‘}fi\
`
`/\.‘\1‘:
`~,
`-,1
`
`l)
`Hg \Ef\H{NT (‘()NT/\IT\JS INFORMATION
`IS 1'1<1\1l,|-I(i1il), CONI=1I)IaN'1‘IAL
`IS me.<> II<,"I’I,I) H{()M DISCLOSURE
`~
`A
`'-
`1.: LAW. T111
`
`_. I1 1:<‘,n1.Es,1NC..
`
`I'll‘ A IRE PHARMACEUTICAL, INC.
`311 WEST LANE
`
`AQUEBOGUE, NEW YORK 11931
`
`IDENTIFICATION STUDY
`
`FOR THE
`
`RACEMIC (—) FORM
`OF
`
`PHENYLEPHRINE HYDROCHLORIDE
`
`IN
`
`PHENYLEPHRINE HYDROCHLORIDE
`
`OPHTHALMIC SOLUTION, USP, 2.5% AND 10%
`
`(STU0328)
`
`$1 a
`
`Written By (1):
`’
`Reviewed By (2):
`Approved By (3); /1. /A
`
`'),[’)[{3
`Date:
`9.13‘ ,5
`Date:
`Date: *5’;/0}/'3
`
`Study: STU0328
`
`1 of 9
`
`Revision: Initial
`
`Exhibit 1012- Page 1 Of 9
`
`Exhibit 1012- Page 1 of 9
`
`
`
`/\.‘\1‘:
`~,
`-,1
`
`l)
`Hg \Ef\H{NT (‘()NT/\IT\JS INFORMATION
`IS 1'1<1\1l,|-I(i1il), CONI=1I)IaN'1‘IAL
`IS me.<> II<,"I’I,I) H{()M DISCLOSURE
`~
`A
`'-
`1.: LAW. T111
`
`_. I1 1:<‘,n1.Es,1NC..
`
`I'll‘ A IRE PHARMACEUTICAL, INC.
`311 WEST LANE
`
`AQUEBOGUE, NEW YORK 11931
`
`IDENTIFICATION STUDY
`
`FOR THE
`
`RACEMIC (—) FORM
`OF
`
`PHENYLEPHRINE HYDROCHLORIDE
`
`IN
`
`PHENYLEPHRINE HYDROCHLORIDE
`
`OPHTHALMIC SOLUTION, USP, 2.5% AND 10%
`
`(STU0328)
`
`$1 a
`
`Written By (1):
`’
`Reviewed By (2):
`Approved By (3); /1. /A
`
`'),[’)[{3
`Date:
`9.13‘ ,5
`Date:
`Date: *5’;/0}/'3
`
`Study: STU0328
`
`1 of 9
`
`Revision: Initial
`
`Exhibit 1012- Page 1 Of 9
`
`Exhibit 1012- Page 1 of 9
`
`
`
`TABLE OF CONTENTS
`
`1.00
`
`INTRODUCTION ..................................................... ..
`
`Page 3
`
`2.00
`
`SCOPE ................................................................... ..
`
`Page 3
`
`3.00
`
`EQUIPMENT ........................................................... ..
`
`Page 3
`
`4.00
`
`PRODUCT ................................................................ ..
`
`Page 3
`
`5.00
`
`STANDARD ........................................................... ..
`
`Page 3
`
`6.00
`
`REAGENTS ............................................................. ..
`
`Page 4
`
`7.00
`
`PREPARATION ....................................................... ..
`
`Page 4
`
`8.00
`
`PROCEDURE ........................................................... ..
`
`Page 5
`
`9.00
`
`RESULTS ................................................................ ..
`
`Page 5
`
`10.00
`
`CONCLUSION ......................................................... ..
`
`Page 9
`
`Exhibit 10 2- Page 2 of 9
`
`
`
`Study:STU0328
`
`
`2 of 9
`Revision: Initial
`
`Exhibit 1012- Page 2 of 9
`
`
`
`1.0
`
`INTRODUCTION:
`
`This study is being performed in response to a request by the FDA to add an
`identification test to determine if Phenylephrine Hydrochloride R (—) form is present
`in the finished product NDA submission 203510.
`
`The test being performed is an identification test by Polarimetry adapted from the raw
`material monograph for Phenylephrine Hydrochloride in the USP to determine if the
`material is in the R (-) form or S (+) form. The limit for the test is -42° to -47.5°
`which will confirm that that the material being used is in the R (-) form.
`
`The finished product was prepared so that the working concentration of
`Phenylephrine Hydrochloride Ophthalmic Solution 2.5% formula A0358 is 25mg/mL
`and Phenylephrine Hydrochloride Ophthalmic Solution 10% formula A0359 is
`50mg/mL. These solutions were then compared to that of Sigma Aldrich
`Phenylephrine Hydrochloride R (-) form as a control.
`
`2.0
`
`SCOPE:
`
`This report is applicable to Phenylephrine Hydrochloride Ophthalmic Solution 2.5%
`and 10% formulas A0358 and A0359 as finished product test method TMQC-205
`used at Altaire Pharmaceuticals Inc.
`
`3.0
`
`EQUIPMENT:
`
`Dr. Steeg & Reuter Optical Polarimeter model SR-6.
`
`4.0
`
`PRODUCT:
`
`4.01
`
`Phenylephrine HCI Ophthalmic Solution, USP 2.5% formula A0358.
`
`4.01.01
`
`Finished Product Lot 11578
`
`4.01.02
`
`Placebo (withoutPheny1ephrine Hydrochloride) batch 06161 1C.
`Reference book 301 p 80-82
`
`4.02
`
`Phenylephrine HCI Ophthalmic Solution, USP 10% formula A03 59.
`
`4.02.01
`
`Finished Product Lot 11582
`
`4.02.02
`
`Placebo (without Phenylephrine Hydrochloride) batch 06161 1A.
`Reference book 301 p 80-82
`
`5.0
`
`STANDARD:
`
`5.01
`
`Phenylephrine Hydrochloride R (-) Sigma Aldrich lot P6126. Purity factor is
`1.00
`
`Exhibit 10 2- Page 3 of 9
`
`
`
`
`
`
`
` Study: TU0328 ‘ Revision: Initial
`
`Exhibit 1012- Page 3 of 9
`
`
`
`6.0
`
`REAGENTS:
`
`6.01 Deionized water
`
`7.0
`
`PREPARATION
`
`7.01
`
`Phenylephrine HC1 Ophthalmic Solution, USP 2.5% formula A0358
`
`7.01.01
`
`Sample Preparation: As is. The concentration is 25mg/mL
`2.5g/l00mL).
`
`7.01.02
`
`Placebo Preparation: As is.
`
`7.02
`
`Phenylephrine HC1 Ophthalmic Solution, USP 10% formula A0359
`
`7.02.01
`
`7.02.02
`
`Sample Preparation: Pipet 25mL of sample into a 50mL volumetric
`flask and then dilute to volume with water and mix well. The
`concentration is 50mg/mL (5g/100mL).
`
`Placebo Preparation: Pipet 25mL of placebo into a 50mL
`volumetric flask and then dilute to volume with water and mix
`well.
`
`7.03
`
`Phenylephrine Hydrochloride Controls
`
`7.03.01
`
`7.03.02
`
`7.03.03
`
`10mg/mL Solution: 1.0l7l4g of Phenylephrine Hydrochloride
`Sigma lot P6126 was weighed into a l00mL volumetric flask, and
`then diluted to volume with water. The concentration is
`10.l714mg/mL (1.01714g/100mL)
`
`25mg/mL Solution: 2.50666g of Phenylephrine Hydrochloride
`Sigma lot P6126 was weighed into a 100mL volumetric flask, and
`then diluted to volume with water. The concentration is
`25.06666mg/mL (2.50666g/100mL)
`
`37mg[mL Solution: 3.702l4g of Phenylephrine Hydrochloride
`Sigma lot P6126 was weighed into a l00mL volumetric flask, and
`then diluted to volume with water. The concentration is
`37.0214mg/mL (3.70214g/100mL).
`
`7.03.04
`
`50mg/mL Solution: 2.50611g of Phenylephrine Hydrochloride
`Sigma lot P6126 was weighed into a 50mL volumetric flask, and
`then diluted to volume with water. The concentration is
`50.1222mg/mL (5.0l222g/100mL).
`
`7.03.05
`
`75mg[mL Solution: 3.75165g of Phenylephrine Hydrochloride
`Sigma lot P126 was weighedfl s1(<),fa§d
`JHIBDIEEIH
`Revision: Initial
`
`
`
`Exhibit 1012- Page 4 of 9
`
`
`
`then diluted to volume with water. The concentration is
`75.033mg/mL (7.5033g/100mL).
`
`8.0
`
`PROCEDURE
`
`8.01
`
`Using an Optical Polarimeter determine the rotation of the blank, placebo,
`sample and control solutions. Make 5 readings of each solution and
`determine the average.
`
`9.0
`
`RESULTS
`
`Table 1 Blank Readins
`
`Blank (de rees)
`
`
`
`Study: ‘ TU0328
`
`Revision: Initial
`
`Exhibit 1012- Page 5 of 9
`
`
`
`9.01
`
`Control Calculation
`
`[oz]=100x1
`2xC
`
`Where:
`
`[CI] = Optical Rotation measured in degrees (°)
`
`1 = Average Specific Rotation
`
`2 = Tube length in decimeters
`
`C = Concentration of the sample in grams/ 100mL
`
`9.01.01
`
`10mg/mL Control Solution Calculation
`
`-0.9 x 100 =
`
`- 44.2°
`
`2 x 1.01714
`
`9.01.02
`
`25mg/mL Control Solution Calculation
`
`-2.32 x 100 = - 46.3°
`2 x 2.50666
`
`9.01.03
`
`37mg/mL Control Solution Calculation
`
`-3.42 x 100 = - 46.2°
`
`2 x 3.70214
`
`9.01.04
`
`50mg/mL Control Solution Calculation
`
`-4.66 x 100 = - 46.5“
`
`2 x 5.01222
`
`9.01.05
`
`75mg/mL Control Solution Calculation
`
`-6.5 X 100 =
`2 x 7.5033
`
`- 43.3"
`
`
`
`Exhibit 1912- Page 6 of 9
`
`Exhibit 1012- Page 6 of 9
`
`
`
`Phenyephrine HCI Control Plot
`
`Reading
`
`y = -0.867x - 0.137
`R2 = 0.9961
`
`Conentration (gI100m L)
`
`_!
`
`Note: The plot of Phenylephrine Hydrochloride R (-) vs. Specific Rotation above
`shows that the results are linear across the range of the method
`
`9.02
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 2.5% Formula
`A0358 Calculation
`
`[oc]=100xI~
`2xC
`
`Where :
`
`[01] = Optical Rotation measured in degrees (°)
`
`1 = Average Specific Rotation
`
`2 = Tube length in decimeters
`
`C = Concentration of the sample in grams/ l00mL calculated as follows:
`
`Assay % x 25mg x l00mL x lg = g/l0OmL
`100% x lmL X 1000mg
`
`9.02.01
`
`Finished Product lot 1 1578
`
`C = 02.9% x 25mg x l00mL x lg = 2.5725g/100mL
`100% x lmL x l000mg
`
`-2.42 x 100 = - 47.0°
`2 x 2.5725
`
`
`
`Study: ' TU0328
`
`
`
`_
`
`Exhibit 1012- Page 7 of 9
`
`7 of 9
`
`Revision: Initial
`
`
`
`Exhibit 1012- Page 7 of 9
`
`
`
`9.03
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 10% Formula A0359
`Calculation
`
`[0t]=l00x7\
`2xC
`
`Where:
`
`[(1] = Optical Rotation measured in degrees (°)
`
`1 = Average Specific Rotation
`
`2 = Tube length in decimeters
`
`C = Concentration of the sample in grams/ 100mL calculated as follows:
`
`Assay % x 100mg 25mL x 100mL x lg = g/100mL
`100% x 1mL x 50mL x 1000mg
`
`9.03.01
`
`Finished Product lot 11582
`
`C = 99.8% x 100mg x 25mg x 100mL x lg = 4.99g/100mL
`100% x lmL x 50mL x 1000mg
`
`-4.54 x 100 = - 45.5°
`
`2 X 4.99
`
`9.04 Control to Sample Comparison
`
`9.04.01
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 2.5%
`Formula A0358 vs. 25mg[mL Control
`
`-47.0° x 100% = 101.5%
`
`-46.3°
`
`9.04.02
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 10%
`Formula A0359 vs. 50mg/mL Control
`
`-45.5° x 100% = 97.8%
`
`-46.5‘’
`
`Exhibit 10 2- Page 8 of 9
`
` Study: TU032 Revision: Initial
`
`Exhibit 1012- Page 8 of 9
`
`
`
`10.0 CONCLUSION
`
`The results of this study show the following:
`
`1.
`
`2.
`
`3.
`
`4.
`
`The solvent reading of 0° is a neutral reading, therefore does not contribute
`any interference to the test.
`
`The placebo (formula A0358 and A0359) reading of 0° is a neutral reading,
`therefore does not contribute any interference with Phenylephrine
`Hydrochloride R (-).
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 2.5% formula
`A0358 Specific Rotation result of - 47.0° is within the - 42° to - 47.5° limit
`and that it is in 101.5% agreement with the Phenylephrine Hydrochloride R (-)
`control. This demonstrates that the production of the product has no impact on
`the Phenylephrine Hydrochloride R (-) form of the API.
`
`Phenylephrine Hydrochloride Ophthalmic Solution, USP 10% formula A0359
`Specific Rotation result of —— 45.5° is within the - 42° to - 47.5° limit and that it
`is in 97.8% agreement with the Phenylephrine Hydrochloride R (-) control.
`This demonstrates that the production of the product has no impact on the
`Phenylephrine Hydrochloride R (-) form of the API.
`
`Based on the above scientific conclusions, the Identification Test by Polarimetry to
`determine if production process impacts the R (-) form of Phenylephrine
`Hydrochloride has shown that the method is capable and selective to identify API
`form in the finished product. The method is suitable for use and will be written into
`Test Method TMQC-205.
`
`Reference: Book 370 pp. 18-27
`
`
`
`
`Stud : STU0328
`
`i
`
`9 of 9
`
`Exhibit 1012- Page 9 of 9
`
`
`Revision: Initial
`
`
`
`Exhibit 1012- Page 9 of 9
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