MedPointe Product & Process Development
`Program Priorities & Issues
`November 18, 2002
`COMMERCIAL PRODUCT TECHNICAL SUPPORT
`
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`ASTELIN NASAL SPRAY
`Issue/ Program
`Priority
`-
`-
`Qualify 34.5 mL
`High
`V-bottom bottle
`
`Critical Path
`Launch of V-Bottom Bottle
`
`Timing Manager1
`-
`-
`JH/ADD/
`Q4/FY03
`CY
`
`Qualify Marlex 5502BN Resin
`Stability program
`
`High
`
`Maintain Component Supply
`
`Q3/FY03
`
`CY/ML
`
`Valois VP3 Pump - Exclusive
`Supply Contract
`
`Medium
`
`Brand Protection
`
`ADD
`
`Status/Comments
`Task Force assembled to investigate path to
`implementation by Spring 03.
`Additional data from Regulatory submissions will be
`reviewed and summarized .
`
`Studies initiated to qualify transfer to new bottle resin.
`Additional samples (4.5 month) have been submitted for
`particulate testing. Results are expected by 11/22/02.
`The additional data is needed to perform a statistical
`analysis.
`Discuss exclusive pump sales arrangement with Valois to
`limit potential use by future generics. Revised meeting
`date 11/15/02 at request of Sarah Maika of Valois.
`
`DORAL TABLETS
`Qualify Decatur to
`manufacture Doral Tablets
`
`High
`
`Maintain Commercial Tablet
`Supply
`
`Q4/FY03
`
`VP/GD
`
`Inter-departmental review of Marketed products resulted
`in recommendation to continue support of this project.
`Three timelines are available but there has been no
`commitment to any of these. Quotation requested from
`PMRS for development and manufacture of commercial
`supply. Request for compliance audit submitted.
`Tateyama Kasei and FIS to be evaluated as suppliers of
`quazepam drug substance. Decatur has tested samples of
`quazepam from FIS. Samples passed USP testing, but
`were not micronized. FIS will provide pricing for
`micronization and activation of DMF. Cost of quazepam
`from TK for experimental work is available.
`1 BA-Beth Andry G B- Gul Balwani, ADD-Alex D' Addio, GO-Grace Dang, JG-Jeff Gazzara, WH-Weixuan He, JH-John Higson, ML-Mary Lehr, RM -Rick Majos, EM-Ed Mikalsen, HM-Hank Mortko, VP(cid:173)
`Vithal Patel, WR-Will Robinson, BR-Bryan Roecklein, CY-Cindy Yayac
`
`Qualification of new drug
`substance supplier
`
`Medium Maintain Drug Substance
`Supply
`
`Q3/FY04
`
`HM/VP
`
`Confidential
`
`- 1 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604890
`
`1
`
`CIP2120
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

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`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 Su bsta nee
`
`r·
`Q2
`
`M
`GD/VP
`
`SOMA350
`Transfer Manaufacturing
`Process to Decatur
`Identify critical process
`parameters
`Validate specificity for USP
`assay
`
`SOMA COMPOUND
`Validate specificity for USP
`assay
`
`Critical
`
`Maintain Commercial Supply of On-going WR/HM/
`Tablets
`JH
`
`High
`
`Response to FDA Inspection
`
`Q3/FY03
`
`HM
`
`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
`
`Status/C
`FDA approved Micron Technologies. The report
`containing three month stability data on first batch and
`second batch was approved on 10/28/02. Two lots of
`milled felbamate are currently under investigation:
`2C0805 for particle size and 2E2007 for presence of
`foreign material.
`
`Work with Ray Chen to develop an experimental design
`that will be used to identify critical parameters in
`manufacturing process for SOMA 350 Tablets. A draft
`protocol has been received for comment.
`Work initiated in response to FDA 483. Experiments for
`Depen and SOMA both completed. Final reports have
`been issued by Magellan.
`
`Work initiated in response to FDA 483. Updated
`quotations from Magellan submitted for approval.
`Estimated completion date- Mid Oct. 02. Magellan
`cannot achieve the salicylic acid retention time specified
`in the USP. Investigations are under way.
`
`Work initiated in response to FDA 483. Updated
`quotations from Magellan submitted for approval.
`Estimated completion - Mid Oct. 02. Magellan cannot
`achieve the salicylic acid retention time specified in the
`USP. Investigations are underway.
`
`Confidential
`
`- 2 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604891
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`2
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`PRODUCT DEVELOPMENT
`
`ASTELIN NASAL SPRAY
`
`--- ~-·-- -o- -----
`Astelin Double-Strength -
`Formulation Development
`
`-------
`High
`
`---------------
`Taste Improvement
`
`- -------o
`On-going
`
`- . -------~--
`GD/VP
`
`Astelin Double-Strength -
`Proprietary pump design
`
`Medium
`
`Brand Protection
`
`ADD
`
`- -------· -------------
`Several formulations at higher active concentrations
`and/or higher viscosity have been stable physically at 4-6
`month stability. Five formulations are selected for the
`second level of screening.
`Xemplar Pharmaceutical identified as alternate to
`Magellan for spray testing. CDA completed. Site visit on
`hold pending evaluation of financial stability of Xemplar.
`Valois has been contacted concerning the proprietary
`design of a pump for reformulated Astelin. Meeting re-
`scheduled for 11/15/02 at request of Sarah Maika of
`Valois.
`
`ASTELIN/STEROID COMBINATION PRODUCT
`New Nasal Solution Product
`Low
`Extension Product for Lifecycle On Hold
`Azelastine HCI and an
`Maintenance
`Approved Steroid
`
`ADD/VP/
`GD/JH/JG
`
`Project on hold based on evaluation of resources and
`analysis of success potential provided by R. Spivey.
`
`FLUOROFELBAMA TE
`Develop Fluorofelbamate for High
`IND
`
`Fluorofelbamate Drug
`Substance Synthesis
`
`High
`
`Demonstration of
`Fluorofelbamate Safety Profile
`
`Drug Supply for Tox Studies
`and Development of
`Commercial Process
`
`Q2/FY03
`
`HM/WH
`
`Q2/FY03
`
`HM/WH
`
`cGMP Preparation of
`Fluorofelbamate
`
`Confidential
`
`High
`
`Phase I Clinical Study
`
`Q2/FY03
`
`HM/WH
`
`- 3 -
`"MM/dd/yy" }
`
`Developing pre-clinical program only at this time "Go/No
`Go" for Phase I Study Fall/Winter.
`
`The preparation fluorofelbamate drug substance for
`preclinical toxicity study (ca. 4.2 kg) has been completed
`and the material has been tested and released to
`MedPointe. The Certificates of Analysis (COA) of all the
`batches of the fluorofelbamate have been reviewed and
`issued. Quotation approved for manufacture of GMP
`supply (2 Kg) of drug substance. Manufacture of GMP
`supply targeted for completion in January 2003.
`Validation of methyl carbamate method required for
`release.
`
`F-diol, the penultimate of fluorofelbamate (ca. 2.2 kg) has
`been prepared in seven batches. All the material is in
`analytical division for certificate of analysis and material
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604892
`
`3
`
`

`

`release when they are meeting the specification. Also, a
`composite sample is taken and a use test is planned soon.
`
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`Confidential
`
`- 4 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604893
`
`4
`
`

`

`FLUOROFELBAMATE (cont.)
`
`PRODUCT DEVELOPMENT( continued)
`
`-
`
`-
`
`-
`
`Impurities required for Tox
`Studies
`
`High
`
`Drug Supply for Tox Studies
`
`Q2/FY03
`
`HM/WH
`
`F-Diol Analysis
`
`High
`
`HM/WH
`
`Analytical Methods
`Polymorph Screen
`
`High
`
`Q4/FY03
`
`HM/WH
`
`II)
`0
`0
`0
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`Bis-F-carbonate dimers isolated from fluorofelbamate
`drug substance and those derived from direct synthesis
`were compared by proton NMR and carbon NMR. Both
`experiments indicated that they are identical in structure.
`Currently, the study is focused on the preparation of 1D-
`15g of the material to be used as a reference standard.
`
`HPLC analytical method of F-diol has been developed
`which can successfully separate and quantify small
`amount of H-diol in F-diol. When the method is validated,
`it will be used in F-diol analysis and release before the
`cGMP campaign of fluorofelbamate.
`
`Six different organic solvents and their different
`combinations have been screened and one major crystal
`form was identified except an unstable form (or a
`preferred orientation) was observed when the crystal was
`prepared by fast evaporation of method solvent. This
`result will be confirmed by repeating the experiment and
`calculating the XRPD powder pattern.
`
`A single crystal of fluorofelbamate was generated in
`aqueous solution and crystallography data has been
`collected. The complete structure of the crystal form may
`be available soon.
`Sample of fluorofelbamate provided to Therimmune for
`pilot PK studies in rodent to determine saturation levels.
`Protocols for dosing solution development have been
`approved. PK plasma methods are being developed.
`A detailed timeline for Phase 1 clinical trial and IND
`submission is being developed. Meetings were held with
`Therimmune and IT to establish a procedure for
`electronic documentation exchange.
`
`Therimmune Pilot PK Studies High
`
`Phase 1 Clinical Trial and
`IND Submission
`
`Confidential
`
`Q3/FY03
`
`HM/BR/
`WH
`
`HM/WH/
`ML
`
`- 5 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604894
`
`5
`
`

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`PRODUCT DEVELOPMENT (continued)
`
`GUAIFENESIN TANNATE
`/P
`-------
`-~~ - - · - - -e- -----
`Product Design Discussions
`Low
`
`c ...
`---------- -----
`New Long Acting Form of
`Guaifenesin by JFC
`
`- -------e
`Ongoing
`
`- · ------e--
`ADD
`
`RYNA-12 TABLETS
`Validate manufacturing
`process
`
`High
`
`New Tannate Tablet Product
`
`Q2/FY03
`
`VP
`
`SINUS-12 SUSPENSION AND TABLETS
`Sinus-12 Suspension
`High
`New Tannate Combination
`Products
`
`Q2/FY04
`
`GD/ML/
`VP/CY
`
`Sinus-12 Tablets
`
`High
`
`New Tannate Combination
`Products
`
`Q2/FY04
`
`VP/GD
`/ML
`
`------~·- -----------~
`
`s
`/C
`JFC has requested a commitment on GG Tannate
`development by their next board meeting on Dec 02.
`Recent communications by FDA indicate that
`successful development of guaifenesin tannate salt
`may require an NDA. C. Fishman and B. Pe to
`discuss with JFC this week.
`
`Three month data for the second & third qualification
`batches have not been received from Decatur. This data,
`as well as the six-month stability data (11/2) needs to be
`reviewed to ensure expiration dating is supported.
`
`Process Evaluation- Sinus-12 Suspension data (D0208)
`look acceptable at 1 month. It is now at 3 month pull.
`PET testing at STS was supposed to start on 9/20/02 with
`only 5 USP organisms still has not been tested. Decatur
`is now testing it at Gibraltar.
`
`Manufacturing of Sinus-12 tablet PQ batches delayed due
`to poor dissolution results for PE batch. Launch re-
`scheduled for August 03. The investigation of poor
`dissolution results for PE batches is underway.
`Dissolution-hardness profiles and other possible factors
`are being reviewed. The specification limits for tablet
`hardness and friability will be re-evaluated. Samples of
`the experimental batches manufactured at Magellan were
`received and testing is underway to compare the results
`of Magellan vs. MedPointe. Additional formulation
`experiments are on going to optimize the dissolution of
`the product.
`
`Stability Programs
`
`High
`
`Confidential
`
`VP/GD/CY Two month testing is in progress.
`Updated as of { DATE \@
`
`- 6 -
`"MM/dd/yy" }
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604895
`
`6
`
`

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`
`- 7 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604896
`
`7
`
`

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`PRODUCT DEVELOPMENT (continued)
`
`SINUS-12 SUSPENSION AND TABLETS (continued)
`
`Sinus-12 Suspension
`Potency Assay:
`
`Dissolution Assay:
`
`Preservative Assay:
`
`Sinus-12 Tablets
`Potency Assay:
`
`Dissolution Assay:
`
`Alternate Contract
`Laboratories
`
`Transfer of methods to
`Decatur
`
`EM
`
`EM
`
`EM
`
`EM
`
`Validation report for assay method received, and is
`circulating for comments.
`
`Validation report for dissolution method received, and is
`circulating for comments.
`
`Validation report for preservative method received, and is
`circulating for comments.
`
`Validation report for assay method received, and is
`currently circulating for comments.
`
`Validation report for dissolution method delayed as a
`number of method validation experiments were
`conducted without performing system suitability.
`
`ADD/EM
`
`It is proposed that QTI assist in the method validation of
`the improvements committed to for the Tussi-12D
`suspension methods.
`
`EM/HM
`
`Protocols have been signed and transferred to Decatur.
`Official method transfer testing still needs to be
`performed.
`
`Confidential
`
`- 8 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604897
`
`8
`
`

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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/GB
`
`Status/Comments
`Data to support platform selection overdue. Status of
`method development unknown.
`
`Shire
`
`TUSSI-12 D SUSPENSION
`Evaluate formulation without High
`Sorbic acid
`
`Potency Assay:
`
`HPLC
`
`GC
`
`Dissolution Assay:
`
`Site visit to Additional Lab facility. Reviewed technology
`and capabilities. Proposal reviewed and will be compared
`to an additional lab (Cardinal, Penwest).
`
`Q2/FY03
`
`GD/VP/ML Validation report completed. Acceptable results on 3
`month accelerated stability samples from PE Lot D0206.
`Six-month stability data (11/2) needs to be reviewed to
`ensure expiration dating is supported. PET testing on one
`qualification batch (2H29) still has not started at STS.
`Decatur is testing it at Gibraltar. In addition, only the 5
`USP organisms are available for testing at this time.
`
`Q3/FY03
`
`EM
`
`EM
`
`A new method is needed that does not have
`Phenylephrine interference.
`
`Additional studies are required to address the accuracy
`failures during validation at the 70% and 80% levels. A
`due date of Nov. 29 is targeted.
`
`Q3/FY03
`
`EM
`
`Experiments underway, solubility using various mixtures
`of water 0.1N HCI, methanol, and acetonitrile completed.
`
`Confidential
`
`- 9 -
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604898
`
`9
`
`

`

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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
`
`High
`
`High
`
`Validate/transfer analytical
`methods
`
`High
`
`Potency Assay:
`
`Dissolution Assay:
`
`PRODUCT DEVELOPMENT (continued)
`
`Critical Path
`
`Timing
`
`Manager
`
`Status/Comments
`
`Q3/FY03
`
`EM
`
`Studies are currently underway here to improve the Tussi-
`12 D suspension preservative method. The conditions
`from the Sinus-12 suspension are not suitable.
`
`Q3/FY03
`
`GD/VP/ML
`
`Status of qualification batches to be discussed.
`
`Q2-Q3
`/FY03
`
`VP/ML/CY
`WR
`
`Q3/FY03
`
`FM/HM/
`EM/VP
`
`EM
`
`EM
`
`All two month data was received 11/13/02. Insufficient
`data for statistical evaluation of expiration dating.
`Disintegration results for tablets stored at 25C/amb RH in
`bulk and 20 ct package exceeded 30 minutes.
`A protocol was developed to qualify Carbetapentane
`citrate analytical standard required for development due
`to limited supply at Decatur. Certification of
`Carbetapentane citrate (obtained from Sigma Chemical
`Co.) as a primary reference standard will be completed by
`10/31.
`
`Validation report for assay issued on 10/9/02.
`Additional testing at the request of F. Martinez to
`demonstrate acceptable accuracy is obtained when
`adding solid tannate drug substances is underway at
`Magellan.
`Validation report for dissolution issued on 10/9/02.
`Plan for additional testing to determine the accuracy
`when adding solid tannate drug substance drafted and
`sent to Magellan (awaiting price quote).
`
`Confidential
`
`- 10-
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604899
`
`10
`
`

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`TWINJECT
`Technical Support for
`Regulatory Submission By
`Hollister-Stier
`
`High
`
`Q3/FY03
`
`HM
`
`Monarch Laboratories site visit by HM 9/27/02 to review
`extractables method validation. Provided data analysis on
`stability data to HS.
`
`AD MINIS TRA TIVE
`
`PRODUCT & PROCESS DEVELOPMENT LABORATORY RELOCATION
`
`Issue/Program
`-
`OSHA Requirements
`
`Priority
`-
`High
`
`Timing Manager
`Critical Path
`-
`-
`Safety of Laboratory Personnel Q2
`RM/EM
`
`Status/Comments
`DOT awareness training conducted on 11/04/02.
`
`Leasehold Improvements
`
`High
`
`Maximize Laboratory
`Functionality
`
`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
`
`Q2
`
`ML
`
`ML
`
`ML
`
`ML/CY
`
`On-going
`
`ML/CY
`
`Budget Preparation
`
`High
`
`Fiscal 2003/2004
`
`Q3
`
`ML
`
`A Liquid/Solvent waste log was drafted and sent out for
`comments.
`
`The emergency lighting was tested. One emergency light
`in lab 133 was not functional.
`Roof repairs to properly seal a roof penetration need to
`be made.
`
`Filing and archiving of files is ongoing.
`
`The application for our DEA license has been received.
`Barbara Beckley will complete and file the application.
`
`Facility contact vendor maintenance is consuming a
`substantial amount of personnel resources. Various
`solutions to this problem are being examined.
`Maintenance of electrical, plumbing, HVAC security &
`general operations. Alternate contractor being
`investigated.
`A budget package was distributed to department heads.
`First draft targeted for completion by 11/15/02.
`
`Confidential
`
`- 11-
`"MM/dd/yy" }
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604900
`
`11
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`PRODUCT & PROCESS DEVELOPMENT LABORATORY RELOCATION
`
`ADMINISTRATIVE (continued)
`
`. --
`
`---
`-
`-
`GMP/GLP Laboratory
`
`- - - ---
`
`- ---- --
`
`---
`
`--------
`
`--
`- -
`ML/HM/
`ADD
`
`- - . ------
`
`---
`Management has directed us to develop a timeline for
`bringing the laboratory into GLP/GMP compliance.
`Meetings were held on 9/20 and 9/27 to discuss issues.
`Several action items were identified to initiate the process
`of bringing the laboratory into GLP/GMP compliance. A
`template CV was distributed for completion and inclusion
`in the personnel files. Position descriptions are also
`needed for the files.
`
`EM
`
`The dissolution equipment calibration completed.
`
`EM/BA
`
`Confidential
`
`- 12-
`"MM/dd/yy" }
`
`A significant amount of time has been spent installing two
`(2) 1050 HPLCs, and performing the maintenance
`required so they are operating properly, i.e., pump heads,
`check valves, and active inlet valves. Parts, and
`communication cables, have been pooled between the
`four (4) instruments we have to get two operational.
`
`A justification memo was written for $62,000 for complete
`IQ,OQ,PV of four 1050 HPLC units. Approval is needed so
`the equipment can be used for analytical development
`activities here.
`
`Updated as of { DATE \@
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01604901
`
`12
`
`