MedPointe Product & Process Development
`Program Priorities & Issues
`September 9, 2002
`
`COMMERCIAL PRODUCT TECHNICAL SUPPORT
`
`ASTELIN NASAL SPRAY
`Priority
`Issue/ Program
`-
`High
`Qualify 34.5 ml
`V-bottom bottle
`
`Critical Path
`Launch of V-Bottom Bottle
`
`Timing Manager1
`Q4/FY03
`
`Status/Comments
`
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`
`Generate stability data
`
`Medium
`
`August 02 ADD/CY
`
`Qualify Marlex 5502BN Resin
`Stability program
`
`High
`
`Maintain Component Supply
`
`Q3/FY03
`
`CY/ML
`
`Issue report with historical stability data for manually
`applied spigot pumps. Historical data summary targeted
`for 9/13/02.
`Studies initiated to qualify transfer to new bottle resin. No
`data has been received for intermediate test points at
`accelerated conditions. Three month pull September 14,
`2002.
`
`ASTELIN/STEROID COMBINATION PRODUCT
`New Nasal Solution Product Medium
`Extension Product for Lifecycle Ongoing
`Combination of Azelastine
`Maintenance
`HCI and an Approved
`Steroid
`DORAL TABLETS
`Qualify Decatur to
`manufacture Doral Tablets
`
`Medium Maintain Commercial Tablet
`Supply
`
`Q4/FY03
`
`ADD/VP/
`GD/JH/JG
`
`Literature search initiated to determine historical
`perspective and evaluate product feasibility. Initial team
`meeting 9/6/02. Need to evaluate market potential,
`patent position and development
`
`VP
`GD
`
`PPD-01-07-Process Validation reviewed. Blending of
`magnesium stearate is a concern. Five cu.ft. blender
`recommended as solution. Project status reviewed on
`8/20/02: major issues need to be resolved prior to next
`PV batch. Timeline needs to be revised to meet April 04
`supply date. Operation has identified and requested
`reference standards. Methods required for recertification
`have been forwarded GD.
`Tateyama Kasei and FIS to be evaluated as suppliers of
`quazepam drug substance. Decatur is looking for samples
`of quazepam from FIS, supposedly sent June 02.
`1ADD-Alex D' Addio, GD-Grace Dang, WH-Weixuan He, JH-John Higson, ML-Mary Lehr, EM-Ed Mikalsen, HM-Hank Mortko, VP-Vithal Patel, WR-Will Robinson, BR-Bryan Roecklein, CY -Cindy Yayac
`
`Qualification of new drug
`substance supplier
`
`Medium Maintain Drug Substance
`Supply
`
`Q3/FY04
`
`VP
`
`Confidential
`
`- 1 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015578
`
`1
`
`CIP2055
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`COMMERCIAL PRODUCT TECHNICAL SUPPORT (continued)
`
`FELBATOL SUSPENSION
`Issue/Pro2ram
`P ·
`Qualify Micron Technologies High
`as approved milling site
`
`-
`
`Critical Path
`Maintain Supply of Micronized
`Drug Substance
`
`r·
`Q2
`
`M
`GD/VP
`
`-
`
`s
`/C -
`FDA approved Micron Technologies. Three month stability
`data on first batch and second batch required to generate
`final report. A report at 3 month stability of first batch
`2C68 has been written and is waiting for review at PPD
`(due 8/6/02). Additional felbamate fine is required. MT
`is milling an additional order of 860kg. Milling by
`Orgamol is reactivated. 280 kg was already sent. Issues
`about protocol and validation are being discussed.
`
`N
`0
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`
`Critical
`
`Maintain Commercial Supply of
`Tablets
`
`On-going WR/HM/
`JH
`
`High
`
`Response to FDA Inspection
`
`Q3/FY03
`
`HM
`
`Work with Ray Chen to develop an experimental design
`that will be used to identify critical parameters in
`manufacturing process for SOMA 350 Tablets.
`Work initiated in response to FDA 483. Updated
`quotations from Magellan submitted for approval.
`Estimated completion date- end of September 02.
`
`SOMA350
`Transfer Manaufacturing
`Process to Decatur
`Identify critical process
`parameters
`
`Validate specificity for USP
`assay
`
`SOMA COMPOUND
`Validate specificity for USP
`assay
`
`High
`
`Response to FDA Inspection
`
`Q3/FY03
`
`HM
`
`SOMA COMPOUND W /CODEINE
`Validate specificity for USP
`High
`assay
`
`Response to FDA Inspection
`
`Q3/FY03
`
`HM
`
`Work initiated in response to FDA 483. Updated
`quotations from Magellan submitted for approval.
`Estimated completion date- end of September 02.
`
`Work initiated in response to FDA 483. Updated
`quotations from Magellan submitted for approval.
`Estimated completion date- end of September 02.
`
`Confidential
`
`- 2 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015579
`
`2
`
`

`

`M
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`
`PRODUCT DEVELOPMENT
`
`ASTELIN NASAL SPRAY
`
`--- ~-·- - -o- -----
`Astelin Double-Strength -
`Formulation Development
`
`- --- - --
`High
`
`---------------
`Taste Improvement
`
`- ----- - -o
`On-going
`
`- . -------~--
`
`GD/VP
`
`FLUOROFELBAMA TE
`Develop Fluorofelbamate for High
`IND
`Fluorofelbamate Drug
`Substance Synthesis
`
`High
`
`Demonstration of
`Fluorofelbamate Safety Profile
`Drug Supply for Tax Studies
`and Development of
`Commercial Process
`
`Q2/FY03
`
`HM/WH
`
`Q2/FY03
`
`HM/WH
`
`Impurities required for Tox
`Studies
`
`High
`
`Drug Supply for Tax Studies
`
`Q2/FY03
`
`HM/WH
`
`- -------· ----- - -- --- --
`Formulations with current azelastine HCIIevel (0.1 %)
`thickened with HPMC or CMC have been stable for 4
`months. Formulations with 0.14% azelastine HCI are
`stable with CMC thickener but not with extra HPMC.
`Formulations with 0.28% azelastine HCI and sorbitol have
`been stable for 2-4 months.
`Several intense sweeteners and thickeners have been
`tested but are not compatible with the formulations.
`Taste masking compounds from flavor suppliers are
`compatible, but are designed to mask mild bitterness
`only. Sucralose, a new sweetener, and PVP and xanthan
`gum as a thickeners are being tested. A few lead
`formulations will be selected with analytical data
`generated.
`
`Developing pre-clinical program only at this time "Go/No
`Go" for Phase I Study Fall/Winter.
`Synthesis of the 4th batch of crude fluorofelbamate has
`completed resulting total of ca . 4600 g of crude
`fluorofelbamate from four batches of operation. The
`material from four batches will be combined for final
`methanoi/H20 crystallization after analytical data are
`obtained from each batch and confirm they are
`comparable to each other in impurity profile.
`CCMF, 39 g, and F-CCMF, 70 g, were from Magellan.
`These samples are designated for in vivo toxicity study.
`
`Magellan is developing a gradient elution HPLC method to
`monitor the fluorofelbmate manufacturing process. This
`method will provide a quick assay during various stages of
`reaction and purification of fluorofelbamate.
`
`Confidential
`
`- 3 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015580
`
`3
`
`

`

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`
`FLUOROFELBAMATE (cont.)
`Issue/Prm!ram
`P ·
`·
`--- ---- -
`-
`- o- -----
`Analytical Methods
`Polymorph Screen
`
`High
`
`------- .~
`
`PRODUCT DEVELOPMENT( continued)
`
`Critical Path
`---------------
`
`r·
`
`- -------o
`
`M
`- . -------o--
`
`Q4/FY03
`
`HM/WE
`
`s
`/C
`--------- -------------
`A polymorphs screen protocol was reviewed and
`approved. The study will start soon after the required PO
`is obtained.
`
`Therimmune Pilot PK Studies High
`
`Q3/FY03
`
`HM/BR/
`WH
`
`GUAIFENESIN TANNATE
`Product Design Discussions
`Medium
`
`Evaluate/Characterize Drug
`Substance
`
`New Long Acting Form of
`Guaifenesin by JFC
`
`On-going
`
`ADD
`
`EM/VP
`
`RYNA-12 TABLETS
`Validate manufacturing
`process
`
`High
`
`New Tannate Tablet Product
`
`Q2/FY03
`
`VP
`
`HPLC analysis revealed two late eluting impurities in each
`batch of fluorofelbamate produced with the current
`process. The level of the two impurities is well above
`0.1% in both crude and recrystallized material. LC/MS/MS
`study indicates that they could be the dimers of two
`fluoromonocarbamate connected through a carbonyl
`group. The exact structures of the two impurities may be
`elucidated by NMR and X-ray study of the isolated
`material or through synthesis.
`Sample of fluorofelbamate provided to Therimmune for
`pilot PK studies in rodent to determine saturation levels.
`
`ADD discussed modifications of GG Tannate with JFC
`chemist for drug product development.
`Initial characterization tests @ SSCI, were unable to
`define the nature of the Guaifenesin-tannate
`complex. Additional studies in progress for further
`characterization.
`
`Validation report completed and approved. Acceptable
`results obtained for 3 month accelerated stability samples.
`Ryna-12 tablets released for commercial distribution on
`8/28/02.
`
`Confidential
`
`- 4 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015581
`
`4
`
`

`

`II)
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`PRODUCT DEVELOPMENT (continued)
`
`SINUS-12 SUSPENSION AND TABLETS
`Issue/Pro2ram
`Prioritv
`Critical Path
`---------------
`--- ---- -
`-
`- o- -----
`-------.~
`Sinus-12 Suspension
`High
`New Tannate Combination
`Products
`
`T''
`- -------o M
`- . -------o--
`Q3/FY03
`GD/ML/
`VP/CY
`
`Sinus-12 Tablets
`
`High
`
`New Tannate Combination
`Products
`
`Q3/FY03
`
`VP/GD
`/ML
`
`s
`/C
`--------- -------------
`Sinus-12 Suspension samples for stability initiation
`received at Decatur on 8/15. Revised price quote signed
`9/4/02. Testing of the suspension samples will take
`precedent over all method validation activities. Stability
`testing on laboratory prototypes will be performed for
`additional information.
`
`Poor granulation flow characteristics observed with first
`full scale evaluation batch. Part of the batch will be used
`in stability study in an attempt to support launch. A
`second evaluation batch was manufactured in Decatur.
`Stabilty studies will be initiated ASAP.
`
`Stability Programs
`
`High
`
`Assay Development and
`Validation
`
`High
`
`Sinus-12 Suspension
`Potency Assay:
`
`VP/GD/ML
`/CY
`
`Review of capacity at Decatur to perform stability testing
`with additional resources. Price quotes approved 8/19 for
`first batch. Price quote approval required for second
`batch. Stability of first batch initiated on 8/16/02.
`Stability of second batch initiated on 8/26/02.
`
`EM
`
`EM
`
`EM submitted a detailed spreadsheet to Magellan to
`facilitate tracking of activities. Testing of the PE batch at
`Magellan has impacted completion of method validations
`in the time required.
`
`Completion of potency method experiments targeted for
`9/24, data reviewed by 10/8, and final report by 10/18.
`Investigations of the potency results (from the PE batch)
`which include using a 4 fold decrease in sample
`concentration and the use of alternative columns have
`been completed. The use of a step gradient to eliminate
`potential late eluting peaks is highly recommended.
`Accuracy testing completed for method validation have
`been received.
`
`Confidential
`
`- 5 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015582
`
`5
`
`

`

`CD
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`Confidential
`
`- 6 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015583
`
`6
`
`

`

`PRODUCT DEVELOPMENT (continued)
`SINUS-12 SUSPENSION AND TABLETS (cont.)
`rr10nty Lrltlcat ratn
`Issue/ rro~ram
`Sinus-12 Suspension (cont.)
`Dissolution Assay:
`
`11mm
`
`lVlana~ er
`EM
`
`.......
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`:status/Lomments
`Completion of dissolution method experiments targeted
`09/6/02, data reviewed by 9/13 and final
`report by 9/20. Results for specificty testing have been
`received. The use of a step gradient to eliminate
`potential late eluting peaks is highly recommended, and
`how the method has been validated.
`
`Preservative Assay:
`
`Sinus-12 Tablets
`Potency Assay:
`
`Dissolution Assay:
`
`Alternate Contract
`Laboratories
`
`EM
`
`EM
`
`EM
`
`Completion of preservative method experiments targeted
`09/6/02, data reviewed by 9/20 and final report by 9/27.
`Results for accuracy testing have been received. The
`current method is sensitive to pH changes.
`
`Completion of potency method experiments targeted for
`9/20, data reviewed by 9/27, and report received by 10/4.
`Linearity, precision and solution stability have been
`completed.
`
`Completion of dissolution method experiments targeted
`for 09/20/02, reviewed 9/27, with report on 10/4.
`Results for specificty testing have been received,
`linearity, precision, solution stability, and filter validation
`have been completed.
`
`ADD/EM
`
`Magellan is having difficulties in meeting timeline
`commitments. Alternate contract labs will be
`investigated. QTI has been contacted. Current CDA for
`MedPointe under review, will be updated if required.
`
`Confidential
`
`- 7 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015584
`
`7
`
`

`

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`PRODUCT DEVELOPMENT (continued)
`
`SOMA
`Issue/Program
`Sustained Release Form.
`Labopharm
`
`Priority
`High
`
`Critical Path
`
`Timing
`On-going
`
`Manager
`ADD/VP/
`JH
`
`Status/Comments
`Labopharm site visit conducted 8/29/02. Discussed
`product development strategies and reviewed
`experimental manufacturing facilities and testing
`laboratories.
`
`Eurand
`
`Shire
`
`TUSSI-12 D SUSPENSION
`Evaluate formulation without High
`Sorbic acid
`
`Potency Assay:
`
`HPLC
`
`GC
`
`Dissolution Assay:
`
`Confidential
`
`Q2/FY03
`
`GD/VP/ML
`
`No further work will be performed at Eurand at this time.
`
`Site visit to Additional Lab facility. Reviewed technology
`and capabilities.
`
`Validation report completed. Acceptable results on 3
`month accelerated stability samples from PE Lot D0206.
`PET testing on one qualification batch still required.
`Tussi-12D Suspension released from Decatur for
`commercial distribution on 8/29/02. EM obtained a price
`quote for the certification of Carbetapentane citrate as a
`primary reference standard at Magellan. Comparison to
`the Decatur SOP for standard certification in underway.
`Current procedure to determine standard potency at
`Decatur is a titration, both HPLC and titration shall be
`used to certify the standard.
`
`EM
`
`Q3/FY03
`
`EM
`
`Q3/FY03
`
`EM
`
`- 8 -
`
`Additional studies are required to address the accuracy
`failures during validation at the 70% and 80% levels.
`Upon completion of Sinus-12 suspension activities at
`Magellan additional testing will begin. Also additional
`extraction steps as recommended by VP will also be
`investigated.
`Method has been validated for the sorbic acid formula.
`Upon identification of improved chromatographic
`conditions as the current method has an unacceptably
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX00015585
`
`8
`
`

`

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`
`TUSSI-12 D SUSPENSION (cont.)
`Issue/Program
`Priority
`Evaluate formulation without
`Sorbic Acid (cont.)
`Preservative Assay:
`
`TUSSI-12D TABLETS
`Formulation Development
`
`Stability Program
`
`Validate/transfer analytical
`methods
`
`High
`
`High
`
`High
`
`Potency Assay:
`
`short column lifetime, & poor chromatography the
`method will be revalidated.
`
`PRODUCT DEVELOPMENT (continued)
`
`Critical Path
`
`Timing -
`Q3/FY03
`
`Manager
`-
`EM
`
`Status/Comments
`Additional studies are required to address the specificity
`failures during validation. Activities at Magellan will begin
`shortly based on the chromatography developed for the
`SINUS-12 suspension.
`
`Q3/FY03
`
`GD/VP/ML
`
`Q2-Q3
`/FY03
`
`VP/ML/CY
`WR
`
`Q3/FY03
`
`EM/VP
`
`Launch Fall 02
`Process evaluation batch scheduled for 8/14- 8/16. The
`requisition for the batch has been initiated.
`Price quote signed 9/4/02.
`Review of capacity at Decatur to perform stability testing
`with additional resources. Stability initiated on 8/26/02.
`EM submitted a detailed spreadsheet to Magellan so they
`may indicate all activities when completed, and reviewed
`by QA. Testing of the PE batch has impacted throughput
`at Magellan to complete the validations in the time
`required.
`
`EM
`
`Completion of potency method experiments targeted for
`10/4, data reviewed by 10/18, and final
`report by 10/25.
`
`Data from testing of developmental formulations made at
`Magellan indicate that a single HPLC assay can be used
`to quantitate all three actives. The use of an alternative
`column with increased lifetime (also to be used for the
`dissolution method) looks very promising, such that a
`single column and mobile phase conditions can be used
`for both dissolution and assay. Method conditions and
`development will be finalized by 9/6.
`
`EM
`
`Completion of dissolution method experiments targeted for
`
`Confidential
`
`- 9 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015586
`
`9
`
`

`

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`
`Dissolution Assay:
`
`10/9, data reviewed by 10/18, and final report by 10/25.
`The use of an alternative column with increased lifetime and
`significantly improved chromatography looks very promising.
`Method conditions and development will be finalized by 9/6.
`
`Confidential
`
`- 10-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015587
`
`10
`
`

`

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`
`AD MINIS TRA TIVE
`
`PRODUCT & PROCESS DEVELOPMENT LABORATORY RELOCATION
`Priority
`Critical Path
`Timing
`Manager
`Issue/Program
`-
`-
`-
`-
`OSHA Requirements
`High
`Safety of Laboratory Personnel Q2
`RM/EM
`
`Leasehold Improvements
`
`High
`
`Maximize Laboratory
`Functionality
`
`Q2
`
`ML/GB
`
`Central Files
`
`ATF License
`Controlled Drug License
`
`Medium
`
`Preserve Historical Drug
`Development Information
`
`Medium Routine Lab Operations
`
`Facility Contracts Set-up and Medium Routine Lab Operations
`manage contracts with
`vendors
`Facility Maintenance
`
`Medium Routine Lab Operations
`
`Q2
`
`Q2
`
`Q2
`
`ML/CY
`
`ML
`
`ML/DW
`
`On-going
`
`ML/CY
`
`Status/Comments
`DOT awareness training price quote received, still waiting
`for confidential disclosure agreement from vendor.
`
`Leasehold improvements are targeted for completion 7/22
`and under budget. Fine tuning security system and
`physical systems. Installation of stability chamber
`monitoring interface is in progress. A burglar alarm
`system required for controlled drug storage has been
`installed but will not be activated until needed.
`All files have either been archived or moved to the Cedar
`Brook facility. Consolidation and archiving will continue
`as time allows.
`Renewal forms forwarded to F. Patterson for processing.
`Site and safe identified for drug storage.
`
`Responsibilities assigned to facilitate set-up, billing, and
`management of various facility services accounts (utilities,
`vending janitorial, laundry, etc.)
`Maintenance of electrical, plumbing, HVAC security and
`general operations. HVAC still not set/working properly.
`No quote received for HVAC contract. Roof leaks were
`reported after last heavy rainfall. Roofer is taking care of
`repairs. For safety reasons, a request for better lighting
`outside the building has been sent to Eastern Properties.
`The request has been forwarded to the building owner.
`
`Confidential
`
`- 11-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`Updated as of { DATE \@
`"MM/dd/yy" }
`
`MEDA_APTX00015588
`
`11
`
`