Food and Drug Administration
`Silver Spring MD 20993
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`INFORMATION REQUEST
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`NDA 203510
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`Paragon BioTeck, Inc.
`c/o Point Guard Partners LLC
`Attention: Jeremy Brace, B.Sc. (Hons)
`400 N. Ashley Street, Suite 1950
`Tampa, FL 33602
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`Dear Mr. Brace:
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`Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for phenylephrine hydrochloride ophthalmic solution, 2.5% and
`10%.
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`We are reviewing the Chemistry, Manufacturing and Controls section of your submission and
`have the following comments and information requests. We request a prompt written response
`in order to continue our evaluation of your NDA.
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`1. Please describe how the drug product manufacturer assures the quality of the in-coming
`drug substance and which tests are conducted in house. If the assay and impurities are
`determined by HPLC testing please describe how the drug product manufacturer has
`validated the method or verified that it is suitable for use.
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`2. Provide a description of the HPLC method used for SOP SAS-037 (the UV 210 nm
`method) described in extract-migration-study. How is the reporting limit of 1 ppm
`defined? 1 ppm with reference to what?
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`3. Conduct extraction and migration studies (in a similar fashion to those already carried
`out) for 1-3 batches after storage at 25°C/60% RH (accelerated) for 6 months and after
`storage refrigerated (long-term) through expiration. We recommend that the control be a
`sealed glass vial containing the drug product solution.
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`4. In the description of the manufacturing Process (3.2.P.3.3) you state “Compounding and
`mixing of Phenylephrine HCl Ophthalmic Solution 2.5% (457.2 kg batch size) will occur
`in a 600 liter mixing tank equipped with a simple propeller-style mixer.” Additionally a
`600 L sterile holding tank is used. However Figures 2 and 3 show only 50 gallon mixing
`tanks. Are these 50 gallon tanks replaced with 600 L tanks when necessary and, if so,
`how does this impact on the cleanliness of the various rooms? Alternatively, is a
`different facility used? Please provide information on the validation of the holding times
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`Reference ID: 3226374
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`Exhibit 1010- Page 1 of 4
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`NDA 203510
`Page 2
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`of product in the mixing and sterile holding tanks. Please indicate if metal from the
`holding or mixing tanks has been found to contaminate the product.
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`5. In 3.2.P.3.4.1 the in-process control is given as 450-550 mOsm/Kg H2O. However in the
`specification the 10% solution is 950-1050 mOsm/Kg H2O. Please reconcile.
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`6. Provide a description of the sampling plan and representative analyses for the Water for
`Injection.
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`7. Specify if the light obscuration or the microscopic particle test method is used to
`determine particulates. Please provide a report verifying that it is suitable for its intended
`purpose.
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`8. Please change the phenylephrine hydrochloride assay acceptance criterion to 90.0-
`110.0% of label claim.
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`9. We note that the highest observed Total Impurities value is 0.02%. Please consider
`reducing the Total Impurities acceptance criterion from ≤ 1.5% to ≤ 0.5%.
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`10. Consider adding a chiral purity test to the dug product specification or provide a
`justification for not doing so.
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`11. Please supply batch numbers, expiration dates, and assigned purities for all the reference
`standards.
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`12. Provide specifications for the in-coming container-closure system components.
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`13. Provide a description (including brand, type, and composition, as far as is known) of the
`labeling materials and inks that may be used for this product. Please note that these
`should not be changed without notifying the Agency.
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`14. Provide a Methods Validation Package. This should consist of a list of samples that
`could be supplied and links to the various analytical methods.
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`15. You state in 3.2.P.2.5 Microbiological Attributes that “The validation of the sterilizing
`filter (Pall Fluorodyne II 0.2 μm) used in the production of Phenylephrine HCl
`Ophthalmic Solution, 2.5.% and 10% has been conducted and can be found in Sterilizing
`Filter Validation.” However the report on the Sterilizing Filter Validation appears to
`describe only the use of the 2.5% solution. Please provide a similar report using the 10%
`solution or a justification for not providing such a report.
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`16. Test the sterilizing filter for extractables.
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`17. Test the drug product for endotoxins on stability, at least annually.
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`Reference ID: 3226374
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`Exhibit 1010- Page 2 of 4
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`NDA 203510
`Page 3
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`If you have any questions, call Althea Cuff, Regulatory Health Project Manager, at (301) 796-
`4061.
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`Sincerely,
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`{See appended electronic signature page}
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`Rapti D. Madurawe, Ph.D.
`Branch Chief, Branch V
`Division of New Drug Quality Assessment II
`Office of New Drug Quality Assessment
`Center for Drug Evaluation and Research
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`Reference ID: 3226374
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`Exhibit 1010- Page 3 of 4
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`RAPTI D MADURAWE
`12/05/2012
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`Reference ID: 3226374
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`Exhibit 1010- Page 4 of 4