UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
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`Petitioner
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`V.
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`SENJU PHARMACEUTICAL CO., LTD.
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`Patent Owner
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`Case IPR2015—0110O
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`Patent 8,927,606 B2
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`DECLARATION OF ADAM C. MYERS, PH.D.
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`SENJU EXHIBIT 2126
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`LUPIN V SENJU
`IPR2015—01100
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`Page 1 of 27
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`I, Adam C. Myers, Ph.D., under penalty of perjury, declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I submit
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`this declaration at
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`the request of Finnegan, Henderson,
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`Farabow, Garrett & Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd.
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`(“Senju”) as an expert in the field of the design, evaluation, and formulation of
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`drug products. My qualifications in these areas, as well as other areas, are
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`established below and by my curriculum vitae, which is EX2l27.
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`II.
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`BACKGROUND AND QUALIFICATIONS
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`2.
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`I am currently a Senior Research Investigator at SSCI, a Division of
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`Albany Molecular Research, Inc. (“AMRI”) in West Lafayette, Indianapolis, which
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`I have been working for over a year.
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`3.
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`I received a B.S. with Honors degree in biochemistry from Purdue
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`University in 2000 and a Ph.D. degree in organic chemistry from Purdue
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`University in 2005.
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`4.
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`Prior to joining SSCI,
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`I worked in the pharmaceutical industry for
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`Quadraspec, Inc. and BASi in West Lafayette. My employment at Qaudraspec, Inc.
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`began in 2006 and continued until I moved to BASi in 2007. My roles at BASi
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`increased over the years from a Senior Scientist/Team Leader to Assistant Director
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`of Pharmaceutical Analysis, and eventually to Director of Pharmaceutical
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`Scientific Operations in 2012. As a Senior Scientist/Team Leader,
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`I was
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`responsible for developing protocols, method and techniques for various analytical
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`testing. As Assistant Director of Pharmaceutical Analysis and Director of
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`Pharmaceutical Scientific Operations, I was responsible for providing scientific
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`directions to a laboratory conducting Current Good Manufacturing Practice
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`(“cGMP”) and Good Laboratory Practice (“GLP”) projects.
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`5.
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`My current expertise in design, evaluation, and formulation of drug
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`products focuses on drug formulation analytics utilizing chromatography, mass
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`spectrometry, UV—Vis, dissolution, in a CGMP laboratory setting.
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`I have extensive
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`research, development, and manufacturing experience and have coauthored
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`publications and given presentations related to pharmaceutical drug products.
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`III. DOCUMENTS AND INFORMATION CONSIDERED IN FORMING
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`OPINIONS
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`6.
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`In forming my opinions, I had available the documents cited herein as
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`well as the publications listed on my curriculum vitae at EX2l27.
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`I also based my
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`opinions on my professional and academic experience in the area of drug
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`formulation and analytics.
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`I reserve the right to testify about these materials and
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`experience.
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`IV.
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`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
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`REASONS THEREFOR
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`A.
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`7.
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`Background
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`Samples of Bausch & Lornb Incorporated’s (“B+L’s”) Prolensa®
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`product samples were sourced from B+L. B+L shipped the samples to Finnegan,
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`Page 3 of 27
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`Henderson, Farabow, Garrett & Dunner, LLP, who then shipped the samples to
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`SSCI for testing. A portion of these samples were further shipped to BioScience
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`Laboratories, Inc. These samples were analyzed for potency, 2'. e. chemical stability,
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`at SSCI and for preservative efficacy at BioScience Laboratories, Inc. during the
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`months of November 2015 and January 2016. Potency measures the amount of an
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`analyte present in the testing sample.
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`In other words, the chemical stability data
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`indicate the percentage amount of bromfenac free acid in the Prolensa® product
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`samples that were subject to stressed and unstressed conditions for four weeks.
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`I
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`was personally present during the chemical stability testing of these samples.
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`8.
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`SSCI has provided a summary report of both the chemical stability
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`testing and preservative efficacy testing, which is attached as Appendix A. The
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`SSCI report correctly details the analytical
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`testing that was performed and
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`accurately reports the chemical stability test results, as well as the preservative
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`efficacy test results. The report describes the analytical methodology to quantitate
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`bromfenac free acid in the stressed and unstressed conditions. The chemical
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`stability results are reported in the document for all of the samples tested.
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`9.
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`SSCI is a cGMP facility providing contract product development
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`services to the pharmaceutical
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`industry.
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`SSCI’s service offerings include
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`analytical
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`testing
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`(e. g.,
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`chemical
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`stability),
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`product
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`development,
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`and
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`Page 4 of 27
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`manufacturing. The chemical stability testing of the B+L’s Proiensa® product
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`samples was performed. in SSCI’s CGMP quality control laboratory.
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`10.
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`B+L’s Prolensa® product samples were received, stored, l“laIl(.“ll€Cl, and
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`maintained according to SSCPS CGMP sample handling procedures. The samples
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`were stored under ambient laboratory conditions in their original containers.
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`ll.
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`A portion of the samples received from B+L were stressed in an oven
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`at 60° C, and the rest were maintained at unstressed (ambient) conditions. All of
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`the samples were tested for potency after four weeks, and percent recoveiy was
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`calculated based on the potency of the stressed samples relative to the unstressed
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`samples. To prevent contamination of the samples and to maintain uniforrnity of
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`analysis, all of the samples were kept in the original containers and were tested for
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`potency after four weeks at either unstressed or stressed conditions. Perforrning
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`the HPLC analyses all at once after the fourwweek duration guarantees the
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`cunifomlity of analysis, by utilizing the same standard preparations, mobile phase,
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`column and instrument, while performing at different
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`time points may add
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`variables that could potentially skew the results.
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`1.2.
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`Usin.g this .method was furth.er justified because all of the samples
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`were storage stable in the containers as provided. Bel-Alfs Prolensa® product is e
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`marlceted product with sufficient stability_for ophthalmic use.
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`(See, e.g.,—EX1049 at 1.) From these known stability
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`profiles of products in the provided containers that have been ma1‘1<:eted,
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`it
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`appropriate to assess stability of the finished product in the provided containers.
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`Therefore, the measured potency of the stressed samples (experimental condition)
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`can be properly compared to the measured potency of the unstressed samples
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`(control condition) to analyze chemical. stability.
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`B.
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`Reported Concentration Results are Reliable
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`13. A single point standard (one concentration), which is a well
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`recognized, scien_tificaI1y Valid method, was used to "measure potency. STD A was
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`used as the single point standard, and STD B was used as 21 check, standard. The
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`single point
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`sta.nda.rci assumes a linear relationship between afbsorbance and
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`concentration of the molecule. This assumption is supported by the Beei‘~La:nbert
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`Law, which states that absorbance is proportional to concentration of the UV active
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`species in the sample. (BX2279 at 414415.)
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`14. Moreover, quantitation by a single point standard is commonly used
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`in the pharmaceutical industry, and it is predominately used in compendial method
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`monographs for many compounds in the U.S. Pharmacopoeia.
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`For example,
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`monographs
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`for ketorolac
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`trometharnine
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`in
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`tablet,
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`injection
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`and
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`active
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`phennaeeutical ingredient (“API”), diclofenao sodium in AP}, delayed release and
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`extended release, and bri.nzolan1ide ophthalmic suspension. and AP} 3.1}. list only a
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`single point standard for assay determination of their active ingredient.
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`(EXZZSO;
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`EX2281; EX2283; EX2284; EX2285; EX2287; EX2288; EX2289.) The single
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`point standard can be used to measure potency for an assay resulting in peak
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`responses either above or below that of the standard injection peak response, as
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`illustrated,
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`example,
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`in US. Pharmacopoeia monographs
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`assays
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`for
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`brinzolamide oplithalmio suspension and ketoroiac iromethamine injection.
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`(EX2281; EX2288.) Furclaennore, this was the method that Mr. Sawa used at
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`Senju in conducting the chemicai stability testing for brornfenac and tyioxapol
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`containing, solutions. (See, e.g., EX2098, Appendix A.)
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`15.
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`It was aiso confirmed that there were no other components in B+L’s
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`Prolen.sa® product that would co~eiute with brornfenac. The injection of the
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`standard solution, which contained bromfenao sodium and water, showed a single
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`peak; in the range of 8.64-8.70 minutes. (EX2266.) Biank injections of the mobile
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`phase showed no interference at the retention time of bromfenac.
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`(See, e.g.,
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`EX2266 at 22.) I understand that the other components contained in the samples of
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`W Wet
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`-{njection of a placebo solution during method familiarization (EX2265
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`at 4), which contained the above listed components, also showed no inmrference at
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`the retention time of bromfenao. That the blank injections and. the placebo solution.
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`showed no i11te1‘fene11ce with the b1'omfez1ac peak confirm that none of the
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`components in the drug product matrix or the mobile phase would co-elute with
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`bromfenac.
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`16.
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`Furthezmore, none of bromfenac’s degradants likely would co~<~:lut;e at
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`the retention time of bromfenac. Certain d.egradantS could theoretically co~elute at
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`similar retention times to their correspondilng; original molecules. But based on the
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`structure: of bromfenac and its potential degradants, the anticipated retention times
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`of the expected degradants would be different from that of bromfenac because of
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`their differences in polarity. Any breakdown of bromfenac resulting from
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`degradation would likely result in degradant compounds having different polarity
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`unlikely that a degradant would co-elute with bromfenac.
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`17.
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`In addritiona comparing the HPLC results of the standard and the
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`stressed samples supports that degradants from this study eluted 9.? different times.
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`For example, the HPLC result for a stressed sample on EX2266 at 51 shows the
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`bromifhnac peak at 8.678 minutes and a very small peak: at 10.138 minutes, but all
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`of the HPLC results for the standard and unstressed samples show only the
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`Page 8 of 27
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`‘oromfenac peak in the range of 8.64~8.7O minutes.
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`In addition, the shape of the
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`bromfenac peak in the HPLC results of the standard, stressed and unstressed
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`samples is consistent, which indicates a lack of co~elution of other species with this
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`peak. If bromfcnac and any degradent had simiiar retention times, the shape of the
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`bromfenac peak would have been aitercd. These ‘factors further support that
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`hromienac and other components, including any degradant, would eiute at different
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`C.
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`Stressed Samples Were Compared to a Proper Baseline
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`18. As discussed in $1 12 above, the chemical. stability of the samples were
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`analyzed by property comparing the potency of stressed (experimental) and
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`unstressed (control) samples after four weeks. As discussed. in fit 12 above,-
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`Furthermore, as discussed
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`potency of the stressed sampies
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`(expenmehtal condition,) can be properly
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`compared to that of the unstressed samples (control condition) to anaiyze chemicai
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`stabi1ity, Based on this information, it is
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`reasonable to expect that the potency of the unstressed sampies at time zero and
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`after four Weeks Wouid not change in any rneaningful way that would impact the
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`Page 9 of 27
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`results. Therefore, by comparing the potency of the stressed samples and the
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`unstressed samples after four weeks, the chemical stability of B+L’s Prolensa®
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`product can be accurately measured.
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`19. Moreover, as discussed in 1] ll above, performing the HPLC analyses
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`all at once after the four—week duration further guarantees the uniformity of
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`analysis, by using the same standard preparations, mobile phase, column and
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`instrument. Performing the HPLC analyses at different time points may add
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`variables that could impact the results. This supports the accuracy of the obtained
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`potency and chemical stability results.
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`D.
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`Stability Tests Used Proper Containers
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`20.
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`As discussed above, to prevent contamination of the samples and to
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`maintain uniformity of analysis, all of the samples were kept
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`in the original
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`containers and were tested for potency after four weeks at either unstressed or
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`stressed conditions. Performing the HPLC analyses all at once after the four—week
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`duration guarantees the uniformity of analysis, by using the same standard
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`preparations, mobile phase, column and instrument, while performing at different
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`time points may add variables that could impact the results. Moreover, the ICH
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`Guideline section 2.2.4 specifies that “the stability testing should be conducted on
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`the dosage form packaged in the container closure system proposed for marketing.”
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`(EX2290 at 7.) Good stability practice should be conducted on the dosage form
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`Page 10 of 27
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`10
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`packaged in the container closure system proposed for marketing, as specified in
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`the ICH Guideline. Additionally, transfer of samples as received to an alternate
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`container, such as polypropylene containers, would have risked affecting the
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`stability results by introducing variables such as contamination or loss of material
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`on transfer. Moreover, the validity of the relative potency values obtained for the
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`stressed and unstressed samples was further ensured because the samples were held
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`in the same container closure system.
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`21. Moreover,
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`in order to maintain consistent storage conditions for
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`samples analyzed for potency and preservative efficacy, the same container type
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`should be used for samples evaluated in both tests. Transfer to a separate container,
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`such as a polypropylene container, requires opening the sealed sample, which
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`could result in a potential contamination of the sample that could affect not only
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`potency but also preservative efficacy testing. Therefore, for at least the reasons
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`discussed above,
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`the best practice is to use the samples in the containers as
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`provided, which the ICH Guideline recommends. (EX229O at 7.)
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`E.
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`Percent Recovery Accurately Reflects the Chemical Stability of
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`Samples
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`22. As discussed above in ‘H 17, based on the structure of bromfenac and
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`its potential degradants, the anticipated retention times of the expected degradants
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`would be different from that of bromfenac because of their differences in polarity.
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`Any breakdown of bromfenac resulting from degradation would likely result in
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`Page 11 of 27
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`11
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`degradant compounds having different polarity from that of bromfenac. This
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` Therefore,
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`the HPLC <:hromatograms would
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`Show not only the bromfenac peak but also peaks of any degradants, if there were
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`any significant degradation.
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`For example, for B+L’s Proler1sa® product, the
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`Hi’LC result for a stressed sample on EX2266 at 51 shows the bromfenac peak at
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`8.678 minutes, which has an area of 98.9896“/o relative to all integrated peaks, and
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`21 very small peak likely attributed to a known degradant at 10.138 minutes, which
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`has an area of l.0l04%. All of the I-IPLC results for the related standard and
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`unstressed samples Show only the bromfenac peak in the range of 8.64~8.7O
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`minutes. Had there been significant degradation, the area of the bromfenac peak
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`relative to other components would have been significantly reduced. It was not.
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`23. Moreover,
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`the HPLC results support that there was little,
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`if any,
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`moisture vaporization from the stressed samples. Minimal, if any, degradation
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`occurred in the stressed samples as demonstrated by the chromatography. If there
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`had been significant moisture vaportzzationl then the measured concentration of
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`brornfenae in sample solutions would have greatly increased. For example, as
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`shown in the HPLC result for a stressed sample of B+L’s Proiensa® product on
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`EZX2266 at Sl, the bromfenac peak. was observed to have an area of 98.9896%
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`reiative to all
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`integrated peaks. Because there were not significant levels of
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`Page 12 of 27
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`degradant peaks, there was no substantial moisture loss that would have affected
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`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 cGl\/[P
`
`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
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`receive no additional compensation for this matter. No part of my compensation is
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`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
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`cases.
`
`U Frlaii
`Date
`
`____
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`5 1
`Adam C. Myers, Ph.D.
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`Page 13 of 27
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`13
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`APPENDIX A
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`Page 14 of 27
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`W
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`A Division of Albany Molecuiar Research inc.
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`3065 Kent Avenue
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`West Lafayette, IN 47906-1076
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`Phone: (765) 463-0112
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`(765) 463 4722
`Fax:
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`
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`info@s-sci—inc.com
`i:
`E—
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`W : www.ssci-inc.com
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`Stability Evaluation of
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`Bromfenac Sodium Drug
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`Product Samples for Potency
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`and Preservative Efficacy
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`Project ID: EL20151326
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`Report Date: 01/08/2016
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`Page 15 of 27
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`TABLE OF CONTENTS
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`SUMMARY ........................................................................................................................................................ ..3
`I.
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`RESULTS AND DISCUSSION ......................................................................................................................... ..3
`II.
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`III. DATA TABLES ................................................................................................................................................. ..5
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`Table 1. Summary of HPLC Data, Sequence 741881 ............................................................................................... ..5
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`Table 2. Summary of HPLC Data, Sequence 742199 ............................................................................................... ..6
`IV. EXPERIMENTAL .............................................................................................................................................. ..7
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`A. HPLC Method ................................................................................................................................................... ..7
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`V. APPENDIX A: PRESERVATIVE EFFICACY DATA .................................................................................... ..8
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`SSCI Report: Stability Evaluation of Compound 5 78 Drug Product Samplesfor Potency and Preservative Eficacy, 01/08/2016
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`page 2 of 13
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`Page 16 of 27
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`I.
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`SUMMARY
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`Bromfenac sodium ophthalmic solution drug products were sourced from Senju. A portion of
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`the samples was used for unstressed (as received) analysis, and the remaining samples were
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`stressed in an oven for four (4) weeks at 60°C. Samples from both the unstressed and stressed
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`conditions were evaluated for potency and preservative efficacy.
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`Potency was determined by HPLC with UV detection as detailed in Section lV.A. Percent
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`recovery (percent initial) was calculated based on the potency after stress conditions relative to
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`that of the unstressed sample. See Table 1 for the unstressed (as received) HPLC data and Table
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`2 for the stressed sample HPLC data.
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`Preservative efficacy was evaluated by BioScience Laboratories, Inc. Samples were evaluated
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`for preservative efficacy as guided in the EP Preservative Effectiveness Test Method against the
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`following organisms: Candida albicans (AATCC# 10231), Aspergillus niger (AATCC# 16404,
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`also referred to as Aspergillus brasiliensis), Pseudomonas aeruginosa (AATCC# 9027) and
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`Staphylococcus aureus (AATCC# 6538).
`See Section V for
`the detailed experimental
`information.
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`Section 11 contains results for both potency and preservative efficacy.
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`II. RESULTS AND DISCUSSION
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`Material was purchased from one (1) lot, which was used for all experiments and time points.
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`Average results are summarized below, with the percent recovery calculated as the amount of
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`active relative to the unstressed sample.
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`
`Lot Number
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`V
`
`240031
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`
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`High = 0.7466
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`Unstressed
`
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`Concentration
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`(mg/ml)
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`Average = 0.7457
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`Low = 0.7451
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`Stressed
`
`Concentration
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`(mg/mt)
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`Average = 0.7445
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`Low = 0.7418
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`High = 0.7473
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`% Recovery
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`Average = 99.8
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`Low = 99.5
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`High = 1002
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`Stressed and unstressed samples were evaluated for preservative efficacy, with the following
`results.
`
`
`SSCI Report: Stability Evaluation of Compound 5 78 Drug Product Samplesfor Potency and Preservative Eficacy, 01/08/2016
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`page 3 of 13
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`Page 17 of 27
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`inocuium
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`Count
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`1.97667 x 10*‘
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`S. am*eu,s~
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`p
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`Z
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`<7<=’7”H§!770St?
`
`7
`C‘
`
` Ceil Count (CFU/mL)
`
`
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`
`
`Days After Inoculation
`
`<1,oo x 10‘
`
`<1.oo x 10‘
`
`<1.oo x 10‘
`
`
`<1.oo x 10‘
`
`
`
`< 1.00 x 10‘
`
`
`
`21
`
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`
`
`< 1.00 x 10’
`
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`
`<1,oo x 10‘
`
`
`<1.00 x 10‘
`
`<1.o0 x 10‘
`
`4.00 x 10’
`
`
`<1.oo x 10‘
`
`
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`<1.oo x 10*
`
`<1.0o x 10’
`
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`<1.oo x 10‘
`
`<1_oo x 101
`
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`<1.o0 x 101
`
`
`<1.o0 x 10’
`
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`<1xGO x 101
`
`<1.oo x 10‘
`
`<1.00 x 10‘
`
`
`<1.o0 x ml
`
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`4.00 x 10’
`
`<1.o0 x 101
`
`<1.oo x 101
`
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`<1.oo x 10‘
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`6
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`1 7070 x 10
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`
`3 3953 x 105
`
`
`
`
`8 8837
`
`.
`
`105
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`
`
`X
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`
`
`Unstressed
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`A
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`_
`. P41
`63 '
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`g I
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`
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`SSCI Refiolt: .S'rabiIi1yEmIz:atio21 of Compound 5 F8 Drug Product Snmpiesfor Potency and Presmvative Efiicaey. 0!/‘O8/2016
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`page 4 of 13
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`Pa ge 1 8 0 f 2 7
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`

`
`III. DATA TABLES
`
`
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`
`
`
`
`
`
`Table 1. Summary of HPLC Data, Sequence 741881
`
`
`
`|nj#
`
`
`
`LIMS
`
`
`
`LC Filename
`
`
`
`
`RT
`
`
`Area(mAU*s)
`
`
`
`
`
`408677
`
`
`
`
`
`
`
`
`408706
`
`
`
`
`
`
`
`
`408705
`
`403489
`
`741882
`
`741889
`
`‘I
`
`741897
`
`741899
`
`
`8.667
`
`8.668
`
`8.666
`
`8.666
`
`
`
`8.665
`
`
`4012.66
`
`4015.13
`
`4016.96
`
`4016.04
`
`
`
`4038.45
`
`8.666
`
`
`
`8.646
`
`
`
`
`8.648
`
`8.647
`
`4019.73
`
`
`
`4556.16
`
`
`
`
`4548.27
`
`4547.03
`
`
`5a"7'°'?
`Description
`Blank
`
`
`STD A
`
`STD A
`
`STD A
`
`STD A
`
`
`STD B
`
`
`
`STD A
`
`
`
`
`
`
`240031
`
`240031
`STD A
`
`
`1
`
`3
`4
`5
`6
`
`8
`
`
`
`
`
`
`
`
`
`
`16
`
`
`
`
`
`20
`
`
`
`741883
`
`741884
`
`741885
`
`741886
`
`741887
`
`
`
`
`
`240031
`741898
`
`
`
`741900
`
`
`SSCI Report: Smbility Evaluation 0fComp0zmd 5 78 Drug Product Samples for Potency and Preservative Eflicacy, 01/O8/2016
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`page 5 of 13
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`Page 19 of 27
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`Table 2. Summary of HPLC Data, Sequence 742199
`
`
`
`Blank
`
`
`Sample
`Description
`Blank
`
`
`STD A
`
`STD A
`
`STD A
`
`STD A
`
`STD A
`
`STD 13
`
`
`Blank
`
`570 A
`
`570 A
`
`570 A
`
`STD A
`
`
`
`
`
`240031
`240031
`240031
`
`570 A
`570 A
`
`STD A
`STD A
`
`
`
`
`
`
`
`
`240031
`240031
`
`240031
`STD A
`
`
`240031
`240031
`240031
`
`240031
`STD A
`
`
`
`
`
`
`
`
`LIMS
`
`
`
`
`
`408677
`
`408705
`
`
`
`408677
`
`
`408705
`
`408705
`
`408705
`
`408705
`
`408706
`408677
`
`
`
`
`
`
`
`
`
`403478
`
`403479
`
`403480
`
`
`
`
`
`403484
`
`403485
`
`403487
`
`
`
`
`408705
`408705
`408705
`408705
`
`408705
`408705
`
`408705
`408705
`
`403481
`403482
`
`403483
`408705
`
`403488
`408705
`
`
`
`742200
`
`742202
`
`LC Filename
`
`
`
`
`
`
`
`
`742208
`
`
`
`
`
`742242
`
`742249
`
`
`
`742263
`
`742264
`
`742265
`
`742266
`
`742267
`
`
`
`742272
`
`742273
`
`742274
`
`742275
`
`742276
`
`
`742222
`742229
`742235
`
`742256
`742262
`
`742268
`742269
`
`
`
`RT
`
`
`‘ Area(mAU*s)
`
`
`
`8.669
`
`
`
`
`
`
`
`
`8.690
`8.691
`
`
`8.676
`
`8.677
`
`8.681
`
`8.682
`
`8.684
`
`
`
`8.670
`
`8.670
`
`8.670
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`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`4522.94
`
`4555.21
`
`
`
`
`
`
`
`
`
`4537.86
`4545.41
`4541.65
`
`4556.05
`4024.68
`
`4541.95
`4541.17
`4524.65
`
`4523.19
`4024.02
`
`SSCI Report: Stabilz'ty Evaluation of Compound 5 78 Drug Product Samples for Potency and Preservative E./ficacy, 01/08/2016
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`page 6 of 13
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`Page 20 of 27
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`

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`IV. EXPERIMENTAL
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`A. HPLC Method
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`HPLC analyses were performed using an Agilent 1100 series liquid chromatograph equipped
`
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`with a diode array detector, degasser, quaternary pump, and autosampler. The chromatographic
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`column was a Shiseido Capcell Pak C18, 2.1 X 100.0 mm column with 5.0 um packing. The
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`column temperature was set to 25°C, and the detector wavelength was 266 nm. The injection
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`Volume was 5.0 uL. The mobile phase was prepared by dissolving 7.9231 g of ammonium
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`dihydrogen phosphate into 3000 mL of water, adding phosphoric acid to adjust the pH to 7.30,
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`and then mixing in 1000 mL of acetonitrile. The flow rate used was 1.5 mL/minute, with a run
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`time of 13 minutes per injection. Method performance was monitored for the following criteria,
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`with the listed range of results.
`
`
`
`
`Criterion
`
`
`Precision (n=5 %RSD)
`
`
`Global %RSD
`
`
`
`
`"failing Factor <1“ standard injection)
`
`
`
`
`Plates (lst standard injection)
`
`
`Percent Agreement
`
`
`
`
`0.05% ~ 0.06%
`0.06% — 0.11%
`
`5251 — 5297
`
`
`
`
`
`
`100.6% - 101.1%
`
`
`
`SSCI Report: Stabilily Evaluation of Compound 5 78 Drug Product Samples for Potency and Preservative Efficacy, 01/08/2016
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`page 7 of 13
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`Page 2 1 of 27
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`V. APPENDIX A: PRESERVATIVE EFFICACY DATA
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`
`
`SSCI Report: Stability Evaluation of Compound 5 78 Drug Product Samplesfar Potency and Preservative Eflicacy, 01/O8/2016
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`page 8 of 13
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`Page 22 of 27
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`

`
`#151 142-20301 ]..e11e1'Finu1 Repofl
`Page 25 of‘65
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`Protocol #151142-203
`
`
`January 07, 2016
`
`
`
`
`
`
`_ TABLE 7
`
`
`Test Product #3: Proicnsam isroiiitbnuc ophthalmic solution 0.07%.
`
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`
`
`
`Bromfcnac Sodium (unstressed)
`
`
`
`Lot Numbers 240031
`
`
`
`
`: Proierisam bromfenac ophthalmic solution 0.07% (w/v)
`
`
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`
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`Bromfenac Sodium (4 weeks @ 60“C))
`
`
`
`
`
`Lot Number 240031
`
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`
`
`99'9988%
`99.9988%
`99.9988%
`
`
`
`YES
`was
`
`YES
`
`
`
`, W
`
`Product
`Fgrofigfi)
`
`lnowlafiogn
`#
`
`
`WWWWWWWm1.._._”__._.,._M_.
`3
`
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`
`
`Initial
`
`Population
`(CFU/mL
`
`OT Product)
`
`
`
`
`4
`
`
`
`8.6818 X 105
`
`
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`
`
`
`
`
`3
`4
`3
`
`
`
`
`
`
`
`I
`‘
`
`MiE£;:ll_e:::sn]
`(ATCE. #)
`
`
`'
`
`
`
`Aspergillzrs bP‘(1Si[fEIiS1S
`
`
`
`W “C #16404)
`
`
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`
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`Protocol #151 142-203
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`Page 6 of15
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`