point : 74.3°C-75.7°C (equipment: Buchi
Melting point B540; from 50°C to95°C, 1°C/min ).
4) DSC Analysis : (equipment: Mettler-Toledo DSC1 Star;
obtaining technique: da 40 a 90°C con scan rate di 5°C.
min-1)
Geometrical Isomerism There is no geometrical Isomerism
pKa 14.25 ± 0.20 Most Acidic Temp: 25°C

-0.48 ± 0.70 Most Basic Temp: 25°C

Very soluble in ethanol, methanol,slightly soluble in
Solubility
water.
Hygroscopicity Bimatorpost does not show any hygroscopic behaviour.
10.4 Biological properties

Table 8: Biological properties of Bimatoprost
Characteristic Properties
Partition coefficient (Log P) 2.779± 0.395 Temp: 25°C
Biopharmaceutics classification BCS Class III
10.5 Solubility profile

Table 9: Solubility Profile of Bimatoprost
Solubility Media Solubility
Ethanol Very soluble
Methanol Very soluble
Water Slightly soluble
10.6 Related substances / Impurities

Following related substances / impurities of Phenylephrine HCl API are summarized in below
table
Table 10: Related substances / Impurities
Related Substances (wt% by Specification (w/w%) B No. 2-IL-D-1060918

Vendor CoA
HPLC) (As per DMF) In House results
results
N.M.T. 0.15%
5466RC01 NLT 0.05 ND
N.M.T. 0.15%
5466RC02 NLT 0.07 ND
10.7 Packing and Storage condition

The Product is packed in brown glass containers, closed with polyethylene seals and screw caps.
Each glass container is placed into a polyethylene bag sealed with a numbered-not reusable
plastic string and then, for shipment into a kraft paper or black paper drum, labelled.
11. Chemical stability in solid state and in solution

The stability study are carried out on batches of Bimatoprost.
Long term test conditions: Batches of drug were placed under stability program. Samples
are stored in freezer at test stations for 3,6,9,12,18,24 months and 3,4 years are scheduled.
Accelerated test conditions: Samples of the drugs were held at 5+-3 degree celcius and stress
testing was performed. A restest period of 3 years complies for Bimatoprost. Stability data of the
drug supports the stability of drug.
Stress testing: Bimatoprost finished product has been tested in different stress conditions, to
study its behaviour under degradation conditions and verify the suitability of the HPLC analysis
method to detect the degradation impurities. The following degradation condition has been
considered.
HCl 60°C,24h Light Light-

(1h,25°C) (Thermal Darksampl 12h
Impurity Initial
H2O2 NaOH H2O Degradation) e, 12h
1h,50°C 1h,25°C (1h,50°C)
0.06 ND ND
Imp.15-epi
ND ND 2.89 8.56 0.06
(5466RC01)

ND ND 0.43
Imp.5,6-trans
ND ND ND ND ND
(5466RC02
Other 0.09 0.14 ND 5.20

ND 68.39 46.09 75.45
Impurities
Table 11 : Degradation study results for Related Substance of Bimatoprost
ND: Not Detected

Table 12: Assay data of Bimatoprost
Mode of degradation Assay %w/w
H2O2 1h,50°C 2.56
NaOH 1h,25°C 43.19
HCl 1h,25°C 14.24
H2O 1h,50°C 100.81
60°C,24h(Thermal Degradation) 99.23
Light Darksample, 12h 101.78
Light 12h 83.40
11.1 Initial Risk Assessment of Drug Substance Attributes

An initial risk assessment of the drug substance attributes was performed to evaluate the impact
that each attribute could have on the drug product CQAs. The outcome of the assessment and the
accompanying justification is provided as a summary in the pharmaceutical development report.
The relative risk that each drug substance attributes presents was ranked as high, medium, or
low. Those attributes that could have a high impact on the drug product CQAs warranted further
investigation whereas those attributes that had low impact on the drug product CQAs required no
further investigation. The same relative risk ranking system was used throughout the
pharmaceutical development and is summarized in Table. For each risk assessment performed,
the rationale for the risk assessment tool selection and the details of the risk identification,
analysis, and evaluation are available to the FDA Reviewer upon request.
Table 13: Overview of Relative Risk Ranking System
Low Broadly acceptable risk. No further investigation is needed.
Risk is acceptable. Further investigation may be needed in order to reduce

Medium
the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
Based upon the physicochemical and biological properties of the drug substance, the initial risk
assessment of drug substance attributes on drug product CQAs is shown in Table.

Table 14: Initial risk assessment of the drug substance attributes

Drug Product Water Related
Description Solubility Assay
CQA Content Substance
Description Low Low Low Low Low
pH Low Low Low Low Low
Osmolality Low Low Low Low Low
Particulate
Low Low Low Low Low
matter
Assay Low Low Low Low Low
Preservative Low Low Low Low Low
Related
Low Low Low Low Low
Substances

11.2 Justification for the initial risk assessment of drug substance attributes
The justification for the assigned level of risk is provided below:
Table 15: Justification for the initial risk assessment of the drug substance attributes
Drug Substance
Drug Products CQAs Justification
Attributes
Drug substance is freely soluble forming clear solution hence would not have
Description
impact on the CQA. The risk is low
pH
Description Osmolality Drus substance description is not directly linked to the following parameters
Particulate matter
Assay hence the risk is low.
Preservative
Related Substance
Description Drug substance is freely soluble hence doesn’t impact this CQA. The risk is low.
pH is driven by the buffering agent hence as such solubility does not impact this
pH
CQA. The risk is low.
Osmolality is not directly linked to solubility hence it is not critical. The risk is
Osmolality
low.
Drug substance is freely soluble and then filtered using sterilizing grade filter,
Solubilty hence risk is low.
Particulate matter
The final product is in the form of solution and Phenylephrine Hydrochloride is

Assay soluble in water and hence particle size does not impact the solubility or time for
dissolution. The risk is low.
Preservative
Drug substance is freely soluble hence doesn’t impact this CQA. The risk is low.
Related substances

Description
pH
Drug substance is freely soluble hence doesn’t impact this CQA. The risk is low.
Osmolality
Particulate matter
Assay is control in drug substance specification, hence doesn’t impact this CQA.
Assay
The risk is low.
Assay
Preservative Content doesn’t have diret impact on the assay of the drug
Preservative
substance hence the risk is low.
Individual known, unknown impurities and total impurities are controlled in
Related substances drug substance specification. Impurities limit comply with ICH Q3A
recommendations hence it is not critical. The risk is low.
Description
pH Water Content is not directly linked to the Description, pH, Osmolality and
Osmolality Particulate matter hence the impact is not critical. The risk is low.
Particulate matter
Assay is control in drug substance specification, hence doesn’t impact this CQA.
Water Content Assay
The risk is low.
Preservative Drug substance doesn’t has the hydrolysis impurity hence the impact is low. The
risk is low.
Related substances
Description Individual known and unknown impurities and total impurities are controlled in
pH
drug substance specification. Impurities limit comply with ICH Q3A
Osmolality
Particulate matter recommendations.Within this range drug substance impurities are unlikely to
Related Substance Assay impact Description, pH, Osmolality, Particulate matter, Assay, Preservative and
Preservative
Related Substance. The formulation is designed based on qualitatively and
Related substances quantitatively same ingredients as that of RLD and no incompatibilities between
API and excipients are expected.The risk is low.

11.3 Excipients
The excipients used in Bimatoprost Ophthalmic Solution 0.01%were selected based on the
excipients used in the RLD. A summary of the excipient-drug substance compatibility studies
and the selection of each excipient grade are provided as follows:
11.4 Selection of Excipients
The excipients used in Bimatoprost Ophthalmic Solution 0.01% were selected based upon PAR
and SBOA. The selection of excipient grade and supplier was based on previous formulation
experience and knowledge about excipients that have been used successfully in approved
products manufactured. The levels of excipients used in the formulation were studied in
subsequent formulation development studies.
Table 16: List of excipients and their respective suppliers
S.No. Excipient Supplier

1. Boric Acid, NF Merck KGaA
2. Sodium Borate, NF Merck KGaA
3. Glycerin, USP Merck KGaA
4. Benzalkonium Chloride 50% ,USP Novo Nordisk Pharmatech A/S
5. Sodium Hydroxide, NF Merck KGaA
6. Hydrochloric Acid, NF Merck KGaA
7. Water for Injection USP In House
Boric Acid
Boric acid has mild antibiotic properties against fungal or bacterial infection. Boric
acid ophthalmic is used as an eye wash to cleanse or irrigate the eyes. Boric acid provides
soothing relief from eye irritation, and helps remove pollutants from the eye such as smog,
chlorine, or other chemicals.
Sodium Borate
Borate buffers such as boric acid combined with sodium borate are commonly used in
ophthalmic preparations and may even lead to improved comfort for the user. Borate buffers
are used in commercially available ophthalmic preparations used to treat dry eye syndrome.
Glycerin
Benzalkonium Chloride

Benzalkonium chloride is a type of cationic surfactant. It is an organic salt classified as a quaternary

ammonium compound. Benzalkonium chloride is a frequently used preservative in eye drops;
typical concentrations range from 0.004% to 0.01%. Stronger concentrations can be caustic and
cause irreversible damage to the corneal endothelium. It acts as an antimicrobial agent by
denaturing proteins and disrupting cytoplasmic membranes.
Sodium hydroxide
Sodium hydroxide occurs as a white or nearly white fused mass. It is available in small pellets,
flakes, sticks, and other shapes or forms. It is hard and brittle and shows a crystalline fracture.
Sodium hydroxide is very deliquescent and on exposure to air it rapidly absorbs carbon dioxide
and water. Sodium hydroxide is widely used in pharmaceutical formulations to adjust the pH of
solutions. It can also be used to react with weak acids to form salts.
Water for Injection

Water for Injection, USP is a sterile, nonpyrogenic preparation of Water for Injection which contains
no bacteriostat, antimicrobial agent or added buffer and is supplied only in single dose
containers to dilute or dissolve drugs for injection. The volume of the preparation to be used for
diluting or dissolving any drug for injection, is dependent on the vehicle concentration, dose and
route of administration as recommended by the manufacturer.
Drug product
12.1 Formulation development
As per the regulatory requirement, the ophthalmic formulation must have qualitatively and
quantitatively same active and inactive ingredients and hence based on RLD composition,
reverse engineering, label claim, and literature search, following composition of generic
Bimatoprost ophthalmic solution 0.01% as base was used, which has been confirmed by
FDA as per the control correspondence.
Table 17: Formulation selected as per process development
S.No. Ingredients Supplier Quantity (mg/mL)
1. Bimatoprost Chemo 0.1 MG

2. Boric Acid Merck KGaA 8.1 MG

3. Sodium Borate Merck KGaA 4.95 MG
4. Glycerin Tonicity Agent 9.9 MG
5. Benzalkonium Chloride Novo Nordisk Pharmatech A/S 0.2 MG
6. Hydrochloric Acid Merck KGaA q.s.
7. Sodium Hydroxide Merck KGaA q.s.
8. Water for Injection Vehicle q.s. to 1 mL
13. Process Selection

The intended drug product equivalent to RLD to be supplied in white opaque round HDPE
bottle. The requirement for the product is sterile formulation and must meet USP <71> and
monograph/compendia requirements. Hence, the bulk solution containing active and
preservative should be sterilized by aseptic filtration then subjected for aseptic filling and
packaging.
The process of preparation of bulk solution was selected based on the solubility nature of
excipient and probable degradation mechanism of active. Based on several development
trials, order of addition was finalized. The bulk solution was filtered through 0.22µm
sterilizing grade filter in white opaque round HDPE bottle under controlled area.
Dispensing of Raw material
Bulk solution compounding
Filtration
Filling and Capping
Finished product sampling for

complete analysis
Figure 1: Flow chart for Process Selection

14. Initial Risk Assessment of Process parameters

An initial risk assessment of the process parameters was performed to evaluate the impact that each parameter could have on the drug product
CQAs. The outcome of the assessment and the accompanying justification is summarized in the subsequent table.
Table 18: Initial risk assessment of the process parameters
Compounding
Drug Product Volume
Dispensing Filling Capping
CQA Mixing Speed Mixing Time Temperature Light Gas Filteration makeup
Descricption Low Low Low Low Low Low Low Low Low Low
pH Low Low Low Low Low Low Low Low Low Low
Osmolality Low Low Low Low Low Low Low Low Low Low
Particulate
Low Low Low Low Low Low Low Low Low Medium
Matter
Assay Medium Medium Medium Medium Medium Medium Medium Medium Low Medium
Preservative
Medium Medium Medium Low Low Low High Medium Low Medium
Content
Related
Low Low Medium Medium Medium Medium Low Low Low Medium
Substances

14.1 Justification for the initial risk assessment of process parameters:

The justification for the assigned level of risk is provided below:
Table 19: Justification for the initial risk assessment of the process parameters
Process Variables Drug Products CQAs Justification
Description Dispensing would not have an impact on description hence, the risk is low.
pH There is no interaction or impact of dispensing on the pH of the finished product. The risk is low.
Osmolality Dispensing is not directly linked to the osmolality of the finished product hence, the risk is low.
Particulate Matter Drug substance is freely soluble in water hence the risk is low
Dispensing will have an impact on assay of drug substance, inadequate weighing balance
Assay
calibration resulting to have an impact on assay of finished product. Hence, the risk is medium.
Dispensing
Inadequate weighing of the preservative will impact the assay content of the preservative hence
Preservative Content
the risk assigned is medium.
Inadequate weighing of the chelating agent will impact the assay content of the chelating agent
Chelating agent
hence the risk assigned is medium.
As the API is very hygroscopic in nature, there might be chances of increased organic impurities
Related Substance in drug product if dispensing is done under uncontrolled humidity condition. Hence, the risk
assigned is medium.
Description
pH
Mixing Speed
Mixing speed is unlikely to affect any of these CQAs. The risk is low.
Osmolality
Compounding
Particulate Matter Drug substance is freely soluble in water hence the risk is low.
Assay Mixing speed during manufacturing directly affects dissolution of drug substance and
preservative. Inadequate mixing may cause incomplete dissolution, which will affect drug
substance and preservative assay. The risk is medium.
Related Substance Mixing speed will not have impact on these CQA’s hence the risk assigned is low.

Description
pH Mixing time is unlikely to affect any of these CQAs. The risk is low.
Osmolality
Mixing Time
Assay Mixing time during manufacturing directly affects dissolution of drug substance and
preservative. Inadequate mixing may cause incomplete dissolution, which will affect drug
substance and preservative assay. The risk is medium.
Related Substance Mixing speed will not have impact on these CQA’s hence the risk assigned is low
Description
pH Temperature is unlikely to affect any of these CQAs. The risk is low.
Osmolality
Temperature
Temperature might impact the degradation of the drug substance hence need to be evaluated in
Assay
further studies. The risk assigned is medium.
Preservative Content Temperature is unlikely to affect any of these CQAs. The risk is low.
Temperature will impact the drug substance which needs to be controlled by maintaining the
Related Substance
process temperature hence the risk is medium.
Description
pH Light is unlikely to affect any of these CQAs. The risk is low.
Osmolality
Light
Light is likely to impact the drug substance assay hence will be evaluated further. The risk
Assay
assigned is medium.
Preservative Content Light is unlikely to affect any of these CQAs. The risk is low.
Light will impact the drug substance which needs to be controlled by maintaining the process
Related Substance
temperature hence the risk is medium.
Gas
Description
pH Gas is unlikely to affect any of these CQAs. The risk is low.
Osmolality
Assay Gas is likely to impact the drug substance assay hence will be evaluated further. The risk

assigned is medium.
Preservative Content Gas is unlikely to affect any of these CQAs. The risk is low.
Gas will impact the Related Substance which needs to be controlled by maintaining the process
Related Substance
temperature hence the risk is medium.
Description
pH Filter is unlikely to affect these CQA hence the risk is low.
Osmolality
Drug substance is freely soluble in water and the final product need to be filter hence the risk
Filtration Particulate Matter
assigned is low.
Assay Filter is likely to impact assay of drug substance hence the risk assigned is medium.
The transfer tubing material may impact assay of preservative as it may adsorb hence the risk is
high.
Related Substance Transfer tubing material is unlikely to affect any of these CQAs. The risk is low.
Description
pH Volume makeup is unlikely to affect any of these CQAs. The risk is low.
Volume Makeup
Osmolality
Particulate Matter Particulate matter is unlikely to affect by the volume makeup hence the risk assigned is low.
Assay of the drug substance is likely to be effected during the Volume makeup hence the risk
Assay
assigned is medium.
Assay of the Preservative Content is likely to be effected during the Volume makeup hence the
risk assigned is medium.
Related Substance Volume makeup is unlikely to affect any of these CQAs. The risk is low.
Description
pH
Osmolality
Filling
Particulate Matter Filling is unlikely to affect any of these CQAs. The risk is low.
Assay
Related Substance Filling is unlikely to affect by this CQA. The risk is low.

Description
Capping is unlikely to affect any of these CQAs. The risk is low.
pH
Osmolality
Capping
Particulate Matter
Assay
Loss of water content is likely to impact these CQA’s hence the risk assigned is medium.
Related Substance

15. Formulation Development Study

Formulation development was focused on evaluation of the Medium/high risk formulation
variables as identified in the initial risk assessments. In view of risk assessment
(Medium/high to Low) and criticality of formulation variables the formulation study was
done to optimize following on drug product CQA’s and manufacturability of the drug
product.
A. Effect of Temperature
B. Effect of pH
C. Effect of Light
D. Effect of Purging inert Gas
E. Effect of Normal Air
F. Effect of Light
G. Stability Batches
H. Hold time study/ Compatibility study with SS 316L vessel
I. Filter compatibility study
J. Tubing compatibility study
K. Photostability study
L. Antimicrobial effectiveness testing
M. Thermal cycling study/ freeze thaw study
N. Final prototype formula and manufacturing process
16. Prototype formulation:

All the batches for the above studies were manufactured as per the aforementioned
procedure. The Bill of Material of the formulation is stated as under:
Table 20: Prototype formulation
S.
Name of Ingredients Specification/ Make Quantity/ Unit (mg/mL)
No
Bimatoprost IH 0.1 mg
Boric Acid NF 8.1 mg
Sodium Borate USP 4.95 mg
Glycerin USP 9.9 mg
Benzalkonium Chloride NF 0.2 mg
Hydrochloric Acid NF q.s.
Sodium Hydroxide USP q.s.
Water for Injection In House q.s. to 1 mL
Packing Materials
10 mL RSP white R2 New (L) BPREX PHARMA
N-Open RSP 30 mL LTR
10. BPREX PHARMA
design
Tamp Safe RSP TARQ R2 -30
11. BPREX PHARMA
New
*Assay and Loss on Drying compensation done during Calculation of API quantity
** pH will comply with USP monograph limit of 7.0-7.2

16.1 Effect of Temperature

The objective of this study was to study the effect of temperature on batch after storing API
at RT for 24 hours. The batches were manufactured at 25ºC and pH 5.8 under
monochromatic light using prepurge nitrogen water and filled 2.5 mL fill in 10 mL HDPE
Gamma Container and subjected to 5°C, 25°C/40% RH, 40°C/25% RH, 30°C/65% RH
Invert conditions.
Table 21: Batch details of Effect of Temperature study
Packaging Stability condition

S.N Batch Batch
preparation material 25°C/40% 30°C/65%
o temperature Number 5°C 40°C/25% RH
sterilization RH RH
Gamma BP1/KE/031/1
1. 25ºC √ √ √ √
Sterilization 98
√-Charged X-Not Charged
Table 22: Analytical results of Effect of Temperature study at 25ºC, BP1/KE/031/198

5°C 25°C/40% RH 40°C/25% RH 30°C/65* RH
S. No Parameter Specs Initial 1M 3M 3M 3M
3M
1. Description
Identification by
2. .
HPLC
3. Weight/ml(g/ml) TBE
4. pH TBE
Osmolality
5. TBE
(mOsmol/kg)
Assay of
6. TBE
Bimatoprost (%)
Preservative BKC
7. TBE
in (%)
Related substance : wt% by HPLC
15(R) –Isomer ….
5,6 trans
TBE
8. Bimatoprost
Unkown at RRT
TBE
0.36
Unkown at RRT
TBE
1.13
13.Total impurities TBE
@ Clear Colorless solution
Conclusion: To be updated
16.2 Effect of Light

Bimatoprost is sensitive to light. Hence experiments were carried out under Subdued light to
evaluate the effect of light on Bimatoprost ophthalmic solution in invert conditions at pH 6.5
gamma sterilized vials with prepurge nitrogen water packed in 2.5mL and fill in 10mL HDPE bottle
in Invert conditions.
Table 23: Batch details of Effect of Light study
Stability condition
Batch Packaging
Batch
S.No preparation material
Number 5°C 25°C/40% RH 40°C/25% RH 30°C/65% RH
Light sterilization
Gamma BP1/KE/0
1. Subdued light √ √ √ √
Sterilization 31/148G
Table 24: Analytical results of Effect of Subdued light, BP1/KE/031/148(Gamma) in Invert conditions.
5°C 25°C/40% RH 40°C/25% RH 30°C/65% RH
S. No Parameter Specs Initial
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @
2. Identification by HPLC # # #
3. Weight/ml(g/ml) TBE 1.0065 1.0065
4. pH TBE 7.06 7.12
5. Osmolality (mOsmol/kg) TBE 327 319
6. Assay of Bimatoprost in (%) TBE 102.0 101.2
Preservative content (BKC)
7. TBE 97.6 96.6
in (%)
15(R) –Isomer …. ND ND
8.
5,6 trans Bimatoprost TBE 0.036 0.022
Unkown at RRT 0.36 TBE 0.007 0.030
Unkown at RRT 1.13 TBE ND 0.014
Total impurities TBE 0.11 0.11

# The retention time of the Bimatoprost peak of sample solution corresponds to that of the reference/working. standard
solution as obtained in the assay
16.3 Effect of Purging Gas

The objective of this study was to understand the sensitivity of the drug product to gases. Two different batches were
manufactured in gamma sterilized vials with without nitrogen and oxygen packed in 2.5mL fill in 10 mL HDPE sterilized
GAMMA containers. Samples were analysed Initially and subjected to 5°C, 25°C/40% RH, 40°C/25% RH, 30°C/65*
RH in Invert conditions at pH 5.8.
Table 25: Batch details of Effect of Gas study

Stability condition
Batch Packaging
S.No preparation material Batch Number
5°C 25°C/40% RH 40°C/25% RH 30°C/65%RH
Light sterilization
Without Gamma
1. BP1/KE/031/154 √ √ √
Nitrogen (N2) Sterilization √
Gamma
2. Oxygen (O2) BP1/KE/031/151 √ √ √ √
Sterilization
√-Charged X-Not Charged
Table 26: Analytical results of Effect of Without Nitrogen Gas study- BP1/KE/031/154G-(Gamma)-Invert
5°C 25°C/40% RH 40°C/25% RH 30°C/65% RH
1M 3M 3M 1M 3M 3M
2. Identification by HPLC # # # #
3. Weight/ml(g/ml) 1.0058 1.0058
4. pH TBE 7.08 7.09
5. Osmolality (mOsmol/kg) TBE 326 318
6. Assay of Bimatoprost in (%) TBE 101.8 101.3
7. TBE 101.9 99.1
in (%)
8.
5,6 trans Bimatoprost TBE 0.033 0.026
Unkown at RRT 1.13 TBE 0.02 0.02

#The retention time of the Bimatoprost peak of sample solution corresponds to that of the reference/working standard
solution as obtained in the assay.
Table 27: Analytical results of Effect of Oxygen Gas study, BP1/KE/031/151(G)(Gamma)-Invert

5°C 25°C/40% RH 40°C/25% RH 30°C/65% RH
1M 3M 3M 1M 3M 3M
3. Weight/ml(g/ml) TBE 1.0067 ND
4. pH TBE 7.09 ND
5. Osmolality (mOsmol/kg) TBE 332 0.009
6. Assay of Bimatoprost in (%) TBE 101.0 ND
7. TBE 97.2 0.04
in (%)

8.
5,6 trans Bimatoprost TBE ND 0.009
Unkown at RRT 0.36 TBE 0.009 ND
Total impurities TBE 0.04 ND

# The retention time of the Bimatoprost peak of sample solution corresponds to that of the reference/working standard
Conclusion:
1. No significant decrease in assay of Phenylephrine HCl is observed.

2. No decrease in assay of preservative is observed.
3. No pH change is observed.
4. Total impurities do not show significant increase.
The formulation can be manufactured under N2, O2, CO2 and Air purging.
16.4 Effect of pH
The effect of pH was studied to evaluate the impact on the degradation products of the drug
product. For this, experimentation plan included maintaining the pH of the drug product at
the extreme values (6.6, 6.8, 7.3, 7.8 & 8.0) of the acceptable range of pH value for the drug
product having Fill volume 2.5mL in 10 mLunder gamma and ETO containter, nitrogen and
monochromatic light at 25ºC. All the samples were kept in stability and analysed as per
protocol for significant changes.
Table 28: Batch details of Effect of pH study

Packaging
SNo pH material Batch Number 5°C 40ºC/25%RH 30ºC/65%RH 25ºC/40%RH
sterilization
Gmma and
1. 6.6 ETO BP1/KE/031/137A √ √ √ √
sterilization
Gmma and √
2. 6.8 ETO BP1/KE/031/137B √ √ √
sterilization
Gmma and √
3. 7.3 ETO BP1/KE/031/137C √ √ √
sterilization
Gmma and √
4. 7.8 ETO BP1/KE/031/137D √ √
sterilization
Gmma and √
5. 8.0 ETO BP1/KE/031/137E √ √ √
sterilization
Table 29: Analytical results of Effect of 6.6 pH study, BP1/KE/031/137A (Gamma)-Invert Study
5°C 25°C/40% 30°C/65% RH
40°C/25% RH
RH
1M 3M 3M 1M 3M 3M

3. Weight/ml(g/ml) @ @ @ @ @ @ @ @
4. pH # # # # # #
5. Osmolality (mOsmol/kg) NA 1.0018 1.0018 1.0018 1.0018 1.0018 1.0018 NA
6. Assay of Bimatoprost in (%) NA 6.47 6.49 6.50 6.47 6.58 NA NA
Preservative content (BKC) NA
7. NA 337 339 336 335 357 NA
in (%)
NMT
15(R) –Isomer ND ND ND 0.02 0.05 ND NMT 1.0%
1.0%
NMT
8. 5,6 trans Bimatoprost 0.012 0.02 0.03 0.02 0.04 0.03 NMT 1.0%
1.0%
NMT
Unkown at RRT 0.36 ND ND 0.05 ND BQL BQL NMT 0.10%
0.10%
NMT
Unkown at RRT 1.13 BQL BQL 0.05 0.07 BQL BQL NMT 0.10%
0.10%
NMT
Total impurities 0.15 0.06 0.12 0.21 0.21 0.15 NMT 2.5%
2.5%
Table 30: Analytical results of Effect of 6.6 pH study, BP1/KE/031/137A (Eto)-Invert study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
2. Identification by HPLC # # # # # #
3. Weight/ml(g/ml) NA 1.00181.0018 1.0018 1.0018 1.0018 1.0018 1.0018
4. pH NA 6.48 6.49 6.49 6.48 6.48 6.47 NA
5. Osmolality (mOsmol/kg) NA 340 339 338 336 329 358 NA
N less than 101.4 NA
90% and Not
6. Assay of Bimatoprost in (%) 101.6 100.0 99.3 100.2 101.4
morethan
110%
Not less than 98.3 NA
Preservative content (BKC) 70% and Not
7. 95.5 102.9 95.5 97.7 95.9
in (%) morethan
120%
15(R) –Isomer NMT 1.0% ND ND ND ND ND 0.05 0.02

8.
5,6 trans Bimatoprost NMT 1.0% 0.02 0.02 0.02 0.03 0.02 0.03 0.02
Unkown at RRT 0.36 NMT 0.10% BQL ND BQL 0.049 BQL BQL 0.04
Unkown at RRT 1.13 NMT 0.10% BQL BQL BQL 0.044 BQL BQL BQL
Total impurities NMT 2.5% 0.10 0.06 0.06 0.12 0.10 0.18 0.13


Table 31: Analytical results of Effect of 6.8 pH study, BP1/KE/031/137B ( Gamma)-Invert Study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) NA 0.99431.0018 0.9943 0.9943 0.9943 0.9943 0.9943
4. pH NA 6.67 6.49 6.68 6.66 6.67 6.62 NA
Not less than 101.9
90% and Not
6. Assay of Bimatoprost in (%) 98.9 100.0 100.0 101.8 101.0 NA
morethan
110%
Not less than 97.8
7. 96.8 102.9 101.8 96.8 98.1 NA
in (%) morethan
120%
15(R) –Isomer NMT 1.0% ND ND ND ND ND 0.04 ND

8.
5,6 trans Bimatoprost NMT 1.0% ND 0.02 0.02 0.02 0.025 0.04 0.02
Unkown at RRT 0.36 NMT 0.10% BQL ND BQL BQL BQL 0.03 BQL
Unkown at RRT 1.13 NMT 0.10% BQL BQL BQL BQL BQL 0.02 BQL

# The retention time of the major peak in chromatogram of the test sample corresponds to the major peak in the
chromatogram of the working / reference standard as obtained under assay method.
Table 32: Analytical results of Effect of 6.8 pH study, BP1/KE/031/137B (Eto)-Invert s
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) NA 0.99431.0018 0.9943 0.9943 0.9943 0.9943 0.9943
4. pH NA 6.68 6.49 6.69 6.66 6.68 6.65 NA
6. Assay of Bimatoprost in (%) Not less than 102.2 100.0 99.3 101.8 101.2 100.6 NA
90% and Not

morethan
110%
Not less than 99.7
7. 95.6 102.9 97.9 96.8 99.5 NA
in (%) morethan
120%
15(R) –Isomer NMT 1.0% ND ND ND ND ND 0.04 ND

8.
Unkown at RRT 0.36 NMT 0.10% BQL ND ND BQL 0.05 BQL BQL
Unkown at RRT 1.13 NMT 0.10% BQL BQL BQL BQL BQL BQL BQL

chromatogram of the working / reference standard as obtained under assay method
Table 33: Analytical results of Effect of 7.3 pH- BP1/KE/031/137C (Gamma container)-Invert study.
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) NA 1.00791.0018 1.0079 1.0079 1.0079 1.0079 1.0079
4. pH NA 7.14 6.49 7.14 7.14 7.14 7.10 NA
Not less than 102.6
90% and Not
6. Assay of Bimatoprost in (%) 100 100.0 100.4 101.1 100.3 NA
morethan
110%
Not less than 98.6
7. 97.0 102.9 98.3 98.3 97.7 NA
in (%) morethan
120%
15(R) –Isomer NMT 1.0% ND ND ND ND ND ND ND

8.
Unkown at RRT 0.36 NMT 0.10% BQL ND ND BQL BQL BQL BQL
Unkown at RRT 1.13 NMT 0.10% ND BQL BQL BQL ND BQL BQL

Table 34: Analytical results of Effect of 7.3 pH study, BP1/KE/031/137C (Eto)-Invert study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @

3. Weight/ml(g/ml) NA 1.00791.0018 1.0079 1.0079 1.0079 1.0079 1.0079
4. pH NA 7.12 6.49 7.19 7.18 7.12 7.14 NA
Not less than 102.4
90% and Not
6. Assay of Bimatoprost in (%) 101.7 100.0 100.1 100.7 101.2 NA
morethan
110%
Not less than 101.6
7. 97.6 102.9 99.2 100.1 97.7 NA
in (%) morethan
120%

8.
Unkown at RRT 0.36 NMT 0.10% BQL ND ND BQL BQL BQL ND
Unkown at RRT 1.13 NMT 0.10% BQL BQL ND BQL BQL ND BQL

Table 35: Analytical results of Effect of 7.8 pH study, BP1/KE/031/137D (Gamma)-Invert Study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) NA 0.99271.0018 0.9927 0.9927 0.9927 0.9927 0.9927
4. pH NA 7.63 6.49 7.58 7.67 7.61 7.65 NA
6. Assay of Bimatoprost in (%) Not less than 98.1 100.0 98.9 98.0 101.4 100.7 NA
90% and Not
morethan

110%
Not less than 99.1
7. 97.5 102.9 94.7 97.5 97.4 NA
in (%) morethan
120%

8.
5,6 trans Bimatoprost NMT 1.0% BQL 0.02 0.02 0.03 0.02 0.03 0.02
Unkown at RRT 0.36 NMT 0.10% ND ND ND ND BQL BQL ND

Table 36: Analytical results of Effect of 7.8 pH study, BP1/KE/031/137D(Eto)-Invert study

5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) 0.9927 1.00180.9927 0.9927 0.9927 0.9927 0.9927 0.9927
4. pH 7.61 6.49 7.67 7.60 7.61 7.61 NA 7.61
5. Osmolality (mOsmol/kg) 282 339 288 270 280 288 NA 282
6. Assay of Bimatoprost in (%) 101.9 100.0 98.4 99.4 100.6 100.9 NA 101.9
Preservative content (BKC) 97.4
7. 96.8 102.9 97.3 96.5 99.1 NA 96.8
in (%)

8.
Unkown at RRT 0.36 NMT 0.10% BQL ND ND BQL BQL BQL BQL

Table 37: Analytical results of Effect of 8.0 pH study, BP1/KE/031/137E (Gamma)-Invert Study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) NA 0.99461.0018 0.9946 0.9946 0.9946 0.9946 0.9946
4. pH NA 7.81 6.49 7.78SSS 7.78 7.80 7.78 NA
Not less than 101.0
90% and Not
6. Assay of Bimatoprost in (%) 98.2 100.0 100 99.4 101.0 NA
morethan
110%
Not less than 97.1
7. 96.0 102.9 96.7 99.2 97.9 NA
in (%) morethan
120%

8.
Unkown at RRT 0.36 NMT 0.10% BQL ND BQL BQL ND BQL BQL

Table 38: Analytical results of Effect of 8.0 pH study, BP1/KE/031/137E ( Eto)-Invert study
5°C 25°C/40 30°C/65% RH
40°C/25% RH
% RH
1M 3M 3M 1M 3M 3M
1. Description @ @ @ # @ @ @
3. Weight/ml(g/ml) TBE 0.9946 0.9946 0.9946 0.9946 0.9946 0.9946
4. pH TBE 7.79 7.80 7.81 7.79 7.83 NA
5. Osmolality (mOsmol/kg) TBE 274 284 282 265 286 NA
6. Assay of Bimatoprost in (%) TBE 101.7 99.5 99.1 100.9 100.7 NA
Preservative content (BKC) 97.2 NA
7. TBE 96.8 99.5 98.6 100.9
in (%)
15(R) –Isomer TBE ND ND ND ND ND ND

8.
5,6 trans Bimatoprost TBE 0.015 0.04 0.04 0.027 0.04 0.02
Unkown at RRT 0.36 TBE BQL BQL BQL BQL ND ND
Unkown at RRT 1.13 TBE BQL BQL BQL BQL ND BQL
Total impurities TBE 0.11 0.09 0.09 0.08 0.13 0.05


Conclusion: to be updated
16.5 Stability Batches

The study conducted illustrate the final stability batches listed in the below table.
Table 39: Batch details of final stability
Packaging Stability condition
S.No material Batch Number

2-80C (40ºC/25%RH) (30ºC/65%RH) (25ºC/40%RH)
steriliation
BP1/KE/031/06 √
1. -- √ √ √
2
√
Gamma
2. BPT- 201 √ √ √
sterilized
Table 40: Analytical results of BP1/KE/031/062 (5ml fill in 10 mL HDPE container –Upright)
S. 2-80C 40°C/25%RH 30°C/65%RH 25°C/40%RH

Parameter Specs Initial 3M 6M 12M
No 1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
1. Description @ @
@ @ @ @ @ @ @ @ @ @ @ @ @
Identification by # # # # # # # # # # # # # # #
2.
HPLC
1.00 1.008 1.008 1.008
3. Weight/ml(g/ml) NA 1.0089 NA NA NA 1.0089 1.0089
89 9 9 9
Betwee 7.12 7.09
4. pH n 6.8 to 7.20 7.35 7.16 7.11 7.08 7.10 7.22 7.09
7.8
1.01 1.011 1.011 1.011
5. Specific gravity NA 1.0119 NA NA NA 1.0119 1.0119
19 9 9 9
Betwee 310 326
Osmolality
6. n 240 to 313 320 324 319 316 323 318 327
(mOsmol/kg)
350
Assay of 101. 102.2 102.
7. 99.9 100.5 98.7 100.4 101.1 100.7 102.9
Bimatoprost (%) 0 6
Preservative 101. 100.2 100.
8. 101.1 99.6 100.6 98.6 101.3 103.3 101.7
BKC in (%) 5 0
9. Related substance: wt% by HPLC
NMT ND ND
15(R) –Isomer ND ND ND ND ND ND ND ND
1.0%
5,6 trans NMT 0.02 0.02
0.016 0.016 0.031 0.08 0.03 0.03 0.02 0.03
Bimatoprost 1.0%
Any unspecified NMT BQL BQL BQL BQL BQL BQL
degradation 0.1%
product

Unkown at RRT NMT

ND ND 0.045 0.07
0.29 0.1%
Unkown at RRT NMT
BQL BQL ND BQL
1.12 0.1%
NMT 0.03 0.02
Total impurities 0.05 0.02 0.11 0.18 0.06 0.03 0.07 0.03
2.5%

Table 41: Analytical results of BP1/KE/031/062 (5ml fill in 10 mL HDPE container –Invert)
2-80C 40°C/25%RH 30°C/65%RH 25°C/40%RH
S.
No 1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
1. Description @ @ @ @ @ @ @ @ @ @ @ @ @ @ @
Identification # #
2. . # # # # # # # #
by HPLC
Weight/ml(g/ 1.0089 1.008 1.008 1.008
3. NA 1.0089 NA NA NA 1.0089 1.0089
ml) 9 9 9
Between 7.14 7.10
4. pH 7.20 7.33 7.14 7.10 7.13 7.09 7.14 7.09
6.8 to 7.8
Specific 1.0119 1.011 1.011 1.011
5. NA 1.0119 NA NA NA 1.0119 1.0119
gravity 9 9 9
Between 313 324
Osmolality
6. 240 to 313 323 323 313 317 329 312 326
(mOsmol/kg)
350
Not more 101.9 102.9
than 90%
Assay of and not
103.
7. Bimatoprost more than 99.9 101.4 99.1 101.1 98.6 101.4 102.6
0
(%) 110% of
label
claim
Not less 102.2 101.0
than 70%
and not
Preservative 101.
8. more than 101.1 99.1 101.0 100.8 101.2 102.4 101.8
BKC in (%) 8
120% of
label
claim
Related substance: wt% by HPLC
15(R) – NMT ND ND
ND ND ND 0.03 ND ND ND ND
Isomer 1.0%
5,6 trans NMT 0.02 0.03
0.016 0.019 0.044 0.08 0.03 0.03 0.02 0.02
Bimatoprost 1.0%
Any BQL BQL
unspecified
NMT
9. degradation BQL BQL BQL BQL
0.1%
product
Unkown at NMT
ND ND 0.027 0.07
RRT 0.29 0.1%
Unkown at NMT
BQL BQL BQL 0.02
RRT 1.12 0.1%
Total NMT 0.04 0.03
0.05 0.04 0.11 0.24 0.10 0.03 0.06 0.02
impurities 2.5%


Table 42: Analytical results of BPT-201(Gamma) (5ml fill in 10 mL HDPE container –Upright)
2-80C
40°C/25%RH 30°C/65%RH 25°C/40%RH
S.
Parameter Specs Initial
No 3M 6M 12M
1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
1. Description @ @ @ @ @
Identification
2. . # # # #
by HPLC
Weight per 0.980to1.050 1.006 1.006 1.006
3. 1.006 1.006 1.006
mL
6.8to7.8 7.47 7.43 7.46
4. pH 7.49 7.46 7.46
Osmolality 240to 350 297 302 318
5. 305 299 301
(mOsmol/kg)
Assay of NLT90%to 98.1 101.3 ND
6. Bimatoprost NMT 110% 99.3 98.9 97.9
in %
Preservative NLT 70 %to 98.6 99.9 ND
7. 98.2 98.8 98.6
BKC in (%) NMT 120%
Related substance : wt % by HPLC
NMT1.0% ND ND ND
15(R) –Isomer ND ND ND
8. 5,6 trans NMT1.0% 0.03 0.02 0.02
0.02 0.03 0.02
Bimatoprost
Unspecified NMT0.1% BQL 0 BQL
impurity at ND .01 BQL BQL
RRT0.74
Total NMT 2.5% 0.03 0.03 0.02
0.02 0.03 0.02
impurities

Table 43: Analytical results of BPT-201(Gamma) (5ml fill in 10 mL HDPE container –Invert)
2-80C
40°C/25%RH 30°C/65%RH 25°C/40%RH
S.
No 3M 6M 12M
1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
@ @
1. Description @ @ @ @ @
Identificatio # #
2. # # # #
n by HPLC

Weight per 0.980to1.050 1.006 1.006 1.00

3. 1.006 1.006
mL 6
6.8to7.8 7.46 7.38
4. pH 7.49 7.48 7.46
Osmolality 240to 350 294 308
5. (mOsmol/kg 305 295 295
)
Assay of NLT90%to 99.7 101.1 ND
6. Bimatoprost NMT 110% 99.3 101.8
in %
Preservative NLT 70 %to 98.8 99.7 ND
7. 98.2 99.6
BKC in (%) NMT 120%
15(R) – NMT1.0% ND ND
ND ND ND
Isomer
8. 5,6 trans NMT1.0% 0.01 0.03
0.02 0.08 0.02
Bimatoprost
Unspecified NMT0.1% BQL 0
impurity at ND .01 BQL BQL
RRT0.74
Total NMT 2.5% 0.01 0.08
0.02 0.08 0.02
impurities

Table 44: Analytical results of BPT-201(ETO) (5ml fill in 10 mL HDPE container –Upright
2-80C
40°C/25%RH 30°C/65%RH 25°C/40%RH
S.
No 1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
@ @ @ @ @ @ @ @ @ @ @ @ @ @ @
1. Description
Identification # # # # # # # # # # # # # # #
2.
by HPLC
0.980to1.05 1.006
3. Weight per mL 1.006 1.006 1.006 1.006
0
6.8to7.8 7.52
4. pH 7.48 7.40 7.46 7.46
Osmolality 240to 350 300
5. 315 302 318 288
(mOsmol/kg)
Assay of NLT90%to 98.1 ND
6. Bimatoprost in NMT 110% 99.2 100.2 100.3
%
NLT 70 98.6 ND
Preservative
7. %to NMT 98.4 98.0 101.8
BKC in (%)
120%
NMT1.0% ND
15(R) –Isomer ND ND ND ND
5,6 trans NMT1.0% 0.02
0.02 0.02 0.03 0.02
8. Bimatoprost
Unspecified NMT0.1% BQL
impurity at BQL BQL BQL BQL
RRT0.74
NMT 2.5% 0.02
Total impurities 0.02 0.02 0.03 0.02

Table 45: Analytical results of BPT-201(ETO) (5ml fill in 10 mL HDPE container –Invert)
2-80C
40°C/25%RH 30°C/65%RH 25°C/40%RH
S.
No 3M 6M 12M
1M 3M 6M 3M 6M 9M 12M 3M 6M 12M
@ @
Description @ @ @ @ @
Identificatio # #
2 . # # # #
n by HPLC
Weight per 0.980to1.050
3 1.006 1.006 1.006 1.006
mL
6.8to7.8
4 pH 7.48 7.40 7.48 7.49
Osmolality 240to 350
(mOsmol/kg 315 306 312 293
)
Assay of NLT90%to ND
Bimatoprost NMT 110% 99.2 101.0 100.4
in %
Preservative NLT 70 %to ND
98.4 100.5 101.3
BKC in (%) NMT 120%
15(R) – NMT1.0%
ND ND ND ND
Isomer
6 5,6 trans NMT1.0%
7 0.02 0.02 0.03 0.01
Bimatoprost
Unspecified NMT0.1%
impurity at BQL BQL BQL BQL
RRT0.74
Total NMT 2.5%
0.02 0.02 0.03 0.01
impurities


16.6 Hold time study/ Compatibility study with SS316L vessel

The product compatibility study with SS316L vessel and PTFE GASKET (Hold time study) was
performed by holding the unfiltered and filtered bulk solution in SS316L vessel and PTFE GASKET
for 48 hours and withdrawing the sample at different tiqme intervals, for evaluating the impact on the
physicochemical attributes to understand the impact of holding time on finished product contact
material i.e. SS316L and PTFE GASKET at room temperature condition (25±5˚C). The batch details
and results are tabulated below.
Table 46: Batch details of Hold time study of Bimatoprost Ophthalmic Solution 0.1%
S.No. Sample withdrawal time point Condition Batch Number

Before filtration
1. Initial BP1/KE/031/046E
(PTFE Gasket)
Before filtration BP1/KE/031/046E1
2. 6 hrs
(PTFE Gasket)
3. 12 hrs
(PTFE Gasket)
4. 24 hrs
(PTFE Gasket)
5. 48 hrs
(PTFE Gasket)
Before filtration BP1/KE/031/046H1
6. 6 hrs
(SS vessel)
7. 12 hrs
(SS vessel)
8. 24 hrs
(SS vessel)
9. 48 hrs
(SS vessel)
After filtration BP1/KE/031/046 I1
10. 6 hrs
(PTFE Gasket)
11. 12 hrs
(PTFE Gasket)
12. 24 hrs
(PTFE Gasket)
13. 48 hrs
(PTFE Gasket)
After filtration (SS BP1/KE/031/046 J1
14. 6 hrs
vessel)
After filtration (SS BP1/KE/031/046 J2
15. 12 hrs
vessel)
After filtration BP1/KE/031/046 J3
16. 24 hrs
(SS vessel)

After filtration BP1/KE/031/046 J4

17. 48 hrs
(SS vessel)
Table 47: Analytical results of Hold Time study of Bimatoprost Ophthalmic Solution 0.1% Before
(Filtration - PTFE Gasket)
S. BP1/KE/031/046E BP1/KE/031/04 BP1/KE/031/046 BP1/KE/031/046E4xx

N Test Specs Initial
1xxxiii 6E2xxxiii E3xxxiii xiii
o
Descripti
@ @ @ @ @
o
6.8to
pH value 7.09 7.11 7.07 7.13
7.8
NLT9
Assay of
0%to
Bimatop 103.4 103.3 103.1 103.1
NMT
rost %
110%
NLT
70
BKC % %to 99.8 101.9 99.1 99.4
NMT
120%
Related Substance: wt% By HPLC
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-
NMT
Trans 0.015 ND 0.013 0.014
1.0%
isomer
Highest
Unknow
n
Impurity 0.074 0.124 0.200 0.310
at
RRT_0.
12
Total
NMT
impuritie 0.16 0.22 0.35 0.56
2.5%
s
Table 48: Analytical results of Hold Time study of Bimatoprost Ophthalmic Solution 0.1% After (Filtration -
PTFE Gasket)
S. BP1/KE/031/046I BP1/KE/031/04 BP1/KE/031/046I BP1/KE/031/046I4xxx

1xxxiii 6I2xxxiii 3xxxiii iii
o
Descripti
@ @ @ @ @
o
6.8to
pH value 7.12 7.13 7.13 7.09
7.8
NLT9
Assay of
0%to
Bimatop 103.0 103.3 103.0 104.2
NMT
rost %
110%
NLT
70
BKC % %to 101.3 101.4 101.3 101.0
NMT
120%
15 (R) NMT ND ND ND ND

Isomer 1.0%
5,6-
NMT
Trans 0.012 0.010 0.011 0.015
1.0%
isomer
Highest
Unknow
n
Impurity 0.021 0.020 0.0 0.021
at
RRT_0.
12
Total
NMT
impuritie 0.06 0.06 0.10 0.08
2.5%
s
Table 49: Analytical results of Hold Time study of Bimatoprost Ophthalmic Solution 0.1% (Before Filtration - SS
vessel)
S. BP1/KE/031/046H BP1/KE/031/04 BP1/KE/031/046 BP1/KE/031/046H4xx

1xxxiii 6H2xxxiii H3xxxiii xiii
o
Descripti
@ @ @ @ @
o
6.8to
pH value 7.10 7.11 7.12 7.10
7.8
NLT9
Assay of
0%to
Bimatop 103.1 103.3 103.6 103.7
NMT
rost %
110%
NLT
70
BKC % %to 101.3 101.9 102.3 99.9
NMT
120%
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-
NMT
Trans 0.018 0.017 0.011 0.016
1.0%
isomer
Highest
Unknow
n
Impurity 0.023 0.026 0.028 0.022
at
RRT_0.
12
Total
NMT
impuritie 0.04 0.05 0.04 0.04
2.5%
s

Table 50: Analytical results of Hold Time study of Bimatoprost Ophthalmic Solution 0.1% (After Filtration - SS
vessel)i
S. BP1/KE/031/046J BP1/KE/031/04 BP1/KE/031/046J BP1/KE/031/046J4xxx

N Test Specs Initial ii
1xxxiii 6J2xxxiii 3xxxiii iii
o
Descripti
@ @ @ @ @ @
o
6.8to
pH value 7.05 7.12 7.12 7.10
7.8
NLT9
Assay of
0%to
Bimatop 103.2 103.1 103.3 103.5
NMT
rost %
110%
NLT
70
BKC % %to 102.4 100.1 100.4 100.4
NMT
120%
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-
NMT
Trans 0.012 0.012 0.013 0.016
1.0%
isomer
Highest
Unknow
n
Impurity 0.019 0.020 0.017 0.022
at
RRT_0.
12
Total
NMT
impuritie 0.05 0.06 0.05 0.08
2.5%
s
Conclusion:
1. No significant decrease in assay of Bimatoprost is observed.
16.7 Filter compatibility study
In addition to filter validation with respect to physical compatibility, the chemical
compatibility of drug product with different filters MOC (Material of construction) of filter
was evaluated to find out the compatible filter with product. Hence, the compatibility of
product solution was performed using PES,PVDF filter membrane (Make: Millipore Express
SHF 47 mm) having 0.2µm pore size.
The study was performed by submerging the filter membrane in bulk solution of
Bimatoprost Ophthalmic Solution 0.1% for 48 hours. During the course of study, the sample
were withdrawn at different time intervals and subjected for chemical analysis to evaluate its

impact on product attributes like pH, Assay (Drug Substance and Preservative) and Related
Substances. The batch details and results are tabulated below.
Table 51: Batch details of Filter compatibility study of Bimatoprost Ophthalmic Solution 0.1%
S.No. Sample withdrawal time point Batch Number

1. Initial BP1/KE/031/046 G
6 hrs BP1/KE/031/046 G1
2.
(PVDF)
12 hrs BP1/KE/031/046 G2
3.
(PVDF)
24 hrs BP1/KE/031/046 G3
4.
(PVDF)
48 hrs BP1/KE/031/046 G4
5.
(PVDF)
6. Initial BP1/KE/031/046 F
6 hrs BP1/KE/031/046 F1
7.
(PES)
12 hrs BP1/KE/031/046 F2
8.
(PES)
24 hrs BP1/KE/031/046 F3
9.
(PES)
48 hrs BP1/KE/031/046 F4
10.
(PES)
Table 52 : Analytical results of Filter compatibility study of Bimatoprost Ophthalmic Solution 0.1% with PVDF
Filter
S. BP1/KE/031/046G BP1/KE/031/04 BP1/KE/031/046 BP1/KE/031/046G4xx

1xxxiii 6G2xxxiii G3xxxiii xiii
o
Descripti
@ @ @ @ @
o
6.8to
pH value 7.10 7.11 7.12 7.10
7.8
NLT9
Assay of
0%to
Bimatop 101.4 103.3 103.6 104.1
NMT
rost %
110%
NLT
70
BKC % %to 98.4 100.7 100.9 98.9
NMT
120%
15 (R) NMT ND ND ND ND
Isomer 1.0%

5,6-
NMT
Trans 0.012 0.013 0.012 0.014
1.0%
isomer
Highest
Unknow
n
Impurity 0.017 0.018 0.016 0.023
at
RRT_0.
12
Total
NMT
impuritie 0.03 0.03 0.03 0.03
2.5%
s
Table 53: Analytical results of Filter compatibility study of Bimatoprost Ophthalmic Solution 0.1% with PES
Filter
S. BP1/KE/031/046F BP1/KE/031/04 BP1/KE/031/046 BP1/KE/031/046F4xx

1xxxiii 6F2xxxiii F3xxxiii xiii
o
Descripti
@ @ @ @ @ @
o
6.8to
pH value 7.09 7.10 7.09 7.10
7.8
NLT9
Assay of
0%to
Bimatop 102.8 103.0 102.9 102.8
NMT
rost %
110%
NLT
70
BKC % %to 100.2 101.2 101.0 99.6
NMT
120%
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-
NMT
Trans 0.014 0.013 0.013 0.015
1.0%
isomer
Highest
Unknow
n
Impurity 0.015 0.011 0.028 0.025
at
RRT_0.
12
Total
NMT
impuritie 0.03 0.03 0.05 0.05
2.5%
s
Conclusion:
1. No significant decrease in assay of Bimatoprost is observed.

The formulation will be compatible with exposure to filtration (PES filter) in our process.
Integrity testing
Compatibility study
Bacterial Retention study
Extractable study
Adsorption study
Filter Contact time
Conclusion:
16.8 Tubing compatibility study

Tubing compatibility study was performed under static and dynamic condition to simulate
the plant process for evaluating the impact of process components which were exposed to the
product during manufacturing operation.
Tubing compatibility under dynamic condition: Bulk solution was kept under circulation
mode in tubing for 8 hrs using peristaltic pump and sample was withdrawn at different time
intervals to evaluate the impact of tubing on physicochemical attributes of drug product.
Tubing compatibility under static condition: Bulk solution was filled in tubing and kept for
48 hrs and withdrawn the sample at different time intervals to evaluate the impact of tubing
on physicochemical attributes of drug product. The batch details and results are tabulated
below.
Table 54: Batch details of Tubing compatibility study for Bimatoprost Ophthalmic Solution 0.1%
Sample
S.No Manufacturing
withdrawal Condition Batch Number
. By
time point
Dynamic - Impure Platinum
1. Initial Saints Gobain BP1/KE/031/046A
cured silicone tubing
2. 6 hrs Saints Gobain BP1/KE/031/046A1


Static - Impure Platinum cured
6. Initial Saints Gobain BP1/KE/031/046B
silicone tubing
Static - Impure Platinum cured BP1/KE/031/046B1
7. 3 hrs Saints Gobain
silicone tubing
silicone tubing
silicone tubing
silicone tubing
Static - Impure Platinum cured
11. 48 hrs Saints Gobain BP1/KE/031/046B5
silicone tubing
Dynamic - Platinum cured
12. Initial Saints Gobain BP1/KE/031/046C
silicone tubing
Dynamic - Platinum cured BP1/KE/031/046C1
silicone tubing
silicone tubing
silicone tubing
silicone tubing
Static - Platinum cured silicone
17. Initial Saints Gobain BP1/KE/031/046D
tubing
Static - Platinum cured silicone BP1/KE/031/046D1
tubing
tubing
tubing
tubing
tubing
Table 55: Analytical results of Tubing compatibility study (Dynamic – Impure Platinum cured silicone)
S. BP1/KE/031/046 BP1/KE/031/0 BP1/KE/031/0

Test Specs Initial BP1/KE/031/046A4xxxiii
No A1xxxiii 46A2xxxiii 46A3xxxiii

Descripti
@ @ @ @ @ @
o
6.8to7
pH value 7.08 7.06 7.06 7.06
.8
NLT9
Assay of
0%to
Bimatopr 103.7 103.9 104.7 105.8
NMT
ost %
110%
NLT
70
BKC % %to 99.8 100.2 99.7 96.6
NMT
120%
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-Trans NMT
0.015 0.016 0.017 0.014
isomer 1.0%
Highest
Unknow
n
Impurity 0.015 0.014 0.025 0.036
at
RRT_0.1
2
Total
NMT
impuritie 0.03 0.05 0.06 0.06
2.5%
s
Table 56: Analytical results of Tubing compatibility study (Static - Impure Platinum cured sssilicone)
BP1/KE/0 BP1/KE/031/0
S. BP1/KE/031 BP1/KE/031/04 BP1/KE/031/046B4
Test Specs Initial 31/046B1xx 46B5xxxiii
No xiii
/046B2xxxiii 6B3xxxiii xxxiii
Descripti
@ @ @ @ @ @
o @
6.8to7 7.08
pH value 7.07 7.06 7.08 7.08
.8
NLT9 103.1
Assay of
0%to
Bimatopr 103.1 102.6 102.8 102.3
NMT
ost %
110%
NLT 99.6
70
BKC % %to 100.9 100.3 100.6 98.4
NMT
120%
15 (R) NMT ND
ND ND ND ND
Isomer 1.0%
5,6-Trans NMT 0.018
0.014 0.014 0.014 0.015
isomer 1.0%
Highest
Unknow
n
Impurity 0.015 0.015 0.020 0.018 0.011
at
RRT_0.1
2
Total NMT 0.03 0.03 0.03 0.04
impuritie 2.5% 0.03

Table 57: Analytical results of Tubing compatibility study (Dynamic - Platinum cured silicone tubing)
S. BP1/KE/031/046 BP1/KE/031/0 BP1/KE/031/0

Test Specs Initial BP1/KE/031/046C4xxxiii
No C1xxxiii 46C2xxxiii 46C3xxxiii
Descripti
@ @ @ @ @ @
o
6.8to7
pH value 7.07 7.07 7.08 7.11
.8
NLT9
Assay of
0%to
Bimatopr 103.4 103.5 103.8 104.0
NMT
ost %
110%
NLT
70
BKC % %to 102.1 102.0 99.9 100.0
NMT
120%
Related Substance: wt% By HPLC Related S
15 (R) NMT
ND ND ND ND
Isomer 1.0%
5,6-Trans NMT
0.013 0.012 0.013 0.013
isomer 1.0%
Highest
Unknow
n
Impurity 0.016 0.012 0.014 0.012
at
RRT_0.1
2
Total
NMT
impuritie 0.03 0.02 0.04 0.03
2.5%
s
Table 58: Analytical results of Tubing compatibility study (Static - Platinum cured silicone tubing)xxxiv
BP1/KE/0 BP1/KE/031/0
S. BP1/KE/031 BP1/KE/031/04 BP1/KE/031/046D4
Test Specs Initial 31/046D1x 46D5xxxiii
No xxiii
/046D2xxxiii 6D3xxxiii xxxiii
Descripti
@ @ @ @ @ @
o @
6.8to7 7.10
pH value 7.08 7.04 7.08 7.07
.8
NLT9
Assay of
0%to 103.5
Bimatopr 103.1 102.4 103.3 104.3
NMT
ost %
110%
NLT 95.6
70
BKC % %to 101.4 100.1 99.5 99.4
NMT
120%
15 (R) NMT ND
ND ND ND ND
Isomer 1.0%
5,6-Trans NMT 0.016 0.023 0.017 0.016 0.010

isomer 1.0%
Highest
Unknow
n
Impurity 0.023 0.022 0.021 0.019 0.011
at
RRT_0.1
2
Total
NMT
impuritie 0.04 0.04 0.04 0.05 0.02
2.5%
s
Conclusion:
1. No significant decrease in assay of Phenylephrine HCl is observed.

16.9 Antimicrobial effectiveness testing

Table 59: Batch details of Antimicrobial effectiveness testing
Quantity of Preservative (Benzalkonium

S.No. Batch Number
Chloride)
1. 50% BKC of label claim BP1/KE/031/043A
2. 75% BKC of label claim BP1/KE/031/043B
3. 100% BKC of label claim BP1/KE/031/043C
4. 125% BKC of label claim BP1/KE/031/043D
S.No. Batch Number Results
The product complies wrt Preservative Efficacy Test as per the

1. BP1/KE/031/043A
specified procedural Reference at 50% preservative content
2. BP1/KE/031/043B
3. BP1/KE/031/043C
4. BP1/KE/031/043D
Table 60: Analytical results of Antimicrobial effectiveness study
Conclusion: The Bimatoprost Ophthalmic solution complies with the Antimicrobial Effectiveness
study at 50, 75, 100, 125 % w/w of Preservative content as per USP <51>.

16.10 Excursion study

The pharmaceutical products should be shipped in a manner that, the products will not be
adversely affected by environmental conditions on the basis of product stability, product
history, packaging information and the transport system used. A shipment may encounter
unforeseen transport events, weather and temperature conditions. These factors should be
therefore considered while designing drug development studies to understand ‘anticipated
extreme challenges’. Hence, Thermal cycling studies for 12 days at -20°C and 40°C
respectively performed and Thermal excursion studies for 4 days at 60°C were conducted
on lab scale sample to evaluate the impact of temperature excursions that may occur during
shipping .
Table 61: Batch details of Thermal cycling study/ Thermal excursion study
S.No Strength Fill volume

Batch Number Condition
. (Pack size)
1. BPT-201 (ETO) 0.1% Thermal cycling 5 mL
2. BPT-201 (Gamma) 0.1% 5 mL
study/ Thermal
3. BPT-201 (ETO) 0.1% 5 mL
4. BPT-201 (Gamma) 0.1% excursion study 5 mL

Table 62: Analytical results of study BPT-201 ( THERMAL EXCURSION ETO) (5 mL Pack) iii
S. No Parameter Specs Initial 400C/75%RH 600C/85%RH

1 Description Clear colorless solution @ @ @
The retention time of the complies
Bimatoprost peak of sample
Identification by
2 solution corresponds to that of the complies
HPLC
reference/working standard solution
as obtained in the assay
3 Weight/ml(g/ml) TBE 1.006 1.006
4 pH TBE 7.40 7.40
Osmolality 310 309
5 TBE
(mOsmol/kg)
Assay of 102.0 101.3
6 TBE
Bimatoprost (%)
Preservative BKC 100.2 97.1
7 TBE
in (%)
5,6 trans ND
TBE 0.023
Bimatoprost
5
Unkown at RRT TBE ND ND
0.48
Unkown at RRT TBE ND 0.014
1.12

Table 63: Analytical results of study BPT-201 ( THERMAL EXCURSION Gamma) (5 mL Pack)

Identification by
HPLC
4 pH TBE 7.48 7.50
Osmolality 293 302
5 TBE
(mOsmol/kg)
Assay of 101.9 101.0
6 TBE
Bimatoprost (%)
7 TBE
in (%)
5,6 trans ND
TBE 0.02
Bimatoprost
5
01.12
1.13

Table 64: Analytical results of study BPT-201 ( THERMAL CYCLING ETO) (5 mL Pack)

Identification by
HPLC
4 pH TBE 7.41 7.41
Osmolality 312 310
5 TBE
(mOsmol/kg)
Assay of 100.4 96.8
6 TBE
Bimatoprost (%)
7 Preservative BKC TBE 97.6 96.8

in (%)
5,6 trans 0.018
TBE 0.017
Bimatoprost
5
Unkown at RRT TBE 0.018 0.018
01.12
1.13

Table 65: Analytical results of study BPT-201 ( THERMAL CYCLING GAMMA) (5 mL Pack)

Identification by
HPLC
4 pH TBE 7.42 7.42
Osmolality 310 310
5 TBE
(mOsmol/kg)
Assay of 100.3 101.8
6 TBE
Bimatoprost (%)
7 TBE
in (%)
5,6 trans 0.016
TBE 0.014
Bimatoprost
5
Unkown at RRT TBE 0.016 0.014
01.12
1.13


16.11 Photostability study
Table 66: Batch details of Photostability study
S.No. Strength Batch Number Fill volume (Pack size)

1. 0.01% BPT201 5mL
Table 67: Analytical results of Photostability study BPT 201 ( 5mL Pack ETO)iv
S. No Parameter Specs Primary pack Secondary pack Aluminium foil

The retention time of the
Identification by
2 solution corresponds to that of the
HPLC
3 Weight/ml(g/ml) NA 1.006 1.006 1.006
4 pH NA 7.40 7.40 7.39
Osmolality 309 313
5 NA 310
(mOsmol/kg)
Assay of 103.3 102.6
6 NLT90.00% NMT 110% 102.4
Bimatoprost (%)
7 NLT 70.00% NMT 120% 96.1
in (%)
15(R) –Isomer NMT 1.0% ND ND ND
5,6 trans 0.02
NMT 1.0% ND 0.02
Bimatoprost
5 Any unspecified NMT 0.10% BQL BQL BQL
Degradation
Product
NMT 2.5% 0.05 0.08 0.06
Total impurities

Table 68: Analytical results of Photostability study BPT 201 (5 mL Pack GAMMA)
S. No Parameter Specs Primary pack Secondary pack Aluminium foil

2 Identification by The retention time of the
HPLC Bimatoprost peak of sample
solution corresponds to that of the


3 Weight/ml(g/ml) NA 1.008 1.008 1.008
4 pH NA 7.43 7.43 7.43
Osmolality 309 308
5 NA 315
(mOsmol/kg)
Assay of 103.7 98.1
6 NLT90.00% NMT 110% 103.1
Bimatoprost (%)
7 NLT 70.00% NMT 120% 96.1
in (%)
15(R) –Isomer NMT 1.0% ND ND ND
5,6 trans 0.034
NMT 1.0% 0.03 0.03
Bimatoprost
5 Any unspecified NMT 0.10% ND ND ND
Degradation
Product
NMT 2.5% 0.03 0.03 0.03
Total impurities

Brief Manufacturing Process and Flow Diagram

Note: 1. The API shall be thawed before dispensing at
Dispensing of API & excipients, 2-80C for NMT 1hour.
Packing Materials from Warehouse. 2. Dispensed API to be stored at -250C to 150C in tight
light resistant containers.
2. Weighing of API: Under Monochromatic Light.
3. Manufacturing area should have Monochromatic
Light
Class C Collection of WFI (pH tests

performed as per the Sampling Plan)
Collect 110% of WFI
Mfg. SS Vessel-1 Mfg. SS Vessel-2
Storage SS Vessel:
70% of WFI at NMT 25ºC is
Transfer 40% of
Nitrogen Purge/ Chilled transferred to Vessel
Excess WFI
water circulation,
temperature NMT 25°C
Shtrijytuikut
eryh6
Order of API & Class C Order of API & Excipients
Class C Excipients Addition Addition Excipients
Excipients
Item.1: Addition Item.1: Addition Item.3:

of 5% Item. 2: Item.2: Addition Addition of
of Sodium
Benzalkonium Addition of of Boric Acid Glycerin
Borate
Chloride (5%) Bimatoprost
All stages should be monitored for complete solubilization (i.e. until clear solution is
obtained)

Class C Addition of Excipients
Adj pH: Adjust

Final Volume Make
pH with NaOH/
up with WFI from
Phosphoric acid SS Vessel
Vessel 1, stir well.
if required
Check pH – MFG
Stir well after addition of pH adjusting agent
Class A
First Sterile
Filtration Filtration
Holding Vessel Buffer Vessel
(0.22 µm) (0.22 µm)
Class A
 Decartoning of HDPE bottles LDPE

(washing area) bottle
Stoppering
 Depyrogenation of bottles Filling
 Sterilization of nozzle,cap
Capping

Visual Inspection and Leak Testing
Storage of unlabelled filled Bottle in Quarantine area
Labeling of filled Bottles
Secondary Packing of labeled vials
Transfer to Finished Goods Area
Secondary Packing of labeled Bottles
Transfer to Finished Goods Area
Figure 2: Flow Diagram of Manufacturing Process

Manufacturing process flow chart for Bimatoprost Opthalmic Solution 0.01%
Steps Ingredients Machine Manufacturing Process Flow Area/ In-Process parameter
Dispensing of Raw
1
materials
API
1a Bimatoprost Weighin Dispensing of API, Bimatoprost in RT: 23±20C
g balance amber glass USP type-1 container RH: NMT 55%
under monochromatic light. Monochromatic light
Excipients
1b Boric acid Weighin Dispensing of Boric acoid in
g balance polybag under normal light.
1c Sodium Weighin Dispensing of Sodium borate in

borate g balance Polybag under normal light.
1d Glycerin Weighin Dispensing of Glycerin in Duran

RT: 23±20C
g balance bottle under normal light. RH: NMT 55%
1e Benzalkoniu Weighin Dispensing of Benzalkonium
m chloride g balance Chloride in Duran bottle under
normal light.
1f Hydrochloric Weighin Dispensing of Hydrochloric acid
acid g balance in Duran bottle under normal light.
1g Sodium Weighin Dispensing of Sodium Hydroxide

Hydroxide g balance in Duran bottle under normal light
2 Dispensing of
Packaging materials
2a 10 mL RSP white R2
New (L)-Berry RT: 23±20C
2b N-Open RSP 45 mL LTR RH: NMT 55%
design - berry
2c Tamp Safe RSP R2 -30
Tarq HDPE CAP -
berry
3 Whole of the manufacturing process of Phenylephrine HCl ophthalmic solution is

performed under Sodium vapour Light
Ingredients Instrum Process Flow Area/In-process Parameter

ent/
Utensil
3a WFI SS Collect 110% of water for Injection Temp: 25±50C
vessel-1 solution in SS vessel-1 and cool it RPM:
with at room temperature with nitrogen Pressure:
pneumati purging. Transfer 40%of the total Time:
c stirrer batch size WFI into storage veseel

for rinsing, volume makeup &
preparation of buffer solution.
1- PREPARATION OF BIMATOPROST AND PRESERVATIVE SOLUTION
3b WFI SS Transfer 10% of water for Injection Temp: 25±50C
vessel-2 solution in SS vessel-2. RPM:
with
pneumati
c stirrer
3c Benzalkoniu SS Add Benzalkonium Chloride in Temp: 25±50C
m chloride vessel-2 purged WFI under continuous RPM:
with stirring in SS vessel-2 till clear
pneumati solution is formed.
c stirrer
3d Bimatoprost SS Add Batch quantity of Bimatoprost Temp: 25±50C
vessel-2 in purged WFI under continuous RPM:
with stirring for NLT 3 hour in SS
pneumati vessel-2 till clear solution is formed
c stirrer
2- PREPARATION OF BULK SOLUTION
3c WFI SS Transfer 60% of water for Injection Temp: 25±50C
vessel-3 solution in SS vessel-3. RPM:
with
pneumati
c stirrer
3e Sodium SS Add Batch quantity of Sodium RPM:
borate vessel-3 borate in purged WFI under Time:
with continuous stirring in SS vessel-3 Temperature: 25±50C
pneumati
till clear solution is formed.
c stirrer
3g Boric acid SS Add Batch quantity of Boric acid

vessel- in above bulk solution under RPM:
23with continuous stirring in SS vessel- Time:
pneumati 3and kept for stirring till clear Initial pH:
c stirrer solution is formed. Temperature:25±50C
3i Glycerin SS Add Glycerin in the above bulk RPM:

vessel- solution under continuous stirring Time:
3with in SS vessel-3 and kept for stirring Initial pH:
pneumati till clear solution is formed. Temperature:25±50C
c stirrer
Addition of SS Add bimatoprost + Benzalkonium

bimatoprost vessel- chloride in to bulk solution under
and 3with continuous stirring. Rinse the
preservative pneumati SS316 vessel or glass beaker
solution in c stirrer thoroughly using WFI from
bulk solution storage veseel and add back
rinsate.Continue stirring for NLT
15 mintute or until clear solution
was obtained.( Note: The stirring of
the solution should be done very
slowly as it should be not form

foam in the solution)
3j pH pH meter Check the initial pH of the solution RPM:
of the Bimatoprost Ophthalmic Time:
solution 0.01%. pH:
Temperature: 25±50C
3k pH pH meter Adjust the pH of the bulk solution RPM:

Adjustment to 7.1 using 1N Sodium hydroxide Time:
and/or 1N Hydrochloric acid . pH:
Temperature: 25±50C
Preparation of 500 ml, 1N
Sodium Hydroxide solution:
Dissolve 20.0 g of Sodium
hydroxide in pre-purged WFI in
500 ml of standard volumetric flask
and adjust the volume upto 500 ml
with same WFI.
Preparation of 500 ml, 1N

Phosphoric acid solution:
Dissolved 11.4 ml of Phosphoric
acid mixed with 100 ml of pre-
purged WFI in 500ml of standard
volumetric flask then adjust the
volume upto 500ml with WFI.
In-process controls
3l Temperature Makeup the volume using pre- RPM:

25±50C purged Water for Injection solution Time:
and keep for stirring till clear Temperature:
solution is formed maintaining
temperature
3m pH Check the pH of the final bulk RPM:

solution of Bimatoprost Time:
Ophthalmic solution 0.01%. pH:
In process test: Description,
Identification, pH , Assay and
RS
3n  Filter pre- Filter First filtration of the bulk solution Filtration Temp.,
integrity Integrity of Phenylephrine HCl ophthalmic Nitrogen pressure for filtration
test (Bubble Tester solution using filter of 0.22 µm.
point) Filter
 Clarity of housing
solution
 Filter post-
integrity
test
Ingredients/ Instrum Process Flow Area/In-process Parameter
Condition ent/
Utensil
3o Holding Collect the Bulk solution of In-process testing after
vessel Bimatoprost Ophthalmic solution filtration (description,
in holding vessel. Identification, pH, Assay, RS)

Loss during filtration and
Temperature of the product
4 Decartoning of LDPE bottles
5 Manufacturing, Filtration Accessories and Filling Machine Parts
6 Filling and Stoppering
 Filter pre- Filter 1. Filtration (Second filtration) of In-process sampling: Flush

integrity Integrity the bulk solution using 0.22 µm with Nitrogen, Machine speed
test (Bubble Tester filter. vial/min
point) Filter 2. Adjust the fill volume.
 Filter post- housing 3. Fill the desired volume of bulk
integrity Filling & solution of Bimatoprost
test stopperin Ophthalmic solution 0.01%.
6a
 Fill volume g in HDPE bottles with pre and post
machine Nitrogen flushing of vials
5. Stoppering the bottle using
natural HDPE nozzle and stoppered
with red cap.
7 Visual Optical Inspection

Visual Inspection of the
Visual Bimatoprost Ophthalmic solution
Particle and 0.01%.
breakages
8 Packaging
RT: 23±20C Labeling Labeling & secondary packing of Machine speed
RH: NMT machine the Bimatoprost Ophthalmic
55% solution .
9 Storage
RT: 23±20C sStorage of the Bimatoprost Final testing as per drug
RH: NMT Ophthalmic solution 0.01%. product specification
55%

i
..\ARD Reports\PH2-PL-025-163.pdf
ii
..\ARD Reports\PH1-PL-025-091..pdf
iii
..\ARD Reports\PH1-VP-013-121(Thermal)(Photo).pdf
iv
..\ARD Reports\PH1-VP-013-121.pdf

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PHARMACEUTICAL DEVELOPMENT REPORT

Name of Product Bimatoprost Ophthalmic Solution 0.01%

PDR No. MRC/BI1/PDR/2020/003/00

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 1 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 2 of 81

16.4 Effect of pH......................................................................................................51-61

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 4 of 81

Table : Physicochemical characterization of the RLD Bimatoprost ophthalmic solution 0.01 %

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 5 of 81

Table 33: Batch details of Effect of Gas study........................................................................54

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 6 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 7 of 81

Table 97: Analytical results of Photostability study PH1/VP/013/121 (15 mL Pack)...........116

Figure 1: Flow chart for Process Selection..............................................................................38

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 8 of 81

Figure 2: Flow Diagram of Manufacturing Process...............................................................123

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 9 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 10 of 81

desired quality. Our investigation during pharmaceutical development focused on those

Analysis of Reference Listed Drug Product

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 11 of 81

3.1 Mechanism of Action

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 12 of 81

sponsor has conducted a number of studies to investigate the endogenous formation of

Product Name Bimatoprost ophthalmic solution 0.01%

Manufacturer Allergan, Inc.

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 13 of 81

Expiry Date Feb- 2021 Mar-2021 Aug- 2020

ND: Not detected

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 14 of 81

6. Reference pack characterization

Product name Bimatoprost ophthalmic solution 0.01%

Label Claim Each mL contains: Bimatoprost 0.1mg/mL

NDC Number 0023-3205-03 0023-3205-08

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 15 of 81

Storage condition details Store at 2° - 25°C (36° - 77°F)

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 16 of 81

7. Sodium Hydroxide NF pH adjusting agent q.s.

8. Quality Target Product Profile (QTPP) for the ANDA product

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 17 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 18 of 81

9. Quality Attributes of Bimatoprost Ophthalmic solution, 0.01%

Table 5: Critical Quality Attributes (CQAs) of Bimatoprost Ophthalmic solution 0.01%

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 19 of 81

working/reference standard solution as

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 20 of 81

critical to product safety.

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 21 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 22 of 81

7. Any unspecified degradation

Pharmacopoeial requirement as this will affect

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 23 of 81

shall not impact the safety and efficacy of the

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 24 of 81

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 25 of 81

Components of Drug Product

Pharmacopoeial Status In-house

10.3 Physicochemical properties

PDR No.: MRC/BI1/PDR/2020/003/00 CONFIDENTIAL Page 26 of 81