UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`Case IPR2015-01099
`Patent 8,669,290 B2
`
`DECLARATION OF ADAM C. MYERS, PH.D.
`
`Page 1 of27
`
`1
`
`SENJU EXHIBIT 2126
`LUPIN v SENJU
`IPR2015-01099
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`Case IPR2015-01099
`Patent 8,669,290 B2
`
`DECLARATION OF ADAM C. MYERS, PH.D.
`
`Page 1 of27
`
`1
`
`SENJU EXHIBIT 2126
`LUPIN v SENJU
`IPR2015-01099
`
`
`
`I, Adam C. Myers, Ph.D., under penalty of perjury, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I submit this declaration at the request of Finnegan, Henderson,
`
`Farabow, GaiTett & Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd.
`
`("Senju") as an expert in the field of the design, evaluation, and formulation of
`
`drug products. My qualifications in these areas, as well as other areas, are
`
`established below and by my curriculum vitae, which is EX2127.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`2.
`
`I am cuiTently a Senior Research Investigator at SSCI, a Division of
`
`Albany Molecular Research, Inc. ("AMRI") in West Lafayette, Indianapolis, which
`
`I have been working for over a year.
`
`3.
`
`I received a B.S. with Honors degree in biochemistry from Purdue
`
`University in 2000 and a Ph.D. degree in organic chemistry from Purdue
`
`University in 2005.
`
`4.
`
`Prior to joining SSCI, I worked in the pharmaceutical industry for
`
`Quadraspec, Inc. and BASi in West Lafayette. My employment at Qaudraspec, Inc.
`
`began in 2006 and continued until I moved to BASi in 2007. My roles at BASi
`
`increased over the years from a Senior Scientist/Team Leader to Assistant Director
`
`of Pharmaceutical Analysis, and eventually to Director of Pharmaceutical
`
`Scientific Operations in 2012. As a Senior Scientist/Team Leader, I was
`
`Page 2 of27
`
`2
`
`
`
`responsible for developing protocols, method and techniques for various analytical
`
`testing. As Assistant Director of Pharmaceutical Analysis and Director of
`
`Pharmaceutical Scientific Operations, I was responsible for providing scientific
`
`directions to a laboratory conducting Current Good Manufacturing Practice
`
`("cGMP") and Good Laboratory Practice ("GLP") projects.
`
`5. My current expertise in design, evaluation, and formulation of drug
`
`products focuses on drug formulation analytics utilizing chromatography, mass
`
`spectrometry, UV-Vis, dissolution, in a cGMP laboratory setting. I have extensive
`
`research, development, and manufacturing experience and have coauthored
`
`publications and given presentations related to pharmaceutical drug products.
`
`III. DOCUMENTS AND INFORMATION CONSIDERED IN FORMING
`OPINIONS
`
`6.
`
`In forming my opinions, I had available the documents cited herein as
`
`well as the publications listed on my curriculum vitae at EX2127. I also based my
`
`opinions on my professional and academic experience in the area of drug
`
`formulation and analytics. I reserve the right to testify about these materials and
`
`expenence.
`
`IV. STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR
`
`A.
`
`7.
`
`Background
`
`Samples of Bausch & Lomb Incorporated's ("B+L's") Prolensa®
`
`product samples were sourced from B+L. B+L shipped the samples to Finnegan,
`
`Page 3 of27
`
`3
`
`
`
`Henderson, Farabow, Garrett & Dunner, LLP, who then shipped the samples to
`
`SSCI for testing. A portion of these samples were further shipped to BioScience
`
`Laboratories, Inc. These samples were analyzed for potency, i.e. chemical stability,
`
`at SSCI and for preservative efficacy at BioScience Laboratories, Inc. during the
`
`months ofNovember 2015 and January 2016. Potency measures the amount of an
`
`analyte present in the testing sample. In other words, the chemical stability data
`
`indicate the percentage amount of bromfenac free acid in the Prolensa® product
`
`samples that were subject to stressed and unstressed conditions for four weeks. I
`
`was personally present during the chemical stability testing of these samples.
`
`8.
`
`SSCI has provided a summary report of both the chemical stability
`
`testing and preservative efficacy testing, which is attached as Appendix A. The
`
`SSCI report correctly details the analytical testing that was performed and
`
`accurately reports the chemical stability test results, as well as the preservative
`
`efficacy test results. The report describes the analytical methodology to quantitate
`
`bromfenac free acid in the stressed and unstressed conditions. The chemical
`
`stability results are reported in the document for all of the samples tested.
`
`9.
`
`SSCI is a cGMP facility providing contract product development
`
`services to the pharmaceutical industry.
`
`SSCI's service offerings include
`
`analytical
`
`testing
`
`(e.g.,
`
`chemical
`
`stability), product development,
`
`and
`
`Page 4 of27
`
`4
`
`
`
`manufacturing. The chemical stability testing of the B+L's Prolensa<W product
`
`samples was performed in SSCI's cGMP quality control laboratory.
`
`10. B+L's Prolensa® product samples were received, stored, handled, and
`
`maintained according to SSCI' s cGMP sample handling procedures. The samples
`
`were stored under ambient laboratory conditions in their original containers.
`
`11. A portion of the samples received from B+L were stressed in an oven
`
`at 60° C, and the rest were maintained at unstressed (ambient) conditions. All of
`
`the samples were tested for potency after four weeks, and percent recovery was
`
`calculated based on the potency of the stressed samples relative to the unstressed
`
`samples. To prevent contamination of the samples and to maintain uniformity of
`
`analysis, all of the samples were kept in the original containers and were tested for
`
`potency after four weeks at either unstressed or stressed conditions. Performing
`
`the HPLC analyses all at once after the four-week duration guarantees the
`
`uniformity of analysis, by utilizing the same standard preparations, mobile phase,
`
`column and instrument, while performing at different time points may add
`
`variables that could potentially skew the results.
`
`12. Using this method was further justified because all of the samples
`
`were storage stable in the containers as provided. B+L's Prolensa® product is a
`
`marketed product with sufficient stabili ·
`
`for ophthalmic use.
`
`(See, e.g.,
`
`EX1049 at 1.) From these known stability
`
`Page 5 of27
`
`5
`
`
`
`profiles of products in the provided containers that have been marketed, it is
`
`appropriate to assess stabilit.Y of the finished product in the provided containers.
`
`(See also, EX2290 at 7.)
`
`Therefore, the measured potency of the stressed samples (experimental condition)
`
`can be properly compared to the measured potency of the unstressed samples
`
`(control condition) to analyze chemical stability.
`
`B.
`
`Reported Concentration Results are Reliable
`
`13. A single point standard (one concentration), which is a well
`
`recognized, scientifically valid method, was used to measure potency. STD A was
`
`used as the single point standard, and STD B was used as a check standard. The
`
`single point standard assumes a linear relationship between absorbance and
`
`concentration of the molecule. This assumption is supported by the Beer-Lambert
`
`Law, which states that absorbance is proportional to concentration of the UV active
`
`species in the sample. (EX2279 at 414-415.)
`
`14. Moreover, quantitation by a single point standard is commonly used
`
`in the pharmaceutical industry, and it is predominately used in compendia1 method
`
`monographs for many compounds in the U.S. Pharmacopoeia.
`
`~·or example,
`
`monographs
`
`for ketorolac
`
`tromethamine
`
`in
`
`tablet,
`
`injection and active
`
`Page 6 of27
`
`6
`
`
`
`phannaceutical ingredient ("API"), diclofenac sodium in API, delayed release and
`
`extended release, and brinzolamide ophthalmic suspension and API all list only a
`
`single point standard for assay determination of their active ingredient. (EX2280;
`
`EX2281; EX2283; EX2284; EX2285; EX2287; EX2288; EX2289.) The single
`
`point standard can be used to measure potency for an assay resulting in peak
`
`responses either above or below that of the standard injection peak response, as
`
`illustrated,
`
`for example,
`
`in U.S. Pharmacopoeia monographs assays
`
`for
`
`brinzolamide ophthalmic suspension and ketorolac
`
`tromethamine
`
`injection.
`
`(EX2281; EX2288.) Furthermore, this was the method that Mr. Sawa used at
`
`Senju in conducting the chemical stability testing for bromfenac and tyloxapol
`
`containing solutions. (See, e.g., EX2098, Appendix A.)
`
`15.
`
`It was also cont1rmed that there were no other components in B+L's
`
`Prolensa ® product that would co-elute with bromfenac. The injection of the
`
`standard solution, which contained bromfenac sodium and water, showed a single
`
`peak in the range of 8.64-8.70 minutes. (EX2266.) Blank injections of the mobile
`
`phase showed no interference at the retention time of bromfenac.
`
`(See, e.g.,
`
`EX2266 at 22.) I understand that the other components contained in the samples of
`
`B+L's Prolensa-19 product
`
`Injection of a placebo solution during method familiarization (EX2265
`
`Page 7 of27
`
`7
`
`
`
`at 4), which contained the above listed components, also showed no interference at
`
`the retention time ofbromfenac. That the blank injections and the placebo solution
`
`showed no interference with the bromfenac peak confirm that none of the
`
`components in the drug product matrix or the mobile phase would co-elute with
`
`bromfenac.
`
`16.
`
`Furthermore, none of bromfenac 's degradants likely would co-elute at
`
`the retention time of bromfenac. Certain degradants could theoretically co-elute at
`
`similar retention times to their conesponding original molecules. But based on the
`
`structure ofbromfenac and its potential degradants, the anticipated retention times
`
`of the expected degradants would be different from that of bromfenac because of
`
`their differences in polarity. Any breakdown of bromfenac resulting t!·om
`
`degradation would likely result in degradant compounds having different polarity
`
`from that of bromfenac.
`
`Therefore, it is highly
`
`unlikely that a degradant would co-elute with bromfenac.
`
`17.
`
`In addition, comparing the HPLC results of the standard and the
`
`stressed samples supports that degradants from this study eluted at different times.
`
`For example, the HPLC result for a stressed sample on EX2266 at 51 shows the
`
`bromfenac peak at 8.678 minutes and a very small peak at 10.138 minutes, but all
`
`of the HPLC results for the standard and unstressed samples show only the
`
`Page 8 of27
`
`8
`
`
`
`bromfenac peak in the range of 8.64-8.70 minutes. In addition, the shape of the
`
`bromfenac peak in the HPLC results of the standard, stressed and unstressed
`
`samples is consistent, which indicates a lack of co-elution of other species with this
`
`peak. Ifbromfenac and any degradant had similar retention times, the shape of the
`
`bromfenac peak would have been altered. These factors further support that
`
`bromfenac and other components, including any degradant, would elute at different
`
`times.
`
`C.
`
`Stressed Samples Were Compared to a Proper Baseline
`
`18. As discussed in ~ 12 above, the chemical stability of the samples were
`
`analyzed by properly comparing the potency of stressed (experimental) and
`
`unstressed (control) samples after four weeks. As discussed in~ 12 above,(cid:173)
`
`samples from B+L are all stabl
`
`Furthermore, as discussed
`
`Therefore, the measured
`
`potency of the stressed samples (experimental condition) can be properly
`
`compared to that of the unstressed samples (control condition) to analyze chemical
`
`stability,
`
`Based on this information, it is
`
`reasonable to expect that the potency of the unstressed samples at time zero and
`
`after four weeks would not change in any meaningful way that would impact the
`
`Page 9 of27
`
`9
`
`
`
`results. Therefore, by comparing the potency of the stressed samples and the
`
`unstressed samples after four weeks, the chemical stability of B+L's Prolensa®
`
`product can be accurately measured.
`
`19. Moreover, as discussed in ~ 11 above, performing the HPLC analyses
`
`all at once after the four-week duration further guarantees the uniformity of
`
`analysis, by using the same standard preparations, mobile phase, column and
`
`instrument. Performing the HPLC analyses at different time points may add
`
`variables that could impact the results. This supports the accuracy of the obtained
`
`potency and chemical stability results.
`
`D.
`
`Stability Tests Used Proper Containers
`
`20. As discussed above, to prevent contamination of the samples and to
`
`maintain uniformity of analysis, all of the samples were kept in the original
`
`containers and were tested for potency after four weeks at either unstressed or
`
`stressed conditions. Performing the HPLC analyses all at once after the four-week
`
`duration guarantees the uniformity of analysis, by using the same standard
`
`preparations, mobile phase, column and instrument, while performing at different
`
`time points may add variables that could impact the results. Moreover, the ICH
`
`Guideline section 2.2.4 specifies that "the stability testing should be conducted on
`
`the dosage form packaged in the container closure system proposed for marketing."
`
`(EX2290 at 7.) Good stability practice should be conducted on the dosage form
`
`Page 10 of27
`
`10
`
`
`
`packaged in the container closure system proposed for marketing, as specified in
`
`the ICH Guideline. Additionally, transfer of samples as received to an alternate
`
`container, such as polypropylene containers, would have risked affecting the
`
`stability results by introducing variables such as contamination or loss of material
`
`on transfer. Moreover, the validity of the relative potency values obtained for the
`
`stressed and unstressed samples was further ensured because the samples were held
`
`in the same container closure system.
`
`21. Moreover, in order to maintain consistent storage conditions for
`
`samples analyzed for potency and preservative efficacy, the same container type
`
`should be used for samples evaluated in both tests. Transfer to a separate container,
`
`such as a polypropylene container, requires opening the sealed sample, which
`
`could result in a potential contamination of the sample that could affect not only
`
`potency but also preservative efficacy testing. Therefore, for at least the reasons
`
`discussed above, the best practice is to use the samples in the containers as
`
`provided, which the ICH Guideline recommends. (EX2290 at 7.)
`
`E.
`
`Percent Recovery Accurately Reflects the Chemical Stability of
`Samples
`
`22. As discussed above in ~ 17, based on the structure of bromfenac and
`
`its potential degradants, the anticipated retention times of the expected degradants
`
`would be different from that of bromfenac because of their differences in polarity.
`
`Any breakdown of bromfenac resulting from degradation would likely result in
`
`Page 11 of27
`
`11
`
`
`
`degradant compounds having different polarity from that of bromfenac. This
`
`concept is further demonstrated
`
`Therefore, the HPLC chromatograms would
`
`show not only the bromfenac peak but also peaks of any degradants, if there were
`
`any significant degradation.
`
`For example, for B+L's Prolensa® product, the
`
`HPLC result for a stressed sample on EX2266 at 51 shows the bromfenac peak at
`
`8.678 minutes, which has an area of 98.9896% relative to all integrated peaks, and
`
`a very small peak likely attributed to a known degradant at 10.138 minutes, which
`
`has an area of 1.0104%. All of the HPLC results for the related standard and
`
`unstressed samples show only the bromf{:mac peak in the range of 8.64-8.70
`
`minutes. Had there been significant degradation, the area of the bromfenac peak
`
`relative to other components vvould have been significantly reduced. It was not.
`
`23. Moreover, the HPI,C results suppmt that there was little, if any,
`
`moisture vaporization fl·om the stressed samples. Minimal, if any, degradation
`
`occurred in the stressed samples as demonstrated by the chromatography. If there
`
`had been significant moisture vaporization, then the measured concentration of
`
`bromfenac in sample solutions would have greatly increased. For example, as
`
`shown in the HPLC result for a stressed sample of B+L's Prolensa:~) product on
`
`EX2266 at 51, the bromfenac peak was observed to have an area of 98.9896%
`
`relative to aH integrated peaks. Because there were not significant levels of
`
`Page 12 of27
`
`12
`
`
`
`degradant peaks, there was no substantial moisture loss that would have affected
`
`the chemical stability results.
`
`F.
`
`The Stability Testing Report Includes Sufficient Detail
`
`24. The validity of the experimental results can be assessed adequately
`
`with the information provided in my declaration. As discussed above, the
`
`chemical stability testing of the samples were performed in SSCI's cGMP
`
`laboratory. Although validation was not required for this study, these tests were
`
`conducted in accordance with our quality system controls, such as instrument
`
`records. Furthermore, the data are internally consistent within the laboratory
`
`notebooks and the LIMS system.
`
`V.
`
`COMPENSATION
`
`25.
`
`I am a salaried employee of AMRI SSCI, LLC and its affiliates and I
`
`receive no additional compensation for this matter. No part of my compensation is
`
`contingent upon the outcome of this matter or any issue in it.
`
`VI. PRIOR EXPERT TESTIMONY
`
`26. During the past four years, I have not testified as an expert in any
`
`cases.
`
`16
`IJ 1-cb
`Date
`
`Page 13 of27
`
`Adam C. Myers, Ph.D.
`
`13
`
`
`
`APPENDIX A
`APPENDIX A
`
`Page 14 of27
`Page 14 of 27
`
`
`
`'" 551:1"
`
`A Division of Albany Molecular Research Inc.
`
`3065 Kent Avenue
`West Lafayette, IN 47906-1076
`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 15 of27
`
`
`
`TABLE OF CONTENTS
`
`I.
`SUMMARY .......................................................................................................................................................... 3
`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 ................................................................................................................................................ ?
`A. HPLC Method ..................................................................................................................................................... ?
`V. APPENDIX A: PRESERVATIVE EFFICACY DATA ...................................................................................... 8
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 2 of 13
`
`Page 16 of27
`
`
`
`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
`See Section V for the detailed experimental
`Staphylococcus aureus (AATCC# 6538).
`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 17 of27
`
`
`
`Organism
`
`S. aureus
`
`Condition
`
`Inoculum
`Count
`
`8 1.97667 X 10'
`
`P.
`aentginosa
`c.
`albicans
`
`A. niger
`
`Unstressed
`
`Stressed
`
`Unstressed
`s·
`
`Unstressed
`
`Stressed
`
`1.7070 X 106
`
`3.3953 X 105
`
`8.8837 X 105
`
`---
`---
`---
`
`Cell Count (CFU/ml)
`Days After Inoculation
`21
`7
`14
`1
`---
`<1.00 X 101 <1.00 X 101 <1.00 X 101
`---
`<1.00 X~ <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
`
`28
`<1.00 X 101
`
`<1.00 X 101
`
`<1.00 X 101
`
`SSCI Repot1: Stability Evaluation of Compound 5 78 Drug Product Samples for Potency and Preservative Efficacy. 0 1!08! 2016
`page 4 of13
`
`Page 18 of27
`
`
`
`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
`
`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
`
`RT
`---
`---
`8.667
`8.668
`8.666
`8.666
`8.666
`8.665
`---
`8.666
`8.646
`8.648
`8.647
`8.663
`
`Area(mAU*s)
`
`---
`---
`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 578 Dmg Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 5 of 13
`
`Page 19 of27
`
`
`
`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
`
`RT
`
`Area(mAU*s)
`
`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
`
`---
`---
`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
`
`---
`---
`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, 01/08/2016
`page 6 of 13
`
`Page 20 of27
`
`
`
`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 ).till packing. The
`column temperature was set to 25°C, and the detector wavelength was 266 nm. The injection
`volume was 5.0 )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 Dmg Product Samples for Potency and Preservative Efficacy, 01108/2016
`page 7 of 13
`
`Page 21 of27
`
`
`
`V. APPENDIX A: PRESERVATIVE EFFICACY DATA
`
`SSCI Report: Stability Evaluation of Compound 5 78 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 8 of 13
`
`Page 22 of27
`
`
`
`#151142~203.01 Letter Final Rt:pmt
`Page 25 of65
`
`Protocol 11151142-203
`January 07, 2016
`
`TABLE 7
`Test Product #3: ProlensaTM l>romfcnac ophthalmic solution 0.07%.
`Bromfenac Sodium (unstressed)
`Lot Numbers 240031
`
`I~.~.t..Pr9<:1.0.ctjl_1: ProlensaT" brornfenac 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
`#
`
`Population
`Recovered
`(CFU/mL)
`
`Log 10
`Reduction
`
`Acceptance
`Criteria
`Met?
`(Yes I No)O
`
`< l.OOx 10 1
`
`4.9386
`
`< 1.00 X \0 1
`
`4.9386
`
`YES
`···--·-··
`YES
`
`Aspergi /Ius brasiliensis
`(ATCC #16404)
`
`8.6818 X 105
`
`14
`
`I
`
`J
`
`4
`
`3
`
`21
`
`4
`t---- ········-··· ····--- ·---
`3
`
`< 1.00 X 10 1
`
`4.9386
`
`< l.OOx 10 1
`
`4.9386
`
`< J.()Q X 10 1
`
`4.9386
`
`28
`
`4
`
`< 1.00 X 10 1
`
`4.9386
`
`Percent
`Reduction
`
`99.9988%
`
`99.9988%
`
`99.9988%
`
`99.9988%
`
`99.9988%
`
`99.9988%
`
`YES
`
`YES
`
`YES
`
`YES
`
`OEuropean Phannacopoem 7.0. 5.1.3. EfFACACY OF ANTIMICROBIAL PRESERVATION. 01/201 ].)0103. Acceptance Cntena,
`Table 5. 1.3.11 Parenteral preparations, eye preparations. intrauterlne preparations and intramammmy preparations: The criteria for
`fungi is a 2 log,o 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.
`
`Protocol 11151142-203
`Page 6 of 15
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 9 of 13
`
`Page 23 of27
`
`
`
`#151142-203.01 Letter Final Repmt
`l\1g~ 26 of 65
`
`Protocol/1151142-203
`January 07,2016
`
`TABLES
`T.~.H .. I'ro.cl.u.<;J..#J.: Prolensa'M bromfenac ophthalmic solution 0.07%.
`Bromfenac Sodium (unstressed)
`Lot Number 240031
`
`Test Product #4: Prolcnsa1
`M bromfcnac ophthalmic solution 0.07% (w/v)
`Bromfenac Sodium ( 4 weeks @ 60°C)
`Lot Number 240031
`
`·-
`Challenge
`Microorganism
`(ATCC#)
`
`lnitial
`Population
`(CFU/mL
`of Product}
`
`Day(s)
`Following
`Inoculation
`
`Produot
`II
`
`Population
`Recovered
`(CFlJ/mL)
`
`Log1o
`Reduction
`
`Acceptance
`Criteria
`Met?
`(Yes/No)O
`
`Percent
`Reduction
`
`Candida albicans
`(ATCC#I0231)
`
`1--·
`
`3.3182x .105
`CFU/1.0 mL
`
`14
`
`21
`
`28
`
`3
`
`4
`
`3
`
`4
`
`3
`
`4
`
`I
`
`< 1.00 x 10 1
`
`4.5209
`
`< 1.00 x 102
`
`4.5209
`
`< 1.00 X 10 1
`
`4.5209
`
`< 1.00 X 102
`
`4.5209
`
`< 1.00 X 10 1
`
`4.5209
`
`< 1.00 X 101
`
`4.5209
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`99.9970%
`
`99.9970%
`
`99.9970%
`
`~
`
`OEuropcan Pharrnacopoera 7.0. 5.1.3. EHACACY Of ANlJMICJWBIAL PRESERVATION. O!r20!1:)0!03. Acceptance
`' "
`"
`Criteria, Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intramammary preparations:
`The criteria lor fungi is a 2 log 10 reduction following 7 days of exposure to the test product with no recovered Colony Fanning
`Units (CFU) recovered alter 28 days of exposure to the product.
`
`Protocol #151142-203
`Page 7 of 15
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 10 of13
`
`Page 24 of27
`
`
`
`#151142-203.01 Letter Final Rep01t
`P.1ge 27 of 65
`
`Protocol #151142-203
`January 07,2016
`
`TABLE 9
`Test Product #3: ProlensaTM bromfen~c ophthalmic solution 0.07%.
`Bromfenac Sodium (unstressed)
`Lot Number 240031
`
`:Lill.!'.m~ucl #4.: ProlensaTM bromfenac ophlhalmic solulion 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
`
`Pt·oduct
`#
`
`Population
`Recovered
`(CFlJ/mL)
`
`<1.0
`-
`<1.00 x 10 1
`<1.00 X 10 1
`<1.00 X 10 1
`<1.00 X )01
`<!.00 X 10 1
`<].00 X 101
`
`Log10
`Reduction
`
`5.2322
`. .--~---.. ~·-
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`Acceptance
`Criteria
`Met?
`(Yes/No)O
`
`Percent
`Reduction
`
`YES
`
`99.9994%
`
`~-·----·· ·--··-~--
`
`YES
`
`99.9994%
`
`99.9994%
`YES
`99.9994%
`YES
`·-- -----
`99.9994%
`YES
`
`YES
`
`YES
`
`99.9994%
`
`99.9994%
`
`l
`
`7
`
`Pseudomonas aeruginosa
`(A TCC #9027)
`
`1.7070 X 106 - -
`14
`
`28
`
`3
`
`4
`
`3
`
`4
`
`3
`
`4
`
`3
`
`4
`
`<J.QQ X 101
`OEuropean Pharmacopoc•a 7.0. 5.l.J. EFFACACY OF ANTIMICROBIAL PRESERVATION. OJ/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 Jog 10 rcduclion 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.
`
`5
`
`YES
`
`99.9994%
`
`Protoco I Ill 51142-203
`Page 8 of 15
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01108/2016
`page 11 of 13
`
`Page 25 of27
`
`
`
`#151142~203.01 Letter Final Rep01t
`Page 28 of65
`
`Protocol 11151142-203
`January 07,2016
`
`TABLJ£10
`Tt::st l'roduct H:l.: Prolcnsa "'' bromfcnac ophthalmic solution 0.07%.
`Bromfenac Sodium {unstressed)
`Lot Number 240031
`
`1£§LEL9!lli£.l1L4: Prolcnsa TM bromfenac ophthalmic solution 0.07% {w/v)
`Bromfenac Sodi urn { 4 weeks @ 60°C)
`Lot Number 240031
`
`Challenge
`I\Iicroorganism
`{ATCC #)
`
`Initial
`Population
`{CFU/mL
`of Product)
`
`Day{s)
`Following
`Inoculation
`
`Product
`#
`
`Population
`Recovered
`(CFU/mL)
`
`<1.00 X 10 1
`
`I
`
`I
`
`7
`
`3
`
`4
`
`3
`
`4
`
`Staphylococcus aureus
`{ATCC#6538)
`
`!.9767 X 106
`
`______ .. ·-------------------- -- ----------------------__ ..
`
`I
`
`3
`
`4
`
`3
`
`14
`
`28
`
`4
`
`5.2959
`
`Acceptance
`Criteria
`Met?
`(Yes/No)O
`5.2959
`YES
`--r---------
`"-''"'"'~~-""''--"• ___ ...... -- f-"
`<1.00 X 10 1
`5.2959
`YES
`<1.00 X 10 1
`<1.00 x 101
`<1.00 X 10 1
`<1.00 x 10 1
`<1.00 X 101
`<1.00 x !0 1
`..
`..
`'
`'
`0European Pharmacopoem7.0. 5.1.3. LHACACY 01- ANIIMJCROB!i\L PRESERVATION. 0112011:50103. Acceptance Cntcna,
`Tahle 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intramammmy preparations: Criteda A for
`bacteria is a 3 1og1o 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.
`
`Log10
`Reduction
`
`Percent
`Reduction
`
`~ .
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`99.9995%
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`5.2959
`
`5.2959
`
`5.2959
`
`5.2959
`
`5.2959
`
`Protocol #151142-203
`Page 9 of IS
`
`SSCI Report: Stability Evaluation of Compound 578 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
`page 12 of 13
`
`Page 26 of27
`
`
`
`#151142-203.01 Letter Final Repmt
`Pagl! 29 of65
`
`Protocol/1151142-203
`.I anuary 07, 20 ](j
`
`TABLE 11
`Neutralization Evaluation- Results
`:r£~LlJ:.o.<I_\!.<J.Ji.,1: ProlensaTM bromfenac ophthalmic solution 0.07%.
`Bromtcnac Sodium (unstressed)
`Lot Numbers 240031
`
`ChaiJenge Microorganism
`
`ATCC# Neut.·alization Phase
`
`Microbial Recovery
`(Average CFIJ/Plate)
`
`Results
`Pass/Fai!O
`
`Aspergillus brasiliensis
`
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