CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`2 2-3 87
`
`CHEMISTRY REVIEW! S)
`
`

`

`CMC BRANCH CHIEF MEMORANDUM
`
`To:
`
`From:
`Date:
`
`NDA 22—387
`
`Ramesh Sood, Ph.D., Branch Chief, ONDQA
`28—Jul—2009
`
`Drug:
`Route of administration:
`
`Tyvaso (treprostinil) inhalation solution
`Oral Inhalation
`
`Strength:
`Subject:
`
`0.6 mg/mL
`“Approval” recommendation for NDA 22—387
`
`Treprostinil for inhalation (TyvasoTM) is being developed as an alternative to the subcutaneously
`and intravenously delivered treprostinil solution (Remodulin Injection, NDA 2i —272, approved
`22—May-2002). Treprostinil is the free acid of a synthetic tricyclic benzindene analogue of
`prostacyclin. The proposed indication is for the treatment of pulmonary arterial hypertension
`(WHO Group I) in patients with New York Heart Association (NYHA) Class III \
`symptoms.
`*
`’
`
`”(4)
`
`Several pending CMC issues were identified in my previous memo. The company has addressed
`these issues to the reviewer’s satisfaction. The issues related to the drug substance have been
`resolved.
`
`The facilities related to the manufacturing of the drug product and described in the NDA have
`been recommended for approval by the Office of Compliance. Categorical exclusion from an
`environmental assessment requested by the applicant is acceptable.
`
`An acceptable recommendation is made by the microbiology reviewer.
`
`Recommended action: The application is recommended for “APPROVAL” from CMC
`perspective.
`
`

`

`Submission
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22387
`
`ORIG 1
`
`UNITED
`THERAPEUTICS
`CORP
`
`TREPROSTINIL FOR
`INHALATION
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`RAM ESH K SOOD
`
`07/28/2009
`
`

`

` ' CHEMISTRY REVIEW
`
`NDA 22-387
`
`Tyvaso (treprostinil)
`Inhalation Solution
`
`United Therapeutics Corporation
`
`Monica D. Cooper, Ph.D.
`ONDQA Pre-Marketing Assessment
`Division I/Branch I
`
`Reviewed for the Division of Cardiovascular
`and Renal Products, HFD—l 10
`
`

`

`7 CHEMISTRY REVIEW
`'
`
`Table of Contents
`
`Table of Contents
`
`.............2
`
`Chemistry Review Data Sheet.................4
`
`The Executive Summary
`
`......9
`
`1. Recommendations .......................................................................................................................9
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability................................................................... 9
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable .............................................................................................. 9
`
`II. Summary of Chemistry Assessments ......................................................................................... 9
`
`A. Description of the Drug Product(s) and Drug Substance(s).................................................................... 9
`
`B. Description of How the Drug Product is Intended to be Used .............................................................. 10
`
`C. Basis for Approvability orNot—Approval Recommendation ................................................................ 11
`
`III. Administrative......................................................................................................................... 11
`
`A. Reviewer’s Signature ............................................................................................................................ 11
`
`B. Endorsement Block ............................................................................................................................... 11
`
`C. CC Block ............................................................................................................................................... 1 1
`
`ChemistryAssessment
`
`12
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 12
`S
`DRUG SUBSTANCE [treprostinil, United Therapeutics Corporation] .................................... 12
`
`General Information [treprostiniL UTC] ........................................................................................ 12
`
`Manufacture [treprostinil, UTC] .......................................................................................................
`.. 12
`Characterization [treprostiniL UTC] ............................................................................................................... 12
`Control of Drug Substance [treprostinil, UTC] ............................................................................................... 12
`
`Reference Standards or Materials [treprostiniL UTC] ...............................
`
`8.1
`82
`5.3
`8.4
`8.5
`
`P
`
`S.6
`3.7
`
`RI
`P.2
`P.3
`R4
`
`Container Closure System [treprostiniL UTC] ................................................................................................ 13
`Stability [treprostiniL UTC] ............................................................................................................................ 13
`DRUG PRODUCT [Tyvaso(treprostini1) Inhalation Solution] ................................................ 13
`Description and Composition of the Drug Product [Tyvaso (treprostinil) Inhalation Solution] ...................... 13
`Pharmaceutical Development [Tyvaso (treprostinil) Inhalation Solution] ...............................
`
`Manufacture [Tyvaso (treprostinil) Inhalation Solution]................................................................................. 14
`Control of Excipients [Tyvaso (treprostinil) Inhalation Solution] ................................................................... 15
`
`

`

`CHEMISTRY REVIEW
`
`P.6
`
`R7
`
`P.8
`
`Reference Standards or Materials [Tyvaso (treprostinil) Inhalation Solution] .....................
`
`
`Container Closure System [Tyvaso (treprostinil) Inhalation Solution] ........................................................... 15
`
`. 15
`
`Stability [Tyvaso (treprostinil) Inhalation Solution] ....................................................................................... 15
`
`P
`
`A
`
`R
`
`DRUG PRODUCT [Optineb-ir Nebulizer] ............................................................................... 20
`
`APPENDICES ........................................................................................................................... 20
`
`REGIONAL INFORMATION ..................................... 20
`
`II. Review Of Common Technical Document—Quality (Ctd-Q) Module 1
`
`...............20
`
`A.
`
`B.
`
`III.
`
`IV.
`
`Labeling & Package Insert ........................................................................................................ 20
`
`Environmental Assessment Or Claim Of Categorical Exclusion .............................................. 28
`
`Establishment Evaluation Report ..................................................................................29
`
`List Of Deficiencies ....................................................................................................... 29
`
`

`

`
`
`_ CHEMISTRY REVIEW
`
`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1.
`
`NDA 22-3 87
`
`2.
`
`REVIEW #: 2
`
`3.
`
`4.
`
`5.
`
`REVIEW DATE:
`
`22-Jul-2009
`
`REVIEWER:
`
`Monica D. Cooper, Ph.D.
`
`PREVIOUS DOCUlVIENTS:
`
`
`
`
`
`
`
`
`Previous Documents
`
`Ori-inal Submission
`
`
`
`Amendment (Nooo BC)
`Amendment (N000 BC)
`
`Amendment (N000 BC)
`
`
`Amendment (N000 BZ)
`
`
`
`
`
`
`
`
`
`
`
`25—Feb-2009
`
`
`6.
`
`SUBMISSION(S) BEING REVIEWED:
`
`
`Document Date
`
`12-Mar-2009
`Amendment (N000 BZ)
`(Revised Carton and Container Labels)
`
`
`
`03-Apr-2009
`Amendment (NOOO BC)
`(In—Use Stability Study)
`
`
`.
`02-Jul-2009
`Amendment (N000 BL)
`(Revised Carton and Container Labels)
`
`
`
`
`Amendment (N000 BL)
`(Revised Carton and Container Labels)
`
`
`Amendment (N000)
`
`
`Submission 3 Reviewed
`
`
`
`
`
`
`
`
`
`09-Jul-2009
`
`22-Jul-2009
`
`
`
`(Revised Carton and Container Labels)
`
`Page 4 of 29
`
`

`

`
`i CHEMISTRY REVIEW .
`
`7.
`
`NAIVIE & ADDRESS OF APPLICANT:
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`
`
`
`8.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`United Theraeutics Co oration
`
`Research Tr1angle Park, NC 27709
`
`FAX Number
`
`919-313-1298
`
`
`
`DRUG PRODUCT NAME/CODE/TYPE:
`
`Non-Prorieta Name US
`
`T aso
`trerostinil
`
`
`
`
`
`
`
`
`-
`.
`o
`
`Submissmn Prion
`
`
`LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`PHARMACOL. CATEGORY:
`
`Prostacyclin analog for pulmonary
`arterial hypertension
`
`DOSAGE FORM:
`
`Sterile Solution
`
`STRENGTH/POTENCY:
`
`0.6 mg/mL
`
`ROUTE OF ADMINISTRATION:
`
`Inhalation
`
`RX/OTC DISPENSED: _X__Rx
`
`OTC
`
`SPOTS gSPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`SPOTS product ~ Form Completed
`
`X Not a SPOTS product
`
`Page 5 of 29
`
`

`

` CHEMISTRY REVIEW _..,
`"
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NANIE, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Names:
`
`( 1) Acetic acid, [[(1R,2R,3aS,9aS)—2,3,3a,4,9,9a—
`hexahydro-Z-hydroxy- l — [(38)-3 -hydroxyoctyl]-
`1H—benz[f]inden—5—yl]oxy]—
`
`(2) [(1R,2R,3 a3,9aS)-2-Hydroxy—l-((3S)-3-
`hydroxyoctyl)—2,3,3 a,4,9,9a-hexahydro- 1H-
`cylopent[b]naphthalen-5-yl]oxy]acetate
`
`US Adopted Name (USAN):
`
`treprostinil
`
`Laboratory Codes:
`
`Structural Formula:
`
`UT-l 5
`LRX-l 5
`
`15AU81
`
`
`
`Chemical Formula:
`Molecular Weight:
`CAS Number:
`
`C23H3405
`390.51
`81846-19—7
`
`Page 6 of 29
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17.
`
`RELATED/SUPPORTING DOCUlVIENTS:
`
`A.
`
`DMFs:
`
`9091.3 1 ”STATUS-
`
`~ COMPLETED
`
`r
`
`
`
`'
`
`24-Apr-2008 (G. Lunn)
`
`‘1 Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not
`need to be reviewed)
`
`B.
`
`Other Documents:
`
`
`
`21—272/SCM—01 0
`
`(approved 01 -May—2009)
`
`New DS (treprostinil)
`Manufacturing Site and Synthetic 1
`Process
`
`Page 7 of 29
`
`

`

`
`
`CHEMISTRY REVIEW '
`
`Chemistry Review Data Sheet
`
`
`
`CMC RELATED
`
`
`:
`REVIEWS'
`.
`
`
`
`
`
`
`‘ Methods Validation
`
`
`
`
`Tradename: Tyvaso
`I OSE-DMEPA
`
`
`Acceptable
`
`
`
`
`
`
`
`Categorical Exclusion:
`EA
`(CMC Review #1)
`23‘Mar'2009
`Acceptable
`
`
`
`
`Microbiology
`J. Metcalfe
`24-Mar-2009
`Acceptable
`
`
`
`
`
`
`M. Cooper
`
`Page 8 of 29
`
`

`

`‘
`'
`CHEMISTRY REVIEW .. g '7 '
`
`Executive Summary Section
`
`The Chemistry Review for NDA 22-387
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This new drug application (22-3 87) is recommended for APPROVAL from the perspective
`of chemistry, manufacturing, and controls.
`
`An information request letter was sent to the applicant on 13-Jan-2009 outlining the CMC
`information needed to complete this application. An Amendment dated 25-Feb-2009
`included a partial response to the issues. The final issue regarding in-use stability of the drug
`product in the Optineb nebulizer was addressed in the Amendment dated 03-Apr-2009. All
`CMC issues have now been adequately resolved.
`
`All drug substance information was referenced to NDA 21-272 for Remodulin Injection. A
`supplement for the new treprostinil drug substance manufacturing facility and synthetic
`process (NDA 21-272/SCM-010) was approved on 01-May-2009 (see reviews by L. Rocca
`dated 14-Apr-2009 and T. Bowie dated 01-May-2009).
`
`The adequacy of the Optineb nebulizer is being evaluated by CDRH. A summary of the
`device issues and the company’s responses to deficiencies were provided separately (see
`consult reviews by Sugato De and Ron Kaye).
`
`The Office of Microbiology (J. Metcalfe) evaluated the sterility assurance of the drug product
`and found it acceptable (see microbiology review dated 24-Mar-2009).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`There are no Phase 4 commitments.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Treprostinil for inhalation (TyvasoTM) was developed as an alternative to the subcutaneously
`and intravenously delivered treprostinil solution (Remodulin Injection, NDA 21-272,
`approved 22-May—2002). Treprostinil is the free acid of a synthetic tricyclic benzindene
`analogue of prostacyclin. The proposed indication is for the treatment of pulmonary arterial
`
`Page 9 of 29
`
`

`

`
`'
`I CHEMISTRY REVIEW
`
`Executive Summary Section
`
`hypertension (WHO Group I) in patients with New York Heart Association (NYHA) Class
`III "' symptoms.
`
`Drug Substance _
`Treprostinil is a chemically-synthesized small molecule with 5 stereocenters, manufactured
`as a single enantiomer.
`It is a white to cream-colored powder, which is practically insoluble
`in water. All of the drug substance information was referenced to the approved NDA 21-272
`for Remodulin Injection. For the convenience of the reviewer, the applicant provided the
`drug substance specification table and batch data for 5 recent lots. The current retest date for
`treprostinil drug substance is _ W when stored at 2 — 8°C.
`
`Drug Product
`The drug product is an aqueous solution of treprostinil (0.6 mg/mL) formulated with sodium
`chloride, sodium citrate, sodium hydroxide, and hydrochloric acid in water for injection. The
`excipients are compendial and have been used in previously approved inhalation solutions.
`The formulation is identical to the currently marketed Remodulin Injection (NDA 21-272),
`except for the absence
`_ fl
`, in the current formulation (Tyvaso).
`
`‘1,
`mtg}?
`
`b(4')
`
`hi4)
`
`Since treprostinil drug substance is practically insoluble in water, the treprostinil sodium salt
`was developed for use in the aqueous drug product formulation. It was noted that the
`treprostinil sodium salt is extremely difficult to handle since the solid is deliquescent. Thus,
`a manufacturing procedure was designed to form the sodium salt of treprostinil
`#— during
`the manufacture of the drug product. A slight molar excess of sodium hydroxide was added
`to the formulation to ensure that all of the treprostinil was converted to the sodium salt.
`Forced degradation studies of treprostinil showed it to be more stable under basic conditions;
`therefore, formulation as the sodium salt provided a stability advantage as well.
`
`
`
`ampoules with nominal
`<- ~
`packaged into
`TyvasolS
`fill volumes of 2.9 mL and a pH of 6.O— 7.2. The filled ampoules are further packaged into 4
`ampoules per pouch.
`
`‘3 43
`
`The product showed good stability when stored under long-term conditions (25°C/40% RH)
`out to 36 months and under accelerated conditions (40°C/20% RH) for 6 months. However,
`the drug product is photosensitive and should be carefully labeled as such. There is support
`for a 36-month shelf-life for the drug product when stored at controlled room temperature in
`LDPE ampoules inside foil pouches (i.e. protected from light). This is consistent with the
`applicant’s proposed expiration date and storage conditions. In-use stability studies
`determined that the drug product is stable for use in the Optineb nebulizer for a maximum of
`24 hours.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Tyvaso (treprostinil) Inhalation Solution, 0.6 mg/mL, is intended for oral inhalation using the
`Optineb—ir, an ultrasonic, pulsed-delivery nebulizer. The Optineb-ir, manufactured by
`
`Page 10 of 29
`
`

`

`
`CHEMISTRY REVIEW
`
` 3
`
`Executive Summary Section
`
`Nebutec Medicinal Products, is intended for single patient use in the administration of
`treprostinil for inhalation. The drug product solution is packaged in 2.9 mL ampoules,
`supplied as 4 ampoules within a foil pouch. One ampoule (2.9 mL) of treprostinil for
`inhalationshould be transferred to the nebulizer for use each day. The solution remaining in
`the nebulizer after 1 day should be discarded. Since the drug is photosensitive, unused
`ampoules should be stored in the foil pouch until use.
`
`Tyvaso is dosed in 4 separate inhalation sessions per day, during waking hours. The
`inhalation sessions should be at least 4 hours apart. Therapy should begin with 3 breaths of
`Tyvaso per inhalation session (each breath delivers approximately 5 — 6 mcg of treprostinil),
`given 4 times daily. Dosage should be increased to 6 breaths per inhalation session (4 times
`daily), and subsequently increased to the target maintenance dose of 9 breaths per inhalation
`session given 4 times daily, as tolerated. The maximum dose used in clinical studies. was 12
`breaths (i.e., 72 mcg of treprostinil) per inhalation session.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This new drug application (22~3 87) is recommended for APPROVAL from the perspective
`of chemistry, manufacturing, and controls. All deficiencies have been adequately resolved.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`/s/ M.D. Cooper, Ph.D.
`
`B. Endorsement Block
`
`Chemistry Reviewer:
`Pharmaceutical Assessment Lead:
`Branch Chief:
`Project Manager:
`
`C. CC Block
`
`Orig. NDA 22-387
`HFD-l 10/Division File
`
`Monica D. Cooper, Ph.D.
`Kasturi Srinivasachar, Ph.D.
`Ramesh Sood, Ph.D.
`Dan Brum, Pharm.D.
`
`Page 11 of 29
`
`

`

`\X Page(s) Withheld
`
`>Q Trade Secret / Confidential (b4)
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld Track Number: Chemistry Review Section—
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Monica Cooper
`7/22/2009 04:36:00 PM
`CHEMIST
`
`Ramesh Sood
`7/23/2009 10:10:19 AM
`CHEMIST
`
`

`

`CMC BRANCH CHIEF MEMORANDUM
`
`To:
`
`NDA 22—387
`
`From:
`Date:
`Drug:
`Route of administration:
`
`Ramesh Sood, Ph.D., Branch Chief, ONDQA
`17-Apr—2009
`Tyvaso (treprostinil) inhalation Solution
`Oral Inhalation
`
`Strength:
`Subject:
`
`06 mg/mL
`“Complete Response” recommendation for NDA 22-387
`
`Introduction: Treprostinil for inhalation (TyvasoTM) is being developed as an alternative to the
`subcutaneously and intravenously delivered treprostinil solution (Remodulin Injection, NDA 21—
`272, approved 22-May-2002). Treprostinil is the free acid of a synthetic tricyclic benzindene
`J
`analogue of prostacyclin. The proposed indication is for the treatment of pulmonary arterial
`hypertension (WHO Group I) in patients with New York Heart Association (NYHA) Class 1]] 4s
`1 symptoms.
`
`“(4)
`
`Drug Substance: Treprostinil is a chemically-synthesized small molecule with 5 stereocenters,
`manufactured as a single enantiomer.
`It is a white to cream—colored powder, which is practically
`insoluble in water. The chemistry, manufacturing and controls information (CMC) for the drug
`substance was referenced to the approved NDA 2] —272 for Remodulin injection. The NDA
`submission included the drug substance specification table and batch data for 5 recent lots. The
`current retest date for treprostinil drug substance is \ when stored at 2 — 8°C. A
`supplement for a new treprostinil drug substance manufacturing facility and synthetic process is
`currently pending (NDA 21-272/SCM—010). The previous treprostinil drug substance
`
`manufacturing site
`‘
`was closed in 2006. So at the time of writing this
`memorandum there is no approved drug substance source for this NDA. The approval ofthis
`NDA is contingent upon the approval ofthe currently pending supplemental application (NDA
`21-272/SCM-010).
`
`Drug product: Tyvaso (treprostinil) Inhalation Solution, 0.6 mg/mL, is intended for oral
`inhalation using the Optineb—ir, an ultrasonic, pulsed—delivery nebulizer. The Optineb-ir,
`manufactured by Nebutec Medicinal Products, is intended for single patient use in the
`administration oftreprostinilfor inhalation. The drug product is an aqueous solution of
`treprostinil (0.6 mg/m L) formulated with sodium chloride, sodium citrate, sodium hydroxide,
`and hydrochloric acid in water for injection. The exeipients are compendial and have been used
`in previously approved inhalation solutions. The formulation is identicaltothe currently
`
`marketed Remodulin injection (NDA 21-272), except for the absence of .
`-——-~
`in the current formulation (Tyvaso).
`
`11(4)
`
`Since treprostinil drug substance is practically insoluble in water, the treprostinil sodium salt was
`developed for use in the aqueous drug product formulation.
`It was noted that the treprostinil
`sodium salt is extremely difficult to handle since the solid is deliquescent. To facilitate handling
`of sodium salt of treprostinil, it is being generated. \ during the manufacture of the drug
`product.
`«WM.
`sodium hydroxide is added to the formulation to ensure that all
`
`“(4)
`
`

`

`of the treprostinil was converted to the sodium salt. The compounded solution is K‘—
`~~—'— ’ packaged into
`- —\
`ampoules with nominal fill volumes of2.9 mL
`and a pH of 6.0 — 7.2. The filled ampoules are further packaged into 4 ampoules per pouch. The
`quality of the drug product is ensured through appropriate in—process controls and acceptable
`final specification that include test and acceptance criteria for appearance, identification
`(HPLC/UPLC and IR), assay (HPLC/UPLC), related substances (HPLC), pH, particulate matter
`(<USP 788>), osmolality, fill weight, weight loss and sterility.
`
`hi4)
`
`The drug product solution is packaged in 2.9 mL ampoules, supplied as 4 ampoules within a foil
`pouch. One ampoule (2.9 mL) of treprostinil for inhalation should be transferred to the nebulizer
`for use each day. The solution remaining in the nebulizer after 1 day should be discarded. Since
`the drug is photosensitive, unused ampoules should be stored in the foil pouch until use.
`
`The requested 36—month expiration period is being assigned to this product when stored at
`controlled room temperature in LDPE ampoules inside foil pouches (i.e. protected from light).
`An in-use stability study of the drug product in the proposed Optineb nebulizer has not been
`completed and is currently pending.
`
`The facilities related to the manufacturing of the drug product and described in the NDA have
`been recommended for approval by the Office of Compliance. Categorical exclusion from an
`environmental assessment requested by the applicant is acceptable.
`
`An acceptable recommendation is made by the microbiology reviewer.
`
`Pending Issues: The drug product cannot be recommended for approval from CMC perspective
`in its current form because of the following pending issues.
`
`l. The approval of the new drug substance source/manufacturing is pending as per NDA 21—
`272/SCM—0l O.
`'
`
`2. Evaluation of the Optineb nebulizer was consulted to CDRH. CDRH recommendation is
`pending at this point. Information requests were sent to the applicant on 03-Mar-2009 and
`06-Apr—2009 that included several device issues related to the usability of the device. The
`applicant has not responded to these requests.
`Some additional labeling related issues will be resolved later during the labeling
`negotiations.
`
`b)
`
`Recommended action: The application cannot be recommended for approval in its current form
`from CMC perspective.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Ramesh Sood
`4/27/2009 10:15:46 AM
`CHEMI ST
`
`'
`
`

`

`
`
` CHEMISTRY REVIEW V
`
`NDA 22-387
`
`Tyvaso (treprostinil)
`Inhalation Solution -
`
`United Therapeutics Corporation
`
`Monica D. Cooper, Ph.D.
`ONDQA Pre—Marketing Assessment
`Division I/Branch I
`
`Reviewed for the Division of Cardiovascular
`
`and Renal Products, HFD-llO
`
`

`

`
`
` CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents ....... . ..........
`
`....... -......2
`
`Chemistry Review Data Sheet..................
`
`................4
`
`The Executive Summary
`
`.........................................
`
`...............................8
`
`1. Recommendations ....................................................................................................................... 8
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability ................................................................... 8
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable .............................................................................................. 8
`
`II. Summary of Chemistry Assessments ......................................................................................... 9
`
`A. Description of the Drug Product(s) and Drug Substance(s) .................................................................... 9 '
`
`B. Description of How the Drug Product is Intended to be Used .............................................................. 10
`
`C. Basis for Approvability or Not—Approval Recommendation ................................................................ 10
`
`III. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature ............................................................................................................................ 10
`
`B. Endorsement Block ............................................................................................................................... 10
`
`C. CC Block ............................................................................................................................................... 11
`
`Chemistry Assessment ......... ...........
`
`........ 12
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 12
`
`S
`
`P
`
`3.1
`
`82
`
`8.3
`
`8.4
`
`8.5
`
`8.6
`
`3.7
`
`P.l
`
`P2
`
`P3
`
`R4
`
`DRUG SUBSTANCE [treprostiniL United Therapeutics Corporation] .................................... 12
`General Information [treprostiniL UTC] ........................................................................................................ 12
`
`Manufacture [treprostini], UTC] ..................................................................................................................... 12
`
`Control of Drug Substance [treprostiniL UTC] ............................................................................................... 12
`
`Characterization [treprostinil, UTC]
`
`12
`
`Reference Standards or Materials [treprostini], UTC] ..................................................................................... 16
`
`Container Closure System [ti-eprostinil, UTC] ................................................................................................ 16
`
`Stability [h'eprostiniL UTC] ............................................................................................................................ 16
`
`DRUG PRODUCT [Tyvaso (treprostinil) Inhalation Solution] ................................................ 16
`
`Description and Composition of the Drug Product [Tyvaso (treprostinil) Inhalation Solution] ...................... 16
`
`Pharmaceutical Development [Tyvaso (treprostinil) Inhalation Solution] ...................................................... 17
`
`Manufacture [Tyvaso (treprostinil) Inhalation Solution] ................................................................................. 2]
`
`Control of Excipients [Tyvaso (treprostinil) Inhalation Solution] ................................................................... 29
`
`

`

`
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`CHEMISTRY REVIEW
`
`Control of Drug Product [Tyvaso (treprostinil) Inhalation Solution] ........................
`P5
`
`Reference Standards or Materials [Tyvaso (treprostinil) Inhalation Solution] ..................................
`P.6
`Container Closure System [Tyvaso (treprostinil) Inhalation Solution] ........................................................... 55
`P.7
`Stability [Tyvaso (treprostinil) Inhalation Solution] ....................................................................................... 60
`RB
`_ DRUG PRODUCT [Optineb-ir Nebulizer] ............................................................................... 68
`Pl
`Description and Composition of the Drug Product [Optineb-ir Nebulizer] ..................................................... 68
`P2
`Pharmaceutical Development [Optineb-ir Nebulizer] ..................................................................................... 73
`P3
`Manufacture [Optineb-ir Nebulizer]......... L...................................................................................................... 79
`P5
`Control ofDrug Product [Optineb-ir Nebulizer] ............................................................................................. 81
`P.6
`Reference Standards or Materials [Optineb-ir Nebulizer] ............................................................ 82
`
`> APPENDICES ................................................................................................................. 82
`
`AI
`Facilities and Equipment (biotech only).................................................................................... 82
`
`Adventitious Agents Safety Evaluation.......................................................................... 82
`A2
`
`Novel Excipients .............................................................................................................................. 82
`A3
`REGIONAL INFORMATION .....................................................................................
`82
`
`Executed Batch Records............................................................................................................... 82
`Comparability Protocols.................................................................................................................................. 83
`Methods Validation Package ........................................................................................................................... 83
`
`RI
`R2
`R3
`
`P
`
`A
`
`R
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 .................................. 83
`A.
`Labeling & Package Insert ........................................................................................................ 83
`B.
`Environmean Assessment Or Claim Of Categorical Exclusion .............................................. 89
`
`III.
`
`IV.
`
`Establishment Evaluation Report .................................................................................. 91
`
`List Of Deficiencies .......................................................................................................94
`
`

`

`
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`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`NDA 22—387
`
`REVIEW #:
`
`I
`
`'
`
`REVIEW DATE:
`
`23—Mar-2009
`
`REVIEWER:
`
`Monica D. Cooper, Ph.D.
`
`PREVIOUS DOCUMENTS:
`
`
`
`Document Date
`None
`
`
`SUBMISSION(S) BEING REVIEWED:
`
`
`
`Submissiongs) Reviewed
`Document Date
`
`Original Submission
`27—Jun—2008
`
`Amendment (N000 BC)
`03-Jul-2008
`
`Amendment (N000 BC)
`14—Aug—2008
`
`29-Oct-2008
`Amendment (N000 BC)
`
`Amendment (N000 BZ) 25-Feb—2009
`
`NAME & ADDRESS OF APPLICANT:
`
`Name
` United Thegpeutics Corporation
`
`
`One Park Drive, Suite 400
`Address
`
`
`
`Research Triangle Park, NC 27709
`
`
`resentative
`
`Dean Bunce, Sr. VP Regulatory Affairs
`
`Tele I hone
`919-485—8350 ext. 1218
`
`
`
`FAX Number
`919-313-1298
`
`
`
`8.
`
`DRUG PRODUCT NAME/CODE/TYPE:
`
`Prorieta Name
`
`
`
`Non—Prorieta Name S
`Code Names
`Chemist T e
`Submission Priori
`
`Page 4 of 94
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`CHEMISTRY REVIEW
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`Chemistry Review Data Sheet
`
`9.
`
`LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10.
`
`PHARMACOL. CATEGORY:
`
`Prostacyclin analog for pulmonary
`arterial hypertension
`
`11. DOSAGE FORM:
`
`Sterile Solution
`
`12.
`
`STRENGTH/POTENCY:
`
`0.6 mg/mL
`
`13.
`
`ROUTE OF ADMINISTRATION:
`
`Inhalation
`
`14.
`
`RX/OTC DISPENSED: _X_Rx
`
`OTC
`
`15.
`
`
` SPOTS SPECIAL PRODUCTS ON—LlNE TRACKING SYSTEM);
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Names:
`
`(1) Acetic acid, [[(1R,2R,3aS,9a.S')—2,3 ,3 a,4,9,9a—
`hexahydro-Z-hydroxy- 1 -[(3S)-3 -hydroxyoctyl]—
`lH—benzMinden-S-ylbxy}
`(2) [(1 R,2R,3aS,9aS)—2—Hydroxy- l -((3S)—3-
`hydroxyoctyl)-2,3,3 a,4,9,9a—hexahydro— 1H—
`cylopent[b]naphthalen-5 -y1]oxy]acetate
`
`US Adopted Name (USAN):
`Laboratory Codes:
`
`treprostinil
`UT—15, LRX-l 5, 15AU81
`
`Page 5 of 94
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`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`OAcozH
`
`
`
`Chemical Formula:
`Molecular Weight:
`CAS Number:
`
`.
`
`C23H3405
`390.51
`81846-19-7
`
`17.
`
`RELATED/SUPPORTING DOCUMENTS:
`
`V DMFs:
`A.
`
`
`j '
`HOLDER
`
`ITEM
`REFERENCED
`
`'
`
`2
`
`STATUS
`
`DATE RIWIE-T
`COMPLETED
`'
`
`I
`
`Adequate
`
`24-Apr-2008 (G. Lunn)
`
`1 Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I DMF
`’ 3 —— Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not
`need to be reviewed)
`
`Page 6 of 94
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`CHEMISTRY REVIEW
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`Chemistry Review Data