PLAINTIFFS'
`TRIAL EXHIBIT
`PTX1663 e
`
`xhibitsticker.com
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`C.A. No. 14-1453-LPS
`
`))))))))
`
`)))))
`
`MEDA PHARMACEUTICALS INC. and
`CIPLA LTD.,
`
`Plaintiffs,
`
`v.
`
`APOTEX INC. and APOTEX CORP. ,
`
`Defendants.
`
`REPORT OF MATTHEW J. HERPIN, PH.D.
`
`PTX1663-00001
`
`1
`
`CIP2029
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`I.
`
`Introduction and Qualifications
`
`1.
`
`I have been retained by Meda Pharmaceuticals Inc. (“Meda”) and Cipla Ltd.
`
`(“Cipla”) (collectively, “Plaintiffs”) to formulate and test the composition described in EP
`
`0780127 (Cramer) Example III.
`
`2.
`
`I attach my curriculum vitae to this report as Appendix A. I am currently a
`
`Postdoctoral Research Fellow at the University of Texas, Austin, College of Pharmacy. I
`
`obtained my Ph.D in Pharmaceutics from the University of Texas, Austin.
`
`3.
`
`I have never testified as an expert witness or prepared an expert report in
`
`connection with any litigation. A list of my publications is included in my CV.
`
`4. My rate is $300 per hour, and my compensation does not depend upon the
`
`ultimate outcome of this case. I will also be compensated for any reasonable expenses,
`
`including travel costs incurred in conducting activities at counsel’s request.
`
`5.
`
`If called to testify, I am prepared to testify regarding the results of my
`
`experiments as reported here and the attached documents.
`
`II.
`
`Summary of Work and Results
`
`6.
`
`Plaintiffs retained me to formulate Cramer Example III using three different
`
`processes: (1) the process Cramer describes in Example I (“Cramer Example I Method”); (2)
`
`the process Geena Malhotra describes in her August 12, 2011 declaration (“Malhotra
`
`Method”); and (3) the first process Dr. Govindarajan used in his June 30, 20016 report
`
`(“Govindarajan Method”). I was instructed to document and photograph the formulation
`
`process. I attach the protocols for the Cramer Example I Method and the Malhotra Method as
`
`Appendix B.
`
`PTX1663-00002
`
`2
`
`

`

`Highly Confidential
`Subject to Protective Order
`7.
`Plaintiffs also retained me to perform the following tests on the formulations
`
`prepared using the three different processes: (1) visually describe the final preparation; (2)
`
`measure the pH; (3) test the sprayability; (4) measure the pH 7 days after preparation; (5)
`
`visually describe the preparation after 7 days with and without mixing; (6) test the Delivered
`
`Dose Uniformity; (7) test the Bulk Blend Uniformity Assay for Triamcinolone Acetonide for
`
`freshly prepared samples, samples after 3 hours, and samples after 7 days; and (8) visually
`
`describe the preparation after 14 days with and without mixing. I did not conduct the Delivered
`
`Dose Uniformity tests and Bulk Blend Uniformity Assay for Trimacinolone Acetonide on
`
`formulations that failed the sprayability test (i.e., produced a jet spray). Additionally, the
`
`preparation made using the Govindarajan Method did not result in a large enough volume for
`
`me to perform the Delivered Dose Uniformity Testing and Bulk Blend Uniformity Assay for
`
`Trimacinolone Acetonide.
`
`8.
`
`The Cramer Reference is silent as to the grade of HPMC to use and whether the
`
`triamcinolone acetonide is micronized or unmicronized. Therefore, I used two different grades
`
`of HPMC, a low-viscosity grade (HPMC-E3-LV) and a medium-viscosity grade (HPMC-
`
`E4M), and I used both micronized and unmicronized triamcinolone acetonide.
`
`9.
`
`Exhibit A shows the following formulation matrix:
`
`Formulation(cid:3)Matrix(cid:3)
`API(cid:3)
`Method(cid:3)
`Formulation(cid:3)(cid:3) Polymer(cid:3)
`Cramer(cid:3)Example(cid:3)I(cid:3) Micronized(cid:3)TAA(cid:3)
`HS(cid:882)D(cid:3)
`HPMC(cid:882)E4M(cid:3)(4000(cid:3)cps)(cid:3)
`Malhotra(cid:3)
`Raw(cid:3)TAA(cid:3)
`Mal(cid:882)A(cid:3)
`HPMC(cid:882)E3(cid:882)LV(cid:3)(3cps)(cid:3)
`Mal(cid:882)B(cid:3)
`HPMC(cid:882)E4M(cid:3)(4000(cid:3)cps)(cid:3) Malhotra(cid:3)
`Raw(cid:3)TAA(cid:3)
`Mal(cid:882)C(cid:3)
`HPMC(cid:882)E3(cid:882)LV(cid:3)(3cps)(cid:3)
`Malhotra(cid:3)
`Micronized(cid:3)TAA(cid:3)
`Mal(cid:882)D(cid:3)
`HPMC(cid:882)E4M(cid:3)(4000(cid:3)cps)(cid:3) Malhotra(cid:3)
`Micronized(cid:3)TAA(cid:3)
`X(cid:882)Form(cid:3)
`HPMC(cid:882)E3(cid:882)LV(cid:3)(3cps)(cid:3)
`Govindarajan(cid:3)
`Micronized(cid:3)TAA(cid:3)
`
`
`
`- 3 -
`
`PTX1663-00003
`
`3
`
`

`

`Highly Confidential
`Subject to Protective Order
`10. The legend for the formulation matrix is:
`
`a. TAA – Triamcinolone Acetonide;
`b. Mal-A, Mal-B, Mal-C, and Mal-D were preparations using the Malhotra Method;
`c. HS-D is a preparation using Cramer Example I Method;
`d. X-Form recreated the Govindarajan Method.
`
`11. Exhibit B reports the process steps, visual results, and pH testing for the Mal-A,
`
`Mal-B, Mal-C, and Mal-D preparations made using the Malhotra Method.
`
`12. Exhibit C reports the process steps, visual results, and pH testing for HS-D. The
`
`exhibit also shows the preparation made using the Cramer Example I Method.
`
`13. Exhibit R reports the Pump Delivery Shot Weight Raw Data and the Sprayability
`
`results for Mal-A, Mal-B, Mal-C, Mal-D, and HS-D formulations.
`
`14. Exhibit D reports the visual results and pH testing results for X-form. I annotated
`
`a copy of Dr. Govindarajan’s lab notebook.
`
`15. Exhibit E reports the results of pH testing of each formulation (Mal-A, Mal-B,
`
`Mal-C, Mal-D, HS-D, and X-Form) 7 days after initial preparation.
`
`16. Exhibit F reports the visual appearance of each formulation (Mal-A, Mal-B, Mal-
`
`C, Mal-D, HS-D, and X-Form) 7 days after initial preparation. It also reports the visual
`
`appearance of each formulation after attempting to re-disperse settled particles. Re-dispersion
`
`was done by swirling and shaking the vessel in a moderate action to minimize foaming.
`
`17. Exhibit G reports the sprayability of formulations Mal-A and Mal-C after 7 days.
`
`Because formulations Mal-B, Mal-D, and HS-D only produced a jet during the initial test, I did
`
`not conduct another sprayability test 7 days after preparation of those formulations.
`
`
`
`- 4 -
`
`PTX1663-00004
`
`4
`
`

`

`Highly Confidential
`Subject to Protective Order
`18. Exhibit H reports the Delivered Dose Uniformity analysis and assay of
`
`formulation Mal-A.
`
`19. Exhibit I reports the Delivered Dose Uniformity analysis and assay of formulation
`
`Mal-C.
`
`20. Exhibit J reports the Delivered Dose Uniformity summary for Mal-A and Mal-C
`
`preparations.
`
`21.
`
`Pictures from Mal-A preparation showing the formulation after step 11 and after 7
`
`days are attached as Exhibit K.
`
`22.
`
`Pictures from Mal-B preparation showing the formulation after step 11 and after 7
`
`days are attached as Exhibit L.
`
`23.
`
`Pictures from Mal-C preparation showing the formulation after step 11 and after 7
`
`days are attached as Exhibit M.
`
`24.
`
`Pictures from Mal-D preparation showing the formulation after step 11 and after 7
`
`days are attached as Exhibit N.
`
`25. Exhibit O contains pictures from the HS-D preparation that show the formulation
`
`after step 11, 7 days after preparation, and pictures of the undissolved EDTA taken during the
`
`initial preparation.
`
`26.
`
`Pictures from the X-Form preparation show the formulation after the addition of
`
`azelastine hydrochloride, after the addition of HPMC, and 7 days after initial preparation are
`
`attached as Exhibit P.
`
`
`
`- 5 -
`
`PTX1663-00005
`
`5
`
`

`

`Highly Confidential
`Subject to Protective Order
`27.
`I also took videos of the sprays from Mal-A and Mal-B preparations, which were
`
`representative of the spay patterns of the low-viscosity HMPC and medium-viscosity HPMC
`
`formulations, respectively, which I attach as Exhibit Q.
`
`28.
`
`Pictures for Mal-A, Mal-B, Mal-C, HS-D, and X-Form formulations 14 days after
`
`the initial preparation are attached as Exhibit S.
`
`29. Exhibit T contains pictures of the visual appearance of each formulation (Mal-A,
`
`Mal-B, Mal-C, HS-D, and X-Form) 14 days after the initial preparation and after attempting to
`
`re-disperse any settled particles of the formulation. Re-dispersion was done by swirling and
`
`shaking the vessel in a moderate action to minimize foaming.
`
`
`
`- 6 -
`
`PTX1663-00006
`
`6
`
`

`

`Ill. Declaration
`
`I declare under penalty ofpteury under the laws of the United States that the foregoing
`
`is true and correct to the best of my knowledge.
`
`
`
` Date: g/Ztis’a’
`
`Matthew J. Herpin, Ph.D
`
`
`
`PTX1663-00007
`
`7
`
`

`

`Appendix A
`Appendix A
`
`00000000000 08
`
`PTX1663-00008
`
`8
`
`

`

`MATTHEW J. HERPIN, Ph.D
`601 Hearn Street #202 • Austin, Texas 78703 • 512.947.8626
`matt.herpin@.utexas.edu
`
`
`
` Personal
`
` Born October 31st 1981 in Corpus Christi, Texas. United States Citizen.
`
`
`I.
`
`
`
`
`II. Education
`
` Ph.D., Pharmaceutics, December 2015
`
` Advisor: Dr. Hugh D.C. Smyth
`
` The University of Texas, Austin, TX
`
`
`
`
`
`
`
`
` Bachelor of Science, Biochemistry, May 2005
`
` The University of Texas, Austin, TX
`
`
`
`
`
`III. Positions Held
`
`January 2016 to Current
`Postdoctoral Research Fellow- University of Texas at Austin, College of Pharmacy
`
`
`
`May 2015 to January 2016
`Graduate Research Assistant- University of Texas at Austin, College of Pharmacy
`
`
`
`January 2012 to January 2014
`PhRMA Foundation Pre-Doctoral Fellow- University of Texas at Austin, College of Pharmacy
`
`
`
`January 2011 to May 2015
`Teaching Assistant- University of Texas at Austin, College of Pharmacy
`Courses:
`Physical and Chemical Principles of Drugs & Laboratory, Fall: 2011
`(cid:120)
`Pharmaceutical Compounding Laboratory, Spring: 2011, 2014, 2015
`(cid:120)
`
`2008 to July 2010
`Research Associate
`Appian Labs, LLC, Austin, TX
`Aeonclad Biomedical, LLC, Austin, TX
`Enavail, LLC, Austin, TX
`
`
`(cid:120) Responsible for leading a product development group with the overall responsibility of
`developing solid dosage forms. The development group is comprised of formulation
`development and analytical team members. Reports directly to the Director of Research and
`Development and company President.
`
`
`
`PTX1663-00009
`
`9
`
`

`

`Curriculum Vitae
`Matthew J. Herpin
`Page 2
`
`o Responsible for the development of solid dosage forms with a strong emphasis on
`products utilizing diffusion based hydrogel controlled release systems, plasma
`enhanced chemical vapor deposition/polymer based controlled release coatings and
`particle engineering
`technologies
`to drug absorption profiles and
`improve
`bioavailability.
`o Provide strategic, scientific and managerial leadership to the formulation and analytical
`teams to solve complex drug development issues
`o Develop experimental plans based on client needs and overall project goals
`o Coordinate the production and analytical testing of pharmaceutical formulations
`o Interpret experimental observations according to sound scientific principles
`o Interact with clients and consultants to provide project updates verbally and in the
`form of technical reports
`o Work closely with the Operations group to coordinate the transfer of technology from
`R&D to cGMP manufacturing
`o Prepare and review batch records and standard operating procedures
`o Provide and submit intellectual property ideas relating to novel pharmaceutical
`formulations, processing techniques or analytical methods.
`
` 2006 to October 2008
`Analytical Chemist, Quality Control
`Inhalation Chemist, Platform Development, and Quality Control
`Pharmaform, LLC, Austin, TX
`
`
`(cid:120) Responsible for the USP testing of pharmaceutical dosage forms in Research and
`Development and in Phase I to III clinical trials. Reported to the Vice President of Quality
`Control
`o Interacted with clients to determine project goals and to provide project updates
`o Planned, designed, and performed experiments relating to the development of as
`standard method of analysis for solid dosage forms and dry powder inhalers.
`o Conducted testing on physical and chemical properties pertaining to product purity
`potency and performance. Including: High Performance Liquid Chromatography, USP
`Dissolution Testing,
`o Worked closely with method development chemists and manufacturing to solve
`problems associated with production.
`o Provide manufacturing analytical support.
`o Coordinated product analytical testing
`o Wrote and reviewed technical reports submitted to clients
`
`
`
` August 2003 to 2006
` Compounding Pharmacy Technician (CPhT)
` Peoples Pharmacy, Austin, TX
`
`
`
`
`
`
`
`
`
`PTX1663-00010
`
`10
`
`

`

`Curriculum Vitae
`Matthew J. Herpin
`Page 3
`
`(cid:120) Responsible for compounding preparation of various pharmaceutical dosage forms including:
`capsules, gels, lotions, creams, suppositories, rapid-disintegrating tablets, medicated lollipops
`and others.
`o Assists pharmacist in the dispensing of medication to patients
`o Managing inventory and ordering supplies
`
`
`IV. Relevant Training Completed
`
`o Inhalation Aerosol Technology Workshop: University of Maryland, Baltimore.
`o Waters HPLC Operation and Utilization Course
`o cGMP Certification Training: Compliance LLC
`
`
`
`
`
`
`
`
`
`V. Relevant Coursework Completed
`
`
`
` Biopolymers: Drug and Gene Delivery
` Biopharmaceutics and Pharmacokinetics
`
` Physical and Chemical Principles of Drugs
`
` Pharmaceutics
`
` Pharmaceutical Compounding
`
` Modern Advances in Pharmaceutics
`
` Advanced Manufacturing Pharmacy
`
` Product Development
`
` Statistics for Translational Scientists
`
`
`
`
`VI. Professional Memberships
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2011 – present
`2011 – present
`2012 – present
`
` American Association of Pharmaceutical Scientists
` American Chemical Society
`
`
`
` American Association of Advancing Science
`
`
`
`
`VII. Current Research Interests
`
`o Precision ophthalmic drug delivery via tunable aerosol dynamics
`o Drug particle engineering by way of super-heated processing and high pressure homogenization
`o Ophthalmic and pulmonary drug delivery device design and development
`o Enhanced aerodynamics and performance of inhalation powders
`o Preformulation, formulation, and characterization of novel delivery systems.
`
`VIII. Formulation Development Proficiencies
`
`o Inhalation Aerosol Based Systems- Including various nebulizers, pMDI and
`evaporation/condensation aerosols
`o Topical Ophthalmic drug delivery systems/vehicles-
`o Diffusion Based Controlled Release Tablets (direct compression)
`o Various Particle Engineering Technologies: High Pressure Homogenization, Solvent
`Precipitation/Evaporation, Spray Drying, Super-Heated Aqueous Particle Engineering
`o Solubilization/Complexation with Cyclodextrins
`o Dry Powder Inhalation formulations
`o Powder Encapsulation
`
`PTX1663-00011
`
`11
`
`

`

`Curriculum Vitae
`Matthew J. Herpin
`Page 4
`o Preparation of Emulsions, Creams, Lotions, Gels, Suspensions
`o Excipient Uses and Functionality
`
`
`IX . Technical Proficiencies and Research Experience
`
`
`
`
`
`
`
`Analytical Instrumentation and Methodology:
`o UV-Vis/Fluorescence Spectrophotometers
`o Fourier Transform Infrared Spectroscopy
`o Laser Diffraction Particle Sizing (Sympatec-Helos)
`o High Performance Liquid Chromatography-Method Development/Qualification
`o Inverse Gas Chromatography
`o Dynamic Light Scattering
`o Atomic Absorption
`o Differential Scanning Calorimetry
`o Faraday Cage for Electrostatic Analysis
`o Powder X-Ray Diffraction
`Physical Testing
`o United States Pharmacopoeia (USP) Dissolution Tests
`o Angle of Repose
`o Moisture Analyzer
`o Next Generation Impactor (aerodynamic assessment of fine particles)
`o Anderson Cascade Impactor/ Twin Stage Impactor
`o Instron Compression and Elongation Analysis
`o Tablet Hardness
`o Tablet Friability
`Biochemical Techniques
`o Polymerase Chain Reaction(PCR)
`o Western Blotting
`o PAGE/Agarose Gel Electrophoresis
`o Various enzyme activity assays
` Microscopy
`o Atomic Force Microscopy (AFM)
`o High Performance Liquid Chromatography-Method Development/Qualification
`o Two Photon Microscopy
`o Scanning Electron Microscopy
`o Raman Microscopy
`
`
`
`X. Awards and Honors
`
`o PhRMA Foundation Pre-Doctoral Fellowship (2012 - 2014)
`o Teaching Excellence Award- Outstanding Teaching Assistant- 2014
`o Student Entrepreneur Acceleration and Launch, Program Graduate- 2015
`o Texas Venture Labs- Founding Company Participant
`
`
`
`XI. Publications and Presentations
`
`
`
`
`PTX1663-00012
`
`12
`
`

`

`Curriculum Vitae
`Matthew J. Herpin
`Page 5
`
`Herpin MJ, Raffa-Carvhalo S, Smyth HDC, McConville JT, Variable Flow Pattern Effects on Fine Particle
`Generation from a Dry Powder Inhaler, Littlefield Excellence in Research Poster Presentation, 2010
`
`Bosselmann S, Owens III DE, Kennedy RL, Herpin MJ, Williams III RO. Plasma deposited
`stability enhancement coating for amorphous ketoprofen. European Journal of Pharmaceutics and
`Biopharmaceutics. 2011;78(1):67-74.
`
`Donovan MJ, Gibbons A, Herpin MJ, Marek S, Mcgill S, Smyth HDC. Novel Dry Powder Inhaler Particle
`Dispersion Systems-A Review. Future Medicine. 2011
`
`Herpin M.J, Smyth HDC, A Novel Ocular Soft Mist Aerosol Device for Tunable Drug Delivery, American
`Association of Pharmaceutical Scientists Conference, Poster Presentation, Oct. 2012
`
`Herpin M.J, Smyth HDC, Non-Aqueous Aerosol Deposition for Ocular Drug Delivery, American
`Association of Pharmaceutical Scientists Conference, Poster Presentation, Oct. 2013
`
`Moraga, D., Bahamondez, T., Herpin, M., Maloney, A. Yazdi, A., Du, P., Du, J., Smyth, H.,
`Hydrofluoroalkane Propellant Driven Metered Dose Inhaler Formulations. In Textbook of Aerosol Medicine.
`
`Herpin M.J, Smyth HDC, Aqueous Based Aerosol Vehicles for Enhanced Ocular Drug Delivery, American
`Association of Pharmaceutical Scientists Conference, Poster Presentation, Oct. 2014
`
`Herpin M.J., Ebi, Dominik, Clemens, N., Smyth H.D.C. Characterization of Toroidal Vortices Generated by
`a Novel Ocular Drug Delivery Device. International Journal of Pharmaceutics. 2016 (In Preparation)
`
`Herpin M.J., Xinfei, X. Smyth, H.D.C., Super Heated Aqueous Particle Engineering for Poorly Water
`Soluble Drugs. International Journal of Pharmaceutics. 2016 (In Preparation)
`
`Herpin M.J., Smyth, H.D.C. Precision Ocular Drug Delivery Via Aerosol Ring Vortices. Drug Delivery in
`Translational Medicine. 2016. (In Preparation)
`
`Bandara, H. M. H. N., Herpin M.J, Kolaccny D., Harb A., Romanovicz D., Smyth H.D.C., . "Incorporation
`of farnesol significantly increases the efficacy of liposomal ciprofloxacin against Pseudomonas aeruginosa
`biofilms in vitro." Molecular Pharmaceutics (2016).
`
`
`
`XI. Intellectual Property
`
`
`1. Smyth, H.D.C., Herpin M.J., Toroidal Pharmaceutical Formulations, U.S. Patent No. 61/501,671
`
`2. Smyth, H.D.C., Herpin M.J., Method for Fine Particle Manufacture, U.S. Patent No. 14/458,818
`
`3. Cannon C., Parth, S., Smolen, J., Smyth H., Yazdi A., Herpin M.J., Antimicrobial and Anti-
`Inflammatory Compositions. Provisional U.S. Patent Application. # 62/168,561
`
`PTX1663-00013
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`13
`
`

`

`Appendix B
`Appendix B
`
`PTX1663-00014
`
`14
`
`

`

`Final Protocol
`7/7/16
`Nasal Spray Manufacturing and Characterization Testing using E4MP HMPC
`and micronized Triamcinolone
`
`I.
`
`Purpose
`
`The purpose of this experiment is to re-create and evaluate the disclosure in EP 0780127
`(“Cramer”) to determine whether it a nasal spray with properties that are suitable for nasal
`administration. Specifically, this experiment will recreate Example III for an intranasally
`administered composition comprising triamcinolone acetonide and azelastine HCL.
`
`Example III from Cramer will be prepared following the mixing techniques described in
`Cramer Example I.
`
`Samples will be evaluated for appearance, spray content uniformity, spray pattern,
`droplet size, particle size, viscosity, stability, and osmolality, for example.
`
`II. Materials
`
`INGREDIENT
`Polysorbate 80
`Benzalkonium chloride
`Glycerin
`Hydroxypropyl
`methylcelluose (HPMC)
`
`Grade
`
`
`
`E4MP (4000 mPas)
`
`SUPPLIER
`
`
`
`Dow
`
`Sodium Chloride
`Ethylenediamine
`tetraacetic acid (EDTA)
`Distilled water -
`Triamcinolone acetonide
`
`Azelastine HCl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`III.
`
`Preparation of Cramer Example III
`
`Cramer Example III is:
`
`NOTES
`
`
`
`HPMC is available in
`multiple grades
`(viscosities) and chemical
`substitution. Since this is
`not defined within the
`patent example, E4MP
`will be tested
`
`
`
`
`This drug will be in
`suspension and will
`therefore need to be
`procured in micronized
`form.
`
`
`PTX1663-00015
`
`15
`
`

`

`Preparation according to Example I
`
`Example III will be prepared by combining the following components utilizing
`“conventional mixing techniques similar to that described in Example 1”:
`
`In an appropriately sized vessel, the dextrose, polysorbate 80 and
`benzalkonium chloride are added one at a time to water with
`mixing, allowing each to dissolve or completely disperse before
`adding the next. To this is added, with mixing, a premixed slurry
`of the avicel and water. Upon forming a uniform solution, the
`beclomethasone, loratadine and phenylethyl alcohol are added.
`After all the ingredients are added, purified water is used to bring
`the batch to the appropriate weight.
`
`Accordingly 500 mL of Example III will be made using the procedure outlined below:
`
`1.
`
`In an appropriately sized vessel to manufacture 500 mL of product,
`a. To 100 mL of distilled water
`b. Add polysorbate 80
`c. Mix step – Approximately 100-300 rpm with an overhead stirrer with a impeller
`stirring system, until visually mixed
`d. Add benzalkonium chloride
`e. Mix - Approximately 100-300 rpm with an overhead stirrer with a impeller
`stirring system, until visually mixed
`f. Add glycerin
`
`PTX1663-00016
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`16
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`

`

`2.
`
`g. Mix- Approximately 100-300 rpm with an overhead stirrer with a impeller
`stirring system, until visually mixed
`h. Add EDTA
`i. Mix - Approximately 100-300 rpm with an overhead stirrer with a impeller
`stirring system, until visually mixed
`j. Add NaCl
`k. Mix - Approximately 100-300 rpm with an overhead stirrer with a impeller
`stirring system, until visually mixed
`In a separate vessel the hydroxyl methylcellulose is prepared”
`a. As per the Handbook of Pharmaceutical Excipients (2nd Edition, 1994) 20% of the
`required water is used to hydrate the HPMC (100 mL distilled water)
`b. The water is vigorously stirred at RPMs adequate to disperse the powder and
`heated to approximately 90 deg C
`c. While stirring, the HPMC is added, and mixing continues until all particles are
`thoroughly wetted
`d. Then to the dispersed HPMC, 200 mL of cold distilled water is added while
`mixing
`e. The mixture is then cooled to between 20 to 25°C (68 to 77°F) or below as
`according to the Methocel™ product guide (“How to Prepare Aqueous Solutions
`of METHOCEL™”).
`3. This premixed HPMC mixture is then added to the ingredients of step 1 to form a
`uniform solution.
`a. Note: Since Example III does not list the grade of HPMC used, this experiment
`will be replicated using grades AAA, BBB, and CCC. The manufacturer has
`stated that each grade is suitable for nasal administration.
`4. To this solution Triamcinolone and Azelastine are added and mixed at 100-300 rpm with
`an overhead stirrer with a impeller stirring system, until visually mixed.
`a. Perform bulk product testing (top, middle, and bottom) to ensure stability over a
`period (2-3 or more hours) sufficient to demonstrate uniformity of the bulk
`following production.
`5. The samples are then mixed using a high-speed homogenizer.
`6. The formulations are then filled into nasal spray bottles (approximately 16.5 g per bottle)
`and spray pumps fitted to the bottles.
`7. Filled bottles will be stored at room temperature and optionally additional bottles not
`stored at room temperature will be stored at accelerated stability conditions (40 deg C and
`75% RH).
`8. Bottles will be tested at time points indicated below using various performance assays.
`
`IV.
`
`Product Performance Testing and Characterization
`
`tests are performed for nasal products as part of standard
`Typically several
`characterization testing protocols to determine pharmaceutical acceptability. For the current
`testing the selected methods to characterize the product in terms of formulation appearance,
`spray characterization, uniformity of dosing, viscosity, osmolarity, and physical stability of the
`suspension.
`
`PTX1663-00017
`
`17
`
`

`

`TEST
`
`EQUIPMENT
`
`Appearance a. Visual Inspection
`
`Assay
`
`a. HPLC Assay to assess the potency of Suspended
`Triamcinolone Acetonide
`
`Pump
`Delivery
`
`a. Analytical Balance
`
`
`Visual
`Inspection
`of spray
`quality
`
`Spray
`Content
`Uniformity
`
`a. Visual observation of emission of formulation
`during actuation of pump
`
`a. Dose collection tubes
`
`b. HPLC drug assay
`
`c. Actuation Station
`
`d. Analytical Balance
`
`Protocol #
`
`Notes
`
`SMA-007-00 Qualitative assessment of
`homogeneity and
`pharmaceutical
`acceptability . Looks at
`sedimentation, separation
`of suspended particles,
`agglomeration,
`redispersability of
`suspension upon shaking.
`This will be done on both
`formulation and the filled
`bottles.
`
`HPLC
`Method
`
`10 mLs of sample will be
`drawn off the top, middle
`and bottom of formulated
`composition, and then
`again after 3 Hrs to
`determine blend
`uniformity/settling stability
`SMA-009-00 Quantitative assessment of
`the variability of
`formulation dispensing
`from the nasal spray pump.
`A Valois Nasal Spray Pump
`from Aptar will be used.
`Pump: VP7
`
`Qualitatively assesses
`acceptability of spray
`
`Observation
`of spray/jet/
`failure to
`emit
`
`SMA-001-00 Quantitative assessment of
`the variability of emitted
`dose from the nasal spray
`pump. Will be quantified
`using Triamcinolone
`acetonide assay.
`
`*The Following Tests Only to be Conducted As Needed to Supplement Previous Findings
`
`PTX1663-00018
`
`18
`
`

`

`Droplet Size
`Analysis*
`
`
`
`a. Sympatec Laser Diffraction
`
`SMA-003-00
`
`Assesses the spray quality.
`
`
`
`Viscosity*
`
`a. Dynamic
`
`SMA-004-00
`
`
`
`Solid
`Particle
`Size*
`
`a. Light Microscopy
`
`
`
`SMA-002-00
`
`Assesses the viscosity of
`the product and will assist
`in interpretation of product
`performance tests.
`
`Assesses the stability of the
`suspended particles and
`can inform on particle
`aggregation/agglomeration.
`
`Osmolality* a. MicroOsmette- Freezing Point Depression
`Osmometer
`a. Spray View or Comparable Analysis Software
`
`Plume
`Geometry*
`
`b. Actuation Station
`
`SMA-008-00
`
`
`
`SMA-005-00 Quantifies spray
`characteristics.
`
`
`
`Spray
`Pattern*
`
`a. Spray View or Comparable Analysis Software
`b. Actuation Station
`
`SMA-005-00 Quantifies spray
`characteristics.
`
`Time points will be evaluated at 0, 7, and 14 days. The samples will be stored in ambient
`storage conditions. pH will be measured at all time points.
`
`V. Report
`
`A report detailing the preparation methods and results of the testing will be provided.
`
`PTX1663-00019
`
`19
`
`

`

`Final Protocol
`7/7/16
`Nasal Spray Manufacturing and Characterization Testing Following Malhotra
`Method using E3 Prem HMPC and micronized Triamcinolone
`
`I.
`
`Purpose
`
`The purpose of this experiment is to re-create and evaluate the disclosure in EP 0780127
`(“Cramer”) to determine whether it a nasal spray with properties that are suitable for nasal
`administration. Specifically, this experiment will recreate Example III for an intranasally
`administered composition comprising triamcinolone acetonide and azelastine HCL.
`
`Example III from Cramer will be prepared following the method set forth in Geena
`Malhotra’s declaration submitted to the U.S. Patent and Trademark Office on August 12, 2011.
`
`Samples will be evaluated for appearance, spray content uniformity, spray pattern,
`droplet size, particle size, viscosity, stability, and osmolality, for example.
`
`II. Materials
`
`INGREDIENT
`Polysorbate 80
`Benzalkonium chloride
`Glycerin
`Hydroxypropyl
`methylcelluose (HPMC)
`
`Grade
`
`
`
`Low viscosity:
`E3 PREM LV (3 mPas)
`
`
`SUPPLIER
`
`
`
`Dow
`
`Sodium Chloride
`Ethylenediamine
`tetraacetic acid (EDTA)
`Distilled water -
`Triamcinolone acetonide
`
`Azelastine HCl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`III.
`
`Preparation of Cramer Example III
`
`Cramer Example III is:
`
`NOTES
`
`
`
`HPMC is available in
`multiple grades
`(viscosities) and chemical
`substitution. Since this is
`not defined within the
`patent example, E3 Prem
`will be tested
`
`
`
`
`This drug will be in
`suspension and will
`therefore need to be
`procured in micronized
`form.
`
`
`PTX1663-00020
`
`20
`
`

`

`Preparation by Method Detailed in Geena Malhotra’s 2011 Declaration
`
`The technique will use the ingredients and process described below:
`
`Process of preparation:
`1) Part quantity of purified water was taken in a vessel.
`2) Sodium chloride and EDTA was added and dissolved under stirring followed by
`heating the bulk.
`3) Hydroxy propyl methyl cellulose was added and dispersed under stirring.
`4) Stirring was done and bulk was held at 2-8°C overnight.
`5) Glycerin was added and mixed in above bulk under stirring.
`6) Part quantity of purified water was taken and Azelastine HCl was dissolved in it to
`form drug slurry.
`7) Drug slurry of step # 6 was added in main bulk of step # 5 under stirring.
`8) Polysorbate 80 was added and dissolved in part quantity of purified water.
`Triamcinolone was added to this solution under stirring.
`9) Drug slurry of step # 8 was added in above bulk of step # 7 under stirring.
`
`PTX1663-00021
`
`21
`
`

`

`10) Benzalkonium chloride was added in part quantity of purified water and this solution
`was added in above bulk under stirring.
`11) Volume was made-up with purified water.
`12) Stirring was done with a high-speed homogenizer and pH was checked.
`Product Performance Testing and Characterization
`
`IV.
`
`tests are performed for nasal products as part of standard
`Typically several
`characterization testing protocols to determine pharmaceutical acceptability. For the current
`testing the selected methods to characterize the product in terms of formulation appearance,
`spray characterization, uniformity of dosing, viscosity, osmolarity, and physical stability of the
`suspension.
`
`TEST
`
`EQUIPMENT
`
`Appearance a. Visual Inspection
`
`Assay
`
`a. HPLC Assay to assess the potency of Suspended
`Triamcinolone Acetonide
`
`Pump
`Delivery
`
`a. Analytical Balance
`
`
`Protocol #
`
`Notes
`
`SMA-007-00 Qualitative assessment of
`homogeneity and
`pharmaceutical
`acceptability . Looks at
`sedimentation, separation
`of suspended particles,
`agglomeration,
`redispersability of
`suspension upon shaking.
`This will be done on both
`formulation and the filled
`bottles.
`
`HPLC
`Method
`
`10 mLs of sample will be
`drawn off the top, middle
`and bottom of formulated
`composition, and then
`again after 3 Hrs to
`determine blend
`uniformity/settling stability
`SMA-009-00 Quantitative assessment of
`the variability of
`formulation dispensing
`from the nasal spray pump.
`A Valois Nasal Spray Pump
`from Aptar will be used.
`Pump: VP7
`
`Visual
`
`a. Visual observation of emission of formulation
`
`Observation Qualitatively assesses
`
`PTX1663-00022
`
`22
`
`

`

`Inspection
`of spray
`quality
`
`Spray
`Content
`Uniformity
`
`Droplet Size
`Analysis*
`
`
`
`during actuation of pump
`
`a. Dose collection tubes
`
`b. HPLC drug assay
`
`c. Actuation Station
`
`d. Analytical Balance
`
`acceptability of spray
`
`of spray/jet/
`failure to
`emit
`
`SMA-001-00 Quantitative assessment of
`the variability of emitted
`dose from the nasal spray
`pump. Will be quantified
`using Triamcinolone
`acetonide assay.
`
`*The Following Tests Only to be Conducted As Needed to Supplement Previous Findings
`a. Sympatec Laser Diffraction
`SMA-003-00
`Assesses the spray quality.
`
`
`
`Viscosity*
`
`a. Dynamic
`
`SMA-004-00
`
`
`
`Solid
`Particle
`Size*
`
`a. Light Microscopy
`
`
`
`SMA-002-00
`
`Assesses the viscosity of
`the product and will assist
`in interpretation of product
`performance tests.
`
`Assesses the stability of the
`suspended particles and
`can inform on particle
`aggregation/agglomeration.
`
`Osmolality* a. MicroOsmette- Freezing Point Depression
`Osmometer
`a. Spray View or Comparable Analysis Software
`
`Plume
`Geometry*
`
`b. Actuation Station
`
`SMA-008-00
`
`
`
`SMA-005-00 Quantifies spray
`characteristics.
`
`
`
`Spray
`Pattern*
`
`a. Spray View or Comparable Analysis Software
`b. Actuation Station
`
`SMA-005-00 Quantifies spray
`characteristics.
`
`Time points will be evaluated at 0, 7, and 14 days. The samples will be stored in ambient
`storage conditions. pH will be measured at all time points.
`
`V. Report
`
`A report detailing the preparation methods and results of the testing will be provided.
`
`PTX1663-00023
`
`23
`
`

`

`24
`
`PTX1663-00024
`
`PTX1663-00024
`
`24
`
`

`

`Final Protocol
`7/7/16
`Nasal Spray Manufacturing and Characterization Testing Following Malhotra
`Method using E3 Prem HMPC and Unmicronized Triamcinolone
`
`I.
`
`Purpo