UNITED STATES PATENT AND TRADEMARK OI?I,~ICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`V.
`
`SENJU PHARl\ttACEUTlCAL CO .• LTD.
`Patent Owner
`
`Case IPR20 15-011 00
`Patent 8,927,606 B2
`
`DECLARATION Oli~DARYL S. PAlJLSON, PH.D., M.A., M.S., M.B.A.
`
`Page 1 of29
`
`1
`
`SENJU EXHIBIT 2128
`LUPIN v. SENJU
`IPR2015-01100
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`V.
`
`SENJU PHARl\ttACEUTlCAL CO .• LTD.
`Patent Owner
`
`Case IPR20 15-011 00
`Patent 8,927,606 B2
`
`DECLARATION Oli~DARYL S. PAlJLSON, PH.D., M.A., M.S., M.B.A.
`
`Page 1 of29
`
`1
`
`SENJU EXHIBIT 2128
`LUPIN v. SENJU
`IPR2015-01100
`
`
`
`T, Daryl S. Paulson, Ph.D., M.A., M.S., M.B.A., under penalty of pe1jury,
`
`declare as follows:
`
`I.
`
`QlJAIJFICATIONS
`
`1.
`
`I submit this declaration at the request of Finnegan, Henderson,
`
`Farabow~ Gan·ett & Dunner, LLP on behalf of Senju Phanm1ceutical, Co., Ltd.
`
`("Senju") in connection with IPR2015-01100 inter partes review ("IPR")
`
`proceeding before the United States Patent and Trademark Office ePTOH) Patent
`
`Trial and Appeal Board ("Board'') as an expert in the field of the evaluation of
`
`drug products. My qualifications in these areas, as well as other areas, are
`
`established below and by my curriculum vitae, which is EX2129.
`
`2.
`
`I am currently the President and CEO of BioScience Laboratories, Inc.
`
`in Bozeman, Montana, which I founded in 1991.
`
`3.
`
`In the field of microbiology, I received a B.S. degree in medical
`
`microbiology from College of Great Falls in 1979 and a M.S. degree in medical
`
`microbiology/biostatistics from University of Montana in 198 I.
`
`I have also
`
`received a M.A. degree in psychology from Pacifka Graduate Institute - Santa
`
`Barbra, California, in 1988, a Ph.D. degree in Psychology from Sierra University
`
`in 1989, and a Ph.D. degree in Human Science from SayBrook Research Institute
`
`and Graduate School. I have also received an M.B.A. degree from University of
`
`Montana in 2002, a Ph.D. degree in Asian art history from \Varnborough
`
`Page 2 of29
`
`2
`
`
`
`University~ UK, and a Ph.D. degree m Psychology from
`
`the Institute of
`
`Transpersonal Psychology in 2008.
`
`4.
`
`I have an extensive experience in the fields of management science,
`
`research and development, clinical trials, biostatistics, and clinical microbiology
`
`and have authored publications and given presentations related to pharmaceutical
`
`drug prod.ucts. Among my numerous publications, I have authored Topical
`
`Antilnicrobial Testing and Evaluation, Taylor & Francis, 2014, and I have also
`
`edited the Handbook of' Topical Antimicrobials, Marcel Dekker, 2002.
`
`II. DOCUlvfENTS AND INFORMATION CONSIDERED IN FORlVUNG
`OPINlONS
`
`5.
`
`Under my direction and control, BioScience Laboratories, Inc.
`
`conducted a Preservative Effectiveness Test ("PET") to evaluate and determine the
`
`antimicrobial preservatives effectiveness of several samples challenged with
`
`resistant microorganisms. In reviewing the PET results, I had available to me the
`
`documents cited herein as well as the publications listed on my curriculum vitae at
`
`EX2129. The data tables for the PET were created using the raw data collected by
`
`the Study Director, Dan .M. Dragotoiu, who conducted this comparative study and
`
`who holds a B.S. degree and has over ten years of professional and academic
`
`experience in the area of microbiology.
`
`I reserve the right to testify about
`
`BioScience Laboratories, Inc. test results and scientific expertise.
`
`Page 3 of29
`
`3
`
`
`
`III. STATE.1VIENT 01~ OPINIONS EXPRESSED AND BASES AND
`IU~ASONS THEREFOR
`
`A.
`
`6.
`
`Background
`
`BioScience L,aboratories, Inc. received from SSCI samples of Bausch
`
`& Lomb Incorporated's ("B+L's") Prolensa® product for PET. Upon receipt of
`
`these samples, BioScience Laboratories, Inc. stored, handled, and maintained
`
`according to BioScience Laboratories, Inc.'s current good manufacturing practice
`
`("GMP") sample handling procedures as specifically outlined in their SOP L-0005.
`
`These samples were evaluated for preservative efficacy during the months of
`
`November 2015 and January 2016. BioScience Laboratories Study Director, Dan
`
`~1. Dragotoiu. was personally present during the preservative efficacy testing of
`
`these santples.
`
`7.
`
`A summary repott of the preservative efficacy testing conducted by
`
`B ioSciencc Laboratories, Inc. on these sarnples is attached as Appendix A. The
`
`report describes the analytical methodology to evaluate preservative efficacy of
`
`stressed and unstressed samples of B+L's Prolensatill product. The preservative
`
`efficacy results are reported in the document for all of the samples tested.
`
`8.
`
`BioScience Laboratories,
`
`Inc.
`
`is a Good Laboratory Practice
`
`("GLP")/GMP facility providing contract product development services to the
`
`pharmaceutical industry. BioScience Laboratories, Inc.'s service offerings include,
`
`but are not limited to analytical testing (e.g., preservative efficacy), product
`
`Page 4 of29
`
`4
`
`
`
`development, and manufactures label claims. The preservative ef11cacy testing of
`
`the B+L's ProlensaUD product samples was performed in BioScience Laboratories,
`
`Inc.'s GLP/GMP In-Vitro laboratory.
`
`9.
`
`The details of the analytical testing that was performed and the
`
`preservative efficacy test results obtained were provided to SSCI for incorporation
`
`in the SSCI report (Appendix A).
`
`B.
`
`Preservative Efficacy Testing of B+L's Prolensa® product
`
`10. As discussed above, samples of B+L's Prolensa® product were
`
`analyzed for preservative efficacy.
`
`Cons.istent with
`
`the
`
`'606 patent,
`
`the
`
`preservative effectiveness tests were conducted based on the methods described in
`
`the European Pharmacopoeia, using the two bacterial species Pseudomonas
`
`aeruginosa (ATCC #9027) and Staphylococcus aureus (ATCC #6538), and the
`
`two fungal species Candida albicans (ATCC #10231) and Aspergillus brasiliensis
`
`(ATCC #16404).
`
`As indicated in the '606 patent, the preservative effectiveness of the vials were
`
`evaluated at the following times: 24 hours, 7 days, 14 days and 28 days following
`
`inoculation with the two bacterial species, and 14 days, 21 days and 28 days
`
`Page 5 of29
`
`5
`
`
`
`following inoculation with the two fungal speciL~s. 1 (EX2267 at 8.) At these time
`
`points, and after further incubation at the appropriate temperature using the
`
`appropriate agar medium for each species, the colonies on the plates were counted.
`
`(EX2267 at 8-9.)
`
`ll. Some aspects of the method used in this study varied slightly from the
`
`European Pharmacopoeia to account for the low volume of available test products
`
`that Lupin and lnnoPharma provided, which were tested at the san1e time with the
`
`B+L's Prolensa()jl product. Still, the test methods are consistent with the '606
`
`patent and scientifically valid, and the results obtained are accurate, as further
`
`described below.
`
`12.
`
`For this study, the test products were transferred from the original
`
`containers to sterilized vials to ensure the accuracy of the volumes and to maintain
`
`sterility of the
`
`test products at
`
`the various
`
`time points. The European
`
`Phannacopoda docs not require using the containers of the test products.
`
`Recognizing f.hat there may be times when the test products arc not challenged in
`
`their final containers, the European Pharmacopoeia states that "the test consists of
`
`challenging the preparation, wherever possible in its tlnal container, with a
`
`The additional data taken at 21 days conforms to the '606 patent (EX1004 at
`
`9:41-50 and 14:4-ll, 15-21, and 26-32), and further confirms the validity of the
`
`results of the preservative effe.ctiveness testing.
`
`Page 6 of29
`
`6
`
`
`
`prescribed
`
`inoculum of suitable
`
`.
`m1cro-orgamsms,
`
`'
`
`storing
`
`the
`
`inoculated
`
`preparation at a prescribed temperature, withdrawing samples from the container at
`
`specified intervals of time and counting the organism in the samples so removed."
`
`(EX2295 at 505, emphasis added.) Indeed, in the previous paragraph, it also states
`
`that the antimicrobial activity "may" be demonstrated by the described test,
`
`making it clear that the exact com.Iitions of the test can be modified, when
`
`appropriate. and stin elucidate a fonnulation's preservative efficacy.
`
`(Id.) For
`
`example, the European Pharmacopoeia allows for different challenge species to be
`
`used and provides a suhjecti.ve evaluation for the sporulation obtained in the
`
`growth of cultures. (!d. at 506, left col., 11. l-23.) Therefore, the use of sterilized
`
`vials for the test products was acceptable for this study.
`
`C.
`
`Reported Preservative Efficacy Testing Result'S are Reliable
`
`1.
`
`l\tfeasurement at the Time Points Required by the Patent
`were l\tlade
`
`13. As discussed above, the preservative effectiveness of the vials were
`
`evaluated at the following times: 24 hours, 7 days, 14 days and 28 days foHowing
`
`inoculation with the two bacterial species, and 14 days, 21 days and 28 days
`
`following inoculation with the two fungal species. (EX2267 at 8.) The tests were
`
`conducted consistent with the '606 patent specif1cation, which do not require data
`
`at the zero hour time point. (See, EX1004 at 9:41-50.) Nor is the zero hour time
`
`point a required time point for the EP-criteria B standard as specit1ed in Table
`
`Page 7 of29
`
`7
`
`
`
`5.1.3.-1.
`
`(EX2295 at 506.)
`
`In any event, we determined the initial inoculum
`
`count, which was provided in the BSL Final Letter Report (EX2267 at 25-29.)
`
`The lack of data for the zero hour time point, therefore, would not have any effect
`
`on the accuracy of the results obtained for other data points.
`
`2.
`
`Neutralization Validation Was Properly Conducted
`
`a.
`
`IVIicroorganisms Were Properly Added to the Test
`Product
`
`14. Consistent with
`
`the method described m
`
`the European
`
`Phannacopoeia, a 1 tnl aliquot of test product was added to 9 ml of the diluent
`
`(neutralizer) prior to the addition of the organism. Thereafter,
`
`recoveries from these neutralized test products were within a factor of 2 of the
`
`recoveries from the controls, consistent with what is set forth in the European
`
`Moreover, the microbial
`
`Phannacopoeia. (EX2295 at 164-165.)
`
`Page 8 of29
`
`8
`
`
`
`b.
`
`Inoculum Count for A. niger
`
`15.
`
`The inoculum counts for some samples with A. niger (also known as
`
`A brasiliensis) for the test products used in the neutralization validation test were
`
`slightly outside the range of the CFUs recommended by the method described in
`
`the European Pharmacopoeia. In all instances, however, the counts recovered frorn
`
`the test product used in the neutralization validation test did not differ by more
`
`than a factor of 2 from the control, as pennitted by the European Pharmacopoeia.
`
`(EX2295 at 165, Section 4-5-3 and 4-6.) Thus, the slight variation in CFUs from
`
`the data obtained from the test products in the neutralization validation test met the
`
`above criteria set forth in 4-5-2 of the European Phannacopoeia. Furthermore, the
`
`recovered populations of 1L niger from the test products were not more than 0.3
`
`log 10 higher than that of the range set forth in the European Pharmacopoeia, which
`
`is an insignificant difference.
`
`c.
`
`Incubation Time for Some Bacterial Samples
`
`16. The incubation period was longer than the time period set fmth in the
`
`European Pharmacopoeia., A prolonged incubation does not decrease the number
`
`of colonies as the incubation continues. Moreover, the plate counts obtained do
`
`not exceed countable ranges per SOP L-2059. (EX2294.)
`
`Page 9 of29
`
`9
`
`
`
`3.
`
`Preservative Effectiveness Test was Properly Conducted
`
`a.
`
`Initial Inoculum Concentrations were Within the
`Range Allowed by the European Pharmacopoeia
`
`17. The European Pharmacopoeia sets forth the use of "an inoculum of
`
`105 to 106 micro-organisms per millilitre or per gram of the preparation." (EX2295
`
`at 506.)
`
`the inoculum concentrations for all of the
`
`microorganisms were within the required range of inoculum concentrations, as
`
`specified in the European Pharmacopoeia. (EX2267 at 41.) In any event, a high
`
`inoculum concentration just challenges the preservative. effectiveness of the
`
`formulation to a greater extent. Eradicating that challenge at the data time
`
`intervals recited in the '606 patent further confirms the preservative effectiveness
`
`of the tested fonnulations.
`
`b.
`
`Incubation Times 'Vere Aligned with the Protocol
`and/or With Validated Procedures
`
`18. The preliminary counts as well as the final counts were recorded on
`
`the Antimicrobial Effectiveness Testing Data Sheets. (See, e.g., EX2267 at 44.)
`
`which the counts changed from the preliminary to the final counting dates, those
`
`In instances in
`
`additional plate counts were
`
`10
`
`Page 10 of29
`
`
`
`which the counts changed from the· preliminary to the final counting dates, those
`
`additional plate counts were recorded. In this example,
`
`4.
`
`Deviations from the Protocol or Standard Operating
`Procedures in the BSL Testing Did Not Impact the Results
`
`19.
`
`In my opinion, any deviations from the Protocol or Standard
`
`Operating Procedures would not have compromised the accuracy or validity of the
`
`results obtained.
`
`a.
`
`Temperature of Molten Agar Did Not Affect the
`Results
`
`20. Although the temperatures for molten agar were slightly higher than
`
`the recommended temperature of 45°C according to the European Pharmacopoeia
`
`(EX2295 at 165),
`
`would not have had an adverse effect on any of the microbial species
`
`tested for this study.
`
`Page 11 of29
`
`But in the end, this very slight temperature
`
`11
`
`I
`
`
`
`variation on these two identified days would not be expected to adversely affect the
`
`microbial species tested.
`
`b.
`
`There was Ade<1uate Monitoring of Incubation
`Temperature for the Test Period
`
`21. The incubation was documented to be within the required ranges,
`
`despite that the electronic temperature monitoring system was not in operation
`
`from 11/19/15 to 11129/15.
`
`Furthermore, the electronic temperature monitming system was
`
`back in operation beginning 11/29/15. In any event, the incubators did not have
`
`any technical issues and were functioning during the time period at issue, and the
`
`temperatures would have remained within the required range of 30-35°C.
`
`c.
`
`Use of Different Medium During Neutralization
`Validation Does Not Invalidate the Obtained Test
`Results for Both Fungi
`
`22. The media used for each test date for the various microorganisms are
`
`documented in the Media/Diluent Tracking Forms, which confirms compliance
`
`with the testing protocol. (EX2267 at 11; EX2275.) The same media was used for
`
`Page 12 of29
`
`12
`
`
`
`the neutralization validation test and the preservative effectiveness test for the test
`
`products.
`
`23. With respect to C. albicans and A. niger., Media/Diluent Tracking
`
`Forms document the media used on 11/30115 in which the neutralization was
`
`conducted.
`
`states the use of the TSA+ media for the neutralization validation,
`
`Therefore, although section 12.8
`
`This typographic error would have been
`
`Page 13 of29
`
`13
`
`
`
`hnmediately apparent to a person of ordinary skill in the art and does not impact
`
`the validity of the results obtained.
`
`24.
`
`can be observed by the tester--"or until good spomlation is obtained." Moreover,
`
`the EP 7.0 at 506 confirms
`
`25.
`
`According
`
`to Table 2.6.12.-1 of
`
`the European
`
`Pharmacopoeia, either SDA media or PDA media could be used for the cultivation
`
`of A. niger. (EX2295 at 164.)
`
`which is consistent with the description m
`
`the European
`
`Pharmacopoeia.
`
`(EX2295 at 164.)
`
`Page 14 of29
`
`14
`
`
`
`IV. COMPENSATION
`
`26.
`
`If called to testify to the facts stated herein, I will be compensated for
`
`my time preparing for and testifying in this n1atter at rate of $500.00 per hour. No
`
`part of my compensation is contingent upon the outcome of this matter or any issue
`
`in it.
`
`V..
`
`PRIOR I~XI>ERT TESTIMONY
`
`27. During the past four years, I have not testified as an expert in any
`
`cases.
`
`Date
`
`'V~~~~
`Daryl S. Paulson, Ph.D., M.A., M.S., M.B.A.
`
`Page 15 of29
`
`15
`
`
`
`APPENDIX A
`APPENDIX A
`
`Page 16 of29
`Page 16 of 29
`
`
`
`A Division of Albany Molecular Research 1nc.
`
`3065 Kent Avenue
`West Lafayette, IN 4 7906-1 076
`Phone: (765) 463-0112
`Fax: (765) 463-4722
`E-mail: info@ssci-inc.com
`Web: www.ssci-inc.com
`
`Stability Evaluation of
`Bromfenac Sodium Drug
`Product Samples for Potency
`and Preservative Efficacy
`
`Project ID: EL20151326
`Report Date: 01/08/2016
`
`Page 17 of29
`
`
`
`TABLE OF CONTENTS
`
`SUMMARY .......................................................................................................................................................... 3
`I.
`II. RESULTS AND DISCUSSION ........................................................................................................................... 3
`III. DATA TABLES ................................................................................................................................................... 5
`Table 1. Summary ofHPLC Data, Sequence 741881 ................................................................................................. 5
`Table 2. Summary ofHPLC Data, Sequence 742199 ................................................................................................. 6
`IV. EXPERIMENTAL ................................................................................................................................................ 7
`A. HPLC Method ..................................................................................................................................................... ?
`V. APPENDIXA: PRESERVATIVEEFFICACYDATA ...................................................................................... 8
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 2 of 13
`Page 18 of29
`
`
`
`I. SUMMARY
`
`Bromfenac sodium ophthalmic solution drug products were sourced from Senju. A portion of
`the samples was used for unstressed (as received) analysis, and the remaining samples were
`stressed in an oven for four (4) weeks at 60°C. Samples from both the unstressed and stressed
`conditions were evaluated for potency and preservative efficacy.
`
`Potency was determined by HPLC with UV detection as detailed in Section IV.A. Percent
`recovery (percent initial) was calculated based on the potency after stress conditions relative to
`that of the unstressed sample. See Table 1 for the unstressed (as received) HPLC data and Table
`2 for the stressed sample HPLC data.
`
`Preservative efficacy was evaluated by BioScience Laboratories, Inc. Samples were evaluated
`for preservative efficacy as guided in the EP Preservative Effectiveness Test Method against the
`following organisms: Candida albicans (AATCC# 10231), Aspergillus niger (AATCC# 16404,
`also referred to as Aspergillus brasiliensis), Pseudomonas aeruginosa (AATCC# 9027) and
`Staphylococcus aureus (AATCC# 6538).
`See Section V for the detailed experimental
`information.
`
`Section II contains results for both potency and preservative efficacy.
`
`II. RESULTS AND DISCUSSION
`
`Material was purchased from one (1) lot, which was used for all experiments and time points.
`Average results are summarized below, with the percent recovery calculated as the amount of
`active relative to the unstressed sample.
`
`Lot Number
`
`240031
`
`Unstressed
`Concentration
`(mg/ml)
`Average= 0.7457
`High= 0.7466
`Low= 0.7451
`
`Stressed
`Concentration
`(mg/ml}
`Average= 0.7445
`High= 0.7473
`Low= 0.7418
`
`%Recovery
`
`Average= 99.8
`High= 100.2
`Low= 99.5
`
`Stressed and unstressed samples were evaluated for preservative efficacy, with the following
`results.
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 3 of 13
`Page 19 of29
`
`
`
`Organism
`
`Condition
`
`S. aureus
`
`P.
`aeruginosa
`c.
`albicans
`
`A. niger
`
`Unstressed
`
`Stressed
`
`Unstressed
`
`Stressed
`
`Unstressed
`
`Stressed
`
`Unstressed
`
`Stressed
`
`Inoculum
`Count
`
`1.97667 X 106
`
`1.7070 X 106
`
`3.3953 X 105
`
`8.8837 X 105
`
`---
`
`---
`
`---
`---
`
`Cell Count (CFU/ml)
`Days After Inoculation
`1
`28
`14
`7
`<1.00 X 101
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`<1.00 X 101
`<1.00 X 101
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`<1.00 X 101
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`---
`---
`< 1.00 X 101 < 1.00 X 101 <1.00 X 101
`---
`< 1.00 X 102 < 1.00 X 102 <1.00 X 102
`---
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`---
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`
`21
`
`---
`
`---
`
`---
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 4 of 13
`Page 20 of29
`
`
`
`III. DATA TABLES
`
`Table 1. Summary of HPLC Data, Sequence 741881
`
`lnj#
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`16
`17
`18
`19
`20
`
`Sample
`Description
`Blank
`Blank
`STDA
`STDA
`STDA
`STDA
`STDA
`STD B
`Blank
`STDA
`240031
`240031
`240031
`STDA
`
`LIMS
`
`lC Filename
`
`RT
`
`Area(mAU*s)
`
`408677
`408677
`408705
`408705
`408705
`408705
`408705
`408706
`408677
`408705
`403486
`403489
`403490
`408705
`
`741882
`741883
`741884
`741885
`741886
`741887
`741888
`741889
`741890
`741897
`741898
`741899
`741900
`741901
`
`---
`---
`8.667
`8.668
`8.666
`8.666
`8.666
`8.665
`---
`8.666
`8.646
`8.648
`8.647
`8.663
`
`---
`---
`4012.66
`4015.13
`4016.96
`4016.04
`4018.79
`4038.45
`---
`4019.73
`4556.16
`4548.27
`4547.03
`4016.40
`
`SSCI Report: Stability Evaluation of Compound 5 78 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 5 of 13
`Page 21 of29
`
`
`
`Table 2. Summary of HPLC Data, Sequence 742199
`
`Sample
`Description
`Blank
`Blank
`STDA
`STDA
`STDA
`STDA
`STDA
`STD B
`Blank
`STDA
`STDA
`STDA
`STDA
`STDA
`STDA
`STDA
`STDA
`240031
`240031
`240031
`240031
`240031
`240031
`STDA
`240031
`240031
`240031
`240031
`STDA
`
`liMS
`
`LC Filename
`
`408677
`408677
`408705
`408705
`408705
`408705
`408705
`408706
`408677
`408705
`408705
`408705
`408705
`408705
`408705
`408705
`408705
`403478
`403479
`403480
`403481
`403482
`403483
`408705
`403484
`403485
`403487
`403488
`408705
`
`742200
`742201
`742202
`742203
`742204
`742205
`742206
`742207
`742208
`742215
`742222
`742229
`742235
`742242
`742249
`742256
`742262
`742263
`742264
`742265
`742266
`742267
`742268
`742269
`742272
`742273
`742274
`742275
`742276
`
`RT
`
`---
`---
`8.669
`8.670
`8.670
`8.670
`8.669
`8.669
`---
`8.673
`8.676
`8.677
`8.681
`8.682
`8.684
`8.690
`8.691
`8.670
`8.670
`8.670
`8.673
`8.671
`8.672
`8.694
`8.676
`8.676
`8.678
`8.680
`8.701
`
`Area(mAU*s)
`
`---
`---
`4011.82
`4013.03
`4010.89
`4010.87
`4015.36
`4055.66
`---
`4015.87
`4019.08
`4018.56
`4017.59
`4019.84
`4017.62
`4017.27
`4023.48
`4537.86
`4545.41
`4541.65
`4522.94
`4555.21
`4556.05
`4024.68
`4541.95
`4541.17
`4524.65
`4523.19
`4024.02
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01108/2016
`page 6 of 13
`Page 22 of29
`
`
`
`IV. EXPERIMENTAL
`
`A. HPLC Method
`
`HPLC analyses were performed using an Agilent 1100 series liquid chromatograph equipped
`with a diode array detector, degasser, quaternary pump, and autosampler. The chromatographic
`column was a Shiseido Capcell Pak C18, 2.1 x 100.0 mm column with 5.0 J..Lm packing. The
`column temperature was set to 25°C, and the detector wavelength was 266 nm. The injection
`volume was 5.0 J..LL. The mobile phase was prepared by dissolving 7.9231 g of ammonium
`dihydrogen phosphate into 3000 mL of water, adding phosphoric acid to adjust the pH to 7.30,
`and then mixing in 1000 mL of acetonitrile. The flow rate used was 1.5 mL/minute, with a run
`time of 13 minutes per injection. Method performance was monitored for the following criteria,
`with the listed range of results.
`
`Criterion
`Precision (n=5 %RSD)
`Global %RSD
`Tailing Factor (1st standard injection)
`Plates (1st standard injection)
`Percent Agreement
`
`Results
`0.05%- 0.06%
`0.06%-0.11%
`1.8
`5251-5297
`100.6%- 101.1%
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 7 of 13
`Page 23 of29
`
`
`
`V. APPENDIXA: PRESERVATIVEEFFICACYDATA
`
`SSCI Report: Stability Evaluation of Compound 578 Dmg Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 8 of 13
`Page 24 of29
`
`
`
`#15 1142-203.01 Letter Final Repmt
`Page 25 of65
`
`Protocollll51142-203
`January 07,2016
`
`TABLE7
`Test Product 113: Prolensa'"' hromfenae oplithalrnic solution 0.07%.
`B romfenac Sodium (unstressed)
`Lot Numbers 240031
`
`Ie..~U:ro<!u<:!./0.: ProlensaTM brornfenac ophthalmic solution 0.07% (w/v)
`Bromtenac Sodium (4 weeks@ 60'C))
`Lot Number 240031
`
`Challenge
`Microorganism
`(ATCC#)
`
`Initial
`Population
`(CFU/mL
`of Product)
`
`Day(s)
`Following
`Inoculation
`
`Prod net
`#
`
`Population
`Recovered
`(CFU/mL)
`
`Log 10
`Reduction
`
`Acceptance
`Criteria
`Met?
`(Yes /No)O
`
`14
`
`3
`
`4
`
`< 1.00 X 10 1
`
`4.9386
`
`< 1.00 X 101
`
`4.9386
`
`YES
`
`YES
`
`Percent
`Reduction
`
`99.9988%
`
`99.9988%
`
`Aspergillus brasiliensis
`(ATCC#l6404)
`
`8.6818x 105
`
`< l.OOx 10 1
`3
`1-----,....._.
`< J.OOx 10 1
`4
`1--------· -···
`.... ,.
`<1.00xl0 1
`,....._ ___ ·------- ---
`< 1.00 X 10 1
`
`21
`
`28
`
`3
`
`4
`
`4.9386
`
`4.9386
`
`4.9386
`
`4.9386
`
`YES
`-----
`YES
`·····-·---·-- - 1--
`YES
`
`_!9.9988~-
`
`99.9988%
`
`99.9988%
`
`YES
`
`99.9988%
`
`0European Pharmacopoeia 7.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATION. 01/2011:50103. Acceptance Cntena,
`Table 5.1.3.1, Parenteral preparations, eye preparalions, intrauterine preparations and intramammary preparations: The criteria for
`fungi is a 2 log 1o reduction tollowing 7 days of exposure to the test product with no recovered Colony Forming Units (CFU) recovered
`after 28 days of exposure to the product.
`
`Protocollll51142-203
`Page 6 of 15
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Presen,ative Efficacy, 01/08/2016
`page 9 of 13
`Page 25 of29
`
`
`
`#1 51142-203.01 Letter Final Rcpoti
`Pag\! 26 of65
`
`Protocol 11151142-203
`January 07,2016
`
`. IA!!.bE.A
`:I.~§tJ'J9.Q.l.I9J.1i.J.: Prolensa'" bromfenac ophthalmic solution 0.07%.
`Bromfcnac Sodium (unstressed)
`Lot Number 24003 I
`
`Test Product #4: ProlcnsaTM bromfenac ophthalmic solution 0.07% (w/v)
`Bromfenac Sodium (4 weeks@ 60"C)
`Lot Number 240031
`
`Challenge
`1\-licroorganism
`(ATCC#)
`
`Initial
`Population
`(CFU/mL
`of Product)
`
`Day(s)
`Following
`Inoculation
`
`Product
`#
`
`Population
`Recovered
`(CFU/mL)
`
`Log10
`Reduction
`
`Acceptance
`Criteria
`Met?
`(Yes /No)O
`
`YES
`
`Percent
`Reduction
`
`Candida a/b;cans
`(ATCC#J0231)
`
`3.3182 X 105
`CFU/1.0 mL
`
`14
`
`21
`
`OEuropean Phannacopocia 7.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATfON. 0!/2011:50103. Acceptance
`Criteria~ Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intramammmy preparations:
`The criteria for fungi is a 2 log 10 reduction toll owing 7 days of exposure to the test product with no recovered Colony Fo1ming
`Units (CFU) recovered after 28 days of exposure to the product.
`
`4
`
`< 1.00 X 102
`
`4.5209
`
`YES
`
`Protocol #151142-203
`Page 7 of J 5
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 10 of 13
`Page 26 of29
`
`
`
`#15 1142-203.01 Letter Final Rcp01t
`Page 27 of65
`
`Protocol #151142-203
`January 07, 2016
`
`. TABLE 9
`Test Product #3: Prolensa"1 1woml\:noc ophthalmic solution 0.07%.
`Brornfenac Sodium (unstressed)
`Lot Number 240031
`
`lf'.§.t Prqductli4.: ProlensaTM bromfenac ophthalmic solution 0.07% (w/v)
`Bromfenac Sodium (4 weeks@ 60°C)
`Lot Number 24003 i
`
`Challenge
`Microorganism
`(ATCC#)
`
`Initial
`Population
`(CFU/mL
`of Product)
`
`Day(s)
`Following
`Inoculation
`
`Product
`#
`
`Population
`Recovered
`(CFU/mL)
`
`~~·-
`
`Log10
`Reduction
`
`Acceptance
`Criteria
`Met?
`(Yes/No)O
`
`Percent
`Reduction
`
`<1.00 x 10 1
`<1.00 x 10 1
`<1.00 x 101
`<1.00 x 10 1
`<1.00 x 101
`<1.00 x 101
`<1.00 x 101
`<1.00 X 101
`4
`OEmopean Phmmacopoeta 7.0. 5.1.3. FFFACALY OF ANTIMICROBfAL PRESERVATION. Ol/2011.50103. Acceptance Cntena,
`Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intrnmammary preparations: Criteria A for
`bacteria is a 3 log 10 reduction following 24 hours of exposure to the test product with no recovered Colony Forming Units (CFU}
`recovered after 28 days of exposme to the product.
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`99.9994%
`
`Pseudomonas aeruginosa
`(ATCC #9027)
`
`1.7070 x 106
`
`l
`
`7
`
`14
`
`28
`
`I
`I
`
`3
`
`4
`
`3
`
`4
`
`3
`
`4
`
`3
`
`Proloco\11151142-203
`Page 8 of 15
`
`SSCI Report: Stability Evaluation a,( Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 11 of 13
`Page 27 of29
`
`
`
`#151142-203.01 Letter Final Repmt
`Page 28 of65
`
`Protocol/1151 142-203
`January 07,2016
`
`TABLEJO
`Tcst.l'r.<)(1uct.!I.J.: ProlcnsaTM bromfenac ophthalmic solution 0.07%.
`Bromfcnm: Sodium (unstressed)
`Lot Number 240031
`
`I.9.o.\...er.R<lll9.Lti.4: Pro1cnsa TM bromfenac ophthalmic solution 0.07% (w/v)
`Bromfenac Sodium ( 4 weeks @ 60°C)
`Lot Number 240031
`
`Challenge
`Microorganism
`(ATCC#)
`
`Initial
`Population
`(CFU/mL
`of Product)
`
`Day(s)
`Following
`Inoculation
`
`Product
`II
`
`Population
`Recovered
`(CFU/mL)
`
`Logto
`Reduction
`
`3
`
`5.2959
`
`<1.00 x 10 1
`1
`<1.00 X 1()1
`5.2959
`4
`- · - - - - - - --··-··-··-- !--···· .. , .. ,_, __ - ··-··--··---~'"'~
`<1.00 X 10 1
`5.2959
`3
`
`7
`
`Acceptance
`Criteria
`Met?
`(Yes/ No)O
`
`~-----
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`-----~------~-
`
`YES
`
`Percent
`Reduction
`
`99.999
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`Staphy/ococcl<s Oll/'eus
`(A TCC #6538)
`
`1.9767 X J06
`
`14
`
`28
`
`4
`
`3
`
`4
`
`3
`
`'<1.00x10 1
`' <1.00 X 10 1
`
`5.2959
`
`5.2959
`
`<J.00xl01
`5.2959
`··-- ---------- --····----~~--~-
`<1.00 X 10 1
`5.2959
`
`<1.00 X 10 1
`-
`'
`OEuropean Pharmacopoem 7.0. 5.1.3. EFFACAC Y OF AN f!MlCROB!AL PRESERVATION. 01/2011:50103. Acceptance Cntena,
`Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intramammary preparations: Criteria A for
`bacteria is a 3 log 10 reduction following 24 hours of exposure to the test product with no recovered Colony Forming Units (CFU)
`recovered after 28 days of exposure to the product.
`
`4
`
`5.2959
`
`YES
`
`99.9995%
`
`Protocol #151142-203
`Page 9 of 15
`
`SSCI Report: Stability Evaluation a,[ Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 12 of 13
`
`Page 28 of29
`
`
`
`#151142-203.01 Letter Final Repo1t
`P~g~ 29 of 65
`
`Protocolli\51142·203
`January 07, 2016
`
`TABLE 11
`Neutralization Evaluation- Results
`I~:.:~t PH~~!.tLt:t I~J.: Prolensa1
`M bromfenac ophthalmic soll.ltion 0.07%.
`Bromfenac Sodium (unstressed)
`Lot Numbers 240031
`
`Challenge Microorgniti'sm, I ;\,T(
`
`Microbial Recovery
`(Average CFIJ/Plate)
`
`Results
`Pass!FailO
`
`Candida albicans
`
`10231
`
`Pseudomonas aeruginosa
`9027
`......................... --------+----!
`Staphylococcus a1rreus
`
`6538
`
`TEST
`
`113.00
`
`188.00
`
`30.00
`- - - -1
`30.00
`
`30.50
`
`34.00
`
`24.00
`
`23.50
`
`Pass
`
`Pass
`
`Pass
`
`Pass
`
`OThe counts (Average CFUiPiate) observed for the TEST sample do not vary by more than a !actor of
`5 thnn those recovered from the respective CONTROL sample; hence, the neutralizing media are considered to be
`effective.
`
`TABLE 12
`Neutralization Evaluation- Results
`Tcsl Pmduct 1!4: ProlcnsaTM bromfenac ophthalmic solution 0.07% (w/v)
`Bromfenac Sodiltm (4 weeks@ 60"C)
`Lot Number 240031
`
`~ "'"""'nw~ ... -. ·-=·w.V'-'.M'"''"'="''
`Challenge Microorganism ATCC# Neutralization J)hase
`
`Microbial Recovery
`(Average CFlJ/Piate)
`
`Results
`Pass/FuiiO
`
`Aspergilius brasiliensis
`
`16404
`
`Candida n!bicans
`---... ~------·-· ...
`
`10231
`
`Pseudomonas aeruginosa
`
`9027
`
`CONTROL
`
`113.00
`--· .. -~<~<------,~-----~-----
`TEST
`213.50
`................................. .......... ___
`CONTROL
`30.00
`TEST
`36.00
`
`Pass
`
`Pass
`
`TEST
`
`35.50
`
`Sraphy!ococcus aurens
`6538
`TEST
`20.00
`0 The counts (Average CFU/Piatc) observed for the-TES;r sar~ple do not vary by more than a factor of
`5 from those recovered from the respective CONTROL sample; hence, the neutralizing media are considered
`to be effective.
`
`Pass
`
`CONTROL
`
`24.00
`
`Protocol #151142-203
`Page 10 of IS
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01108/2016
`page 13 of 13
`Page 29 of29
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