TABLE OF CONTENTS
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`----- 1
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`BOOK
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`PAGE
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`11)13/1'3 DATE
`PROJECT
`TITLE
`:_1 C_:_o_:_~~_:in_:~:,_ci__~-!!!!!-,P-a-q~----------------.,--------7-l_-__ -;-_L-__ "' ___ ,-_-____ ,~ ____ -____ ',------'-,------,--~-------"'--T------'--.,..'~--,.-~---. --,---, ___ j _______ j_ _____ l _______ t _______ ~--------l ____ J_ ____ ~ ____ j _______ [__ _j _______ J _____ j ____ l ___ j _____ j _________ [ ____ J ____ j ______ ! ____ j
`
`November 11, 2013
`
`To:
`
`Anita Kumar
`
`From: Dr. Tony Palmieri
`Dr. Vivian Gray
`
`Re:
`
`Endo Pharms., Inc. v. Amneal Pharms., LLC, Case No. 1:12-cv-8115 (S.D.N.Y.)
`Formulation and Testing Protocol of Controlled-Release Oxymmphone Tablets
`
`The following memorandum sets forth a protocol to formulate controlled-release
`oxymorphone hydrochloride as disclosed in WO 01/08661 A2 (Maloney) and to conduct in vitro
`dissolution testing of sample batches under the conditions detailed in U.S. Patent Nos. 8,309,122
`and 8,309,216, which are recited below. As you prepare and test these tablets, please be sure to
`record any variables (e.g., air compression) that you may need to adjust but are not explicitly
`noted below. Retain copies of documents and information generated during the manufacture and
`testing of the sample batch, including but not limited to lab notebooks, batch records, and
`calibration curves.
`
`I. Create Sample Batches of Controlled-Release Tablets Containing Oxymorphone
`Hydrochloride
`
`Subparts A and B outline the formulas and steps required to formulate and
`manufacture two batches of at least 1,000 controlled-release tablets each.
`
`A. Formula #1
`
`The formula for the first sample batch of controlled-release tablets should include the
`following ingredients by weight:
`
`INGREDIENT
`
`AMOUNT
`
`30 mg (20% w/w)
`Oxymorphone hydrochloride
`-+-~~--~---~
`39.5% w/w
`
`Lactose, NF (Fast Flo)
`
`Amberlite IRP 69M Fine
`Particle Size
`
`Methocel KIOOM (Premium)
`CR
`(hydroxypropyhnethylcellulose,
`USP)
`
`5.0% w/w
`
`30.0%w/w
`
`0 'i% w/w
`
`3
`
`

`
`TABLE OF CONTENTS
`
`~~~~ I<Or'T
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`
`n
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`I
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`AGE
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`97
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`1 16
`
`'
`
`Stea1ic Acid, NF (Powder)
`Theoretical Tablet Weight
`
`5.0%w/w
`150mg
`
`B. Formula #2
`
`The formula for the second sample batch of controlled-release tablets should include the
`following ingredients by weight:
`
`INGREDIENT
`
`AMOUNT
`
`Oxymorphone hydrochloride
`
`30 mg (20% w/w)
`
`Lactose, NF (Fast Flo)
`
`Amberlite IRP 69M Fine
`Particle Size
`Methocel KlOOM (Premium)
`CR
`(hydroxypropyhnethylcellulose,
`USP)
`
`24.5% w/w
`
`5.0%w/w
`
`45.0%w/w
`
`Cab-0-Sil (M-5)
`Stearic Acid, NF (Powder)
`
`Theoretical Tablet Weight
`
`0.5%w/w
`
`5.0%w/w
`
`150mg
`
`C. Manufacturing Steps
`
`In manufacturing the sample batch of controlled-release tablets, please follow these steps
`in order. Please let us know immediately if you need to deviate from these steps in any
`manner.
`
`Obtain Amberlite IRP 69M Fine Particle Size. If Fine Particle Size is not
`a)
`available, please process the Amberlite by passing it through a 325 mesh (U.S. Standard
`mesh size) or by using other conventional methods to achieve a mean particle size that is
`about 27 Jlm, or at least less than 44-50 Jlffi
`
`b)
`
`c)
`
`d)
`
`Pass Lactose NF (Fast Flo) through a No. 20 mesh screen for de lumping;
`
`Mill the Lactose;
`
`Pass the Cab-0-Sil (M-5) (a glidant), oxymorphone hydrochloride USP
`and Amberlite IRP-69M fine particle size through a No. 20 mesh screen
`for delumping and mix with the lactose for 10 minutes to create a drug
`powder blend;
`
`4
`
`

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`AGE
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`TABLE OF CONTENTS
`
`<:1 IR ""'T
`
`DATE
`
`.
`
`..
`
`e)
`
`f)
`
`g)
`
`h)
`
`i)
`
`(Methocel KlOOM
`the hydroxhypropy!methylcellulose USP
`Pass
`(premium) CR) through a No. 20 mesh screen for delumping;
`
`Then add the drug powder blend and mix for 20 minutes;
`
`Pass stearic acid NF (powder) through a No. 40 mesh screen and add to
`the batch;
`
`Then mix the batch for 5 minutes;
`
`Then compress the final blend to form tablets using a conventional tablet
`press and conventional tooling to form tablets of conventional hardness for
`extended-release dosage forms.
`
`II. Testing of Dissolution Rate of Sample Batches Created in Step 1
`
`The steps below outline in vitro dissolution tests, using six samples from each batch
`created in part I. For the "USP Paddle Method," see Attachment A at § 711, Dissolution for
`explanation on the parameters of the USP Paddle Method.
`
`Please perform the following in vitro dissolution testing method: USP Paddle
`in vitro
`Method at 50 rpm in 500 mL media at 37° C. Please perform the
`dissolution test using three different pH levels: 1.2, 4.5, and 6.8.
`
`For each tablet and pH tested, measure and record below the release of
`oxymorphone hydrochloride (in milligrams) at hours: 1, 2, 3, 4, 5, 6, 8, 10, and
`12.
`
`Time (Hr)
`
`pH
`
`Oxymorphone Hydrochloride
`released into the solution (mg).
`
`1
`2
`3
`4
`5
`6
`8
`10
`12
`
`Again, please retain copies of documents and information generated during this expert,
`including but not limited to lab notebooks, batch records, and calibration curves.
`
`5
`
`

`
`2
`
`PAGE
`
`BOOK
`
`TITLE 6~1ffY)<1-tp ryii>'U'_ Htl ER
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`Tl TLE 6 ?' \{ I'VU>-'1-p itPniL
`Continued from vaae
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`Formulation:
`
`Batch # PD161-01
`
`'
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`
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`
`5
`
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`
`Batch# PD161-02
`
`Formulation:
`
`[
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`
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`
`PAGE
`
`BOOK
`
`! I
`
`•
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`.
`
`/?, 13
`'
`
`DATE
`i
`
`.
`
`•
`
`'
`.
`
`•
`
`Ingredients
`
`Qty (g)
`
`mg/tablet
`
`Oxymorphone HCl
`Lactose monohydrate
`Amberlite IRP 69
`Methocel Kl OOM Premium CR
`Cab-o-Sil (colloidal silicon dioxide)
`Stearic acid, NF
`Total
`
`Manufacturing Procedure:
`
`30.00
`59.25
`07.50
`45.00
`00.75
`07.50
`150
`
`30.00
`59.25
`07.50
`45.00
`00.75
`07.50
`ISO
`
`I. Weigh the above stated ingredients in a cleaned tmred polyethylene lined containers.
`
`2. Screen Amberlite IRP 69 through a 325 mesh screen.
`
`3. Screen the weighed lactose monohydrate through a 20 mesh screen and mill through a
`comminuting mill fitted with 1532-0040 screen at medium speed.
`
`.
`
`'
`'
`
`'
`
`'
`
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`
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`•
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`•
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`•
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`10
`
`'
`
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`
`15
`
`20
`
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`•
`
`'
`
`. '
`
`Ingredients
`
`Qty (g)
`
`mg/tablet
`
`Oxymorphone HCI
`Lactose monohydrate
`Amberlite IRP 69
`Methocel KlOOM Premium CR
`Cab-o-Sil (colloidal silicon dioxide)
`Stearic acid, NF
`Total
`
`Manufacturing Procedure:
`
`30.00
`36.75
`07.50
`67.50
`00.75
`07.50
`!50
`
`30.00
`36.75
`07.50
`67.50
`00.75
`07.50
`ISO
`
`I. Weigh the above stated ingredients in a cleaned tan·ed polyethylene lined containers.
`
`2. Screen Amberlite TRP 69 through a 325 mesh screen.
`
`3. Screen the weighed lactose monohydrate through a 20 mesh screen and mill through a
`comminuting mill fitted with 1532-0040 screen at medium speed.
`
`.
`
`'
`
`--·---
`
`·--·--
`
`4. Screen the weighed Oxymorphone HCI, Amberlite IRP 69 and colloidal silicon dioxide through a
`20 mesh screen. Transfer to a 1 qt V -blender and mix for 10 minutes at 24 RPM along with above
`milled lactose.
`
`Actual Mixing Time: 10 minutes at 24 RPM
`
`5. Screen the weighed Methocel Kl OOM through a 20 mesh screen and add it to the above blender.
`Mix for 20 minutes at 24 RPM.
`
`Actual Mixing Time: 20 minutes at 24 RPM
`
`6. Screen the weighed Stearic acid through a 40 mesh screen and add it to the above blender. Mix for
`5 minutes at 24 RPM.
`
`<
`
`Actual Mixing Time: 5 minutes at 24 RPM
`
`7. Unload the blend into a cleaned tared polyethylene lined container and label it as fmal blend for
`compression.
`
`8. Compress the final blend into tablets using a 10 station gravity feed tablet press at intennediate
`speed.
`
`! •
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`
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`
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`
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`
`4. Screen the weighed Oxymorphone HCI, Amberlite IRP 69 and colloidal silicon dioxide through a
`20 mesh screen. Transfer to a 1 qt V -blender and mix for 10 minutes at 24 RPM along with above
`milled lactose.
`
`Actual Mixing Time: 10 minutes at 24 RPM
`
`5.
`
`Screen the weighed Methocel KlOOM through a 20 mesh screen and add it to the above blender.
`Mix for 20 minutes at 24 RPM.
`
`Actual Mixing Time: 20 minutes at 24 RPM
`
`6. Screen the weighed Stearic acid through a 40 mesh screen and add it to the above blender. Mix for
`5 minutes at 24 RPM.
`
`Actual Mixing Time: 5 minutes at 24 RPM
`
`7. Unload the blend into a cleaned tared polyethylene lined container and label it as final blend for
`compression.
`
`8. Compress the final blend into tablets using a 10 station gravity feed tablet press at intennediate
`speed.
`
`.
`
`•
`
`.
`
`.
`
`I
`'
`
`_,_ -
`
`9. Tooling: B tooling, 0.2953" round standard concave upper and lower punches and 0.2953" die.
`
`I 0. Collect the tablets into a cleaned tared polyethylene lined container.
`
`Actual tablet hardness:~ lOkp
`
`The compressed tablets were randomly divided into 3 parts weighing 15g, 15g and 17g
`respectively.
`
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`Ito page
`
`11 /l't Irs
`
`PROPRIETARY INFORMATION
`
`I I I !
`I :
`I I
`I I I !
`"'"""'uno ~ DATE
`'"(}
`D-:::,. ~ ~~lrt.dr3
`
`I
`'
`
`DATE
`
`9. Tooling: B tooling, 0.2953" round standard concave upper and lower punches and 0.2953" die.
`
`•
`
`'
`
`:
`
`10. Collect the tablets into a cleaned tared polyethylene lined container.
`
`Actual tablet hardness:~ lOkp
`
`The compressed tablets were randomly divided into 3 parts weighing 15g, 15g and 22g
`respectively.
`
`•
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`.
`.
`
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`
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`SIGNATURE
`
`J!lAJ_~
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`
`DATE
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`DATE
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`Continued to page
`
`i
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`! '
`11 /r'-f /rs
`PROPRIETARY INFORMATION
`
`4
`0
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`4 5
`
`6