CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
` APPLICATION NUMBER:
`
`
` 208276Orig1s000
`
` PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

`
` QUALITY ASSESSMENT
`
`
`
`
`Recommendation: APPROVAL
`
`
`
`
`NDA 208276
`
`Resubmission After 2017 Complete Response
`
`
`
`Review #1
`
`
`
`
`
` Drug Name/Dosage Form Treprostinil Injection
`
`
` Strength
` 10 mg/mL
`
` Route of Administration
`Intravenous
`
`
` Rx/OTC Dispensed
` Rx
` United Therapeutics Corporation
` Applicant
`
`
` US agent, if applicable
`
` n/a
`
`
`
`
`
`
`
`
`
`
`
` SUBMISSION(S)
`
` REVIEWED
`
` Amendment
`
` Resubmission
`
`
`
`
`
`
` DISCIPLINE
` Drug Substance
`
`
` Drug Product
`Process
` Environmental Analysis
`
` Microbiology
`
` Facility
`
` Regulatory Business
`
` Process Manager
` Application Technical Lead
`
`
`
`
`DOCUMENT
`
` DATE
`19-JUN-2018
`30-JAN-2018
`
`
`
` DISCIPLINE(S) AFFECTED
`
`
`
` Quality Labeling
`
` All
`
`Quality ReviewTeam
`
`
`
` REVIEWER
` Thomas Wong
`
`
`
` OPQ OFFICE
`
` ONDP
`
` John Metcalfe
`
` Christina Capacci-Daniel
`
` Grafton Adams
`
`
`
`
`
` Wendy Wilson-Lee
`
`
` OPF
`
` OPF
` OPRO
`
`
`
`
` ONDP
`
`OPQ-XOPQ-TEM-0001v03 Page 1 of 4
`
`
`
`
`
`
`
`Effective Date: 18 Feb 2016
`
`
`
`Reference ID: 4409052
`
`

`

`
` QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`
` Quality Review Data Sheet
`
`
`
`
`
`
`
`
`
`
`
` 1. RELATED/SUPPORTING DOCUMENTS
`
`
`
`A. DMFs:
`
`None.
`
`
`
`
` B. Other Documents: IND, RLD, or sister applications
`
`DOCUMENT
`
` APPLICATION NUMBER
`21272
`
`
`
`
` DESCRIPTION
`
` Treprostinil Injection
` Implantable Pump Device
`
`
`
`
`
` NDA
`
` PMA
`
`
`
` 2. CONSULTS
`
` No consults requested.
`
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v03 Page 2 of 4
`
`
`
`
`
`
`
`Effective Date: 18 Feb 2016
`
`
`
`Reference ID: 4409052
`
`(b) (4)
`
`

`

`
`
` I. Recommendations and Conclusion on Approvability
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`Executive Summary
`
`
`
` OPQ recommends APPROVAL of NDA 208276 for Remodulin (treprostinil) Injection,
`
`
`
`
`
`
`
`
`
`10 mg/mL drug product with the implantable infusion pump.
`
`
`
`
`Summary of Quality Assessments
`
`
`II.
`
`
`A.
`
`
`
` Product Overview
`
` Proposed Indication(s) including
`
`
` Intended Patient Population
` Duration of Treatment
`
`
`
` Maximum Daily Dose
` Alternative Methods of
`
`
`
` Administration
`
`
`
`
`
`
`
` Treatment of pulmonary arterial hypertension
`
`
`
` 16 weeks
`
` 2.5 ng/kg/min per week
`
`
`
`
` Initial administration will be via external infusion
`
` system until implantation.
`
`
`
`
`
`
`
`
`
` NDA 208276 seeks approval of the use of Remodulin (treprostinil) Injection with a fully
`
` intravenous delivery of
`the chronic
`implanted, programmable
`infusion system
`for
`
` treprostinil. The NDA is a sister application to Medtronic, Inc. Premarket Approval
`
`
`
` Application (PMA) P140032 for the device components of the implantable system. The
`
`
`
`
`
` applicant references approved NDA 21272 for all relevant chemistry, manufacturing, and
`
`
` controls (CMC) information for the treprostinil drug substance and drug product. The
`
`
` chemical and physical compatibility of the drug product with the implantable system was
`
`
`
` reviewed under PMA P140032.
`
`
`
`
` This NDA was initially submitted in February 2015. Due to Refuse to File status, the
`
` applicant resubmitted this NDA in December 2015. The December 2015 resubmission
`
`
`
`
` was recommended for Complete Response due to insufficient data to evaluate the risk of
`
`
`
`
` potential patient exposure to microbial contaminants when the treprostinil injection drug
`
`
`
`
`
`
` product is used in the proposed implantable pump system.
`
`
`
`
` In December 2016, the applicant resubmitted this NDA, addressing all deficiencies.
`
` Changes provided in the December 2016 resubmission were in response to the Complete
`
`
`
` Response Letter deficiencies (October 2016) and the elimination of the 2.5 mg/mL and
`
`
`
`5.0 mg/mL drug product strengths
` in the initial filing and first resubmission
`
`
`
`
`listed
` (December 2015). The applicant retained only the 10.0 mg/mL strength for proposed
`
`
`
`the
`commercialization and use with
` the December 2016
`
`implantable pump
`in
`
`
`
` resubmission. There are no changes made to any of the CMC information filed in the
` referenced NDA 21272. An approval recommendation was made by OPQ at the end of
`
`
`
`
`
` the review cycle. However, due to deficiencies identified under the PMA and insufficient
`
`
`
`
` human factors data, a Complete Response letter was issued (June 2017).
`
`
`
`
`
`
`Page 3 of 4
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`
`
`
`
`
`Effective Date: 18 Feb 2016
`
`
`
`Reference ID: 4409052
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`
` The 2018 resubmission did not include any new CMC information. All referenced CMC
`
`
`
`
` Therefore, OPQ
`
`information under NDA 21272 remained unchanged as well.
`
`
`recommends approval of NDA 208276.
`
`
`
`B. Quality Assessment Overview
`
`
`
`
`It is a white to
`Treprostinil is a tricyclic benzindene analog of prostacycline (PGI2).
`
`
`
`
`
`
`
`cream-colored powder, and is insoluble in water. There are five chiral centers in
`
`
` treprostinil and the drug substance is a single enantiomer. The retest date of the drug
`
`
`
`
`
`
`substance is
` months
`
`.
`
`
`
`
`
`The drug product, Remodulin® (treprostinil injection), is a sterile, 10 mg/mL, ready to
`
`
`intravenous
`use, solution packaged
`injection administered by
`in a 20-mL vial for
`
`
`
`
`continuous infusion. The vial and carton labels for the 10 mg/mL strength include the
`
`
`
`following statement: “When used with
`the Implantable System for Remodulin, no
`
`
`
`
`
`
`dilution is required.” Other strengths of Remodulin are approved but will not be indicated
`
`
`
`
`
`
`for use with the implantable pump system. Since the drug in the newly proposed drug-
`
`device combination product is the identical drug as the approved Treprostinil injection in
`
`NDA 021272, a Biopharmaceutics review is not needed. An expiration dating period
`
`
`
`
` months will be granted for the drug product when stored at 25ºC. The
`of
`
`
`
`
`categorical exclusion is granted based on compliance with both 21 CFR 25.31(a) and
`
`25.15 (d).
`
`
`
`
`
`
`
` There appears to be no significant or outstanding risks to the manufacturing process or
` final product based on the individual and composite evaluation of the listed facility’s
`
`
`
`
`
`
` inspection results, inspectional history, and relevant experience. There is no change to the
`
`
`
`
` proposed facilities, responsibilities, or assessment outcomes in the resubmission. All
`
`
`facilities are acceptable to support approval of NDA 208276.
`
`
`
`
`
`
`
`
`
`
`
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`
`
`
`None.
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`
`
`
`
`Page 4 of 4
`
`
`
`Effective Date: 18 Feb 2016
`
`
`
`
`
`Reference ID: 4409052
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Wendy
`Wilson- Lee
`
`Digitally signed by Wendy Wilson- Lee
`Date: 7/09/2018 02:41:38PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Reference ID: 4409052
`
`
`

`

`CHAPTERS: Primary Quality Assessment
`
`
`
` History of submission:
`
`
`
`
`
`
`
`
`Initial submission and first resubmission: This NDA was initially submitted in 2/13/2015.
`
`
`
`
`
`
`
`Due to Refuse to File status, the applicant resubmitted this NDA in 12/16/2015 (Seq.
`
`
`
`
`
`
`#0007). The applicant references their approved NDA (NDA 21272) and all
`
`
`
`
`
`
`
`subsequent supplements for all relevant drug substance and drug product CMC
`
`
`
`
`information in both submissions. The resubmission dated 12/16/2015 was
`
`
`
`
`recommended for Complete Response. One of the reasons for CR is due to
`
`
`
`
`
`
`
`
`insufficient data to evaluate the risk of potential patient exposure to microbial
`
`
`
`
`contaminants when the Remodulin drug product is used in the proposed implantable
`pump system.
`
`
`
`
`Second resubmission: In 12/15/2016 (Seq. #0014), the applicant resubmitted this NDA to
`
`
`
`
`
`
`
`address all deficiencies. There are no changes made to any of the CMC information
`
`
`
`
`
`filed in the referenced NDA 21272. The only changes provided in this resubmission
`
`are:
`
`
`
`
`
`
`
`
`Provided justification for insufficient microbial data to support the use of the
`-
`
`proposed implantable pump system.
`
`
`
`
`
`
`- Eliminated the strengths of 2.5 mg/mL and 5.0 mg/mL proposed in the initial
`
`
`
`
`
`
`filing and resubmission dated 12/16/2015 and retains only 10.0 mg/mL for
`
`
`
`commercialization in this submission dated 12/15/2016.
`
`
`
`
`
`
`This second resubmission was recommended for Complete Response on 6/2/17 due
`
`to:
`
`-
`
`
`
`
`
`
`
`
`
`A Not Approvable letter on the PMA for the device component on March 11,
`2016.
`
`
`
`
`
`
`Insufficient human factors data to demonstrate that the Implantable System for
`
`
`
`
`Remodulin (ISR) user interface supports safe and effective use for the intended
`
`
`users, uses and use environments.
`
`
`
`
`Third resubmission: In 1/30/2018 (Seq. #0019), the applicant resubmitted this NDA to
`
`address the above deficiencies.
`
`
`Evaluation and Recommendation:
`
`
`
`
`
`
`
`
`
`CMC information on both drug substance and drug product is found adequate and this
`
`
`NDA is recommended for approval.
`
`
`
`
`-
`
`
`
`Reference ID: 4409052
`
`2 Pages have been Withheld in Full as
`B4(CCI/TS) Immediately Following this Page
`
`

`

`
`
` QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`
` Expiry Dating (NDA 21272 Supplement #14 dated 12/30/2010):
`
`
`
`
`
` In Supplement #14, the applicant stated that the current shelf life is months and
`
`
`
`
`
` proposes to continue to use the established shelf life of months based on the primary
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and supporting stability data contained in this submission. This supplement was
`
`approved.
`
`Evaluation: There has been no change in the drug product information in the cross-
`
`
`
`
`
`
`
`
`
`
`
`referenced NDA 21272 since the last resubmission of this NDA 208276
`
`
`
`
`
`(Seq. # 0014) dated 12/16/2015. The review of Seq. #0014 was found
`
`adequate.
`Recommendation: This NDA 208276 is recommended for approval.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4409052
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
` CHAPTER III: Environmental Analysis
`
`
`
`
`
`
` Firm has submitted a request on 2/9/2017 for a categorical exclusion under 21 CFR 25.31
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` (a). And further states to their knowledge there exist no extraordinary circumstances [21
` CFR 25.15(d)], and no increased use of active moiety. Since there is no change in the
`
`
`
`
`
`
`
`
`
`
` proposed commercial batch size, manufacturing process, patient populations and
` additional indication, it is not necessary to resubmit the request for a categorical
`
`
`
`
`
`
`
`
`
` exclusion.
`
`
` Evaluation: Acceptable
` Recommendation: This NDA 208276 is recommended for approval.
`
`
`
`
`
`
`
`
`
`Reference ID: 4409052
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`CHAPTER IV: Labeling
`
` There is no change in labeling from the Package Insert and container labels since the last
`
`
`
`
`
`
` resubmission (Seq. #0014).
`
`
`
` Evaluation: Acceptable
`
` Recommendation: This NDA 208276 is recommended for approval.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4409052
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
` CHAPTER V: Process
`
`
`
` There is no change made to the manufacturing process.
`
`
`
`
`
`
`
`Reference ID: 4409052
`
`
`

`

`Thomas
`Wong
`
`Wendy
`Wilson- Lee
`
`Digitally signed by Thomas Wong
`Date: 5/09/2018 11:30:28AM
`GUID: 508da7230002a25bbe89865c0c14bc44
`
`Digitally signed by Wendy Wilson- Lee
`Date: 5/09/2018 02:26:32PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Reference ID: 4409052
`
`4 Pages have been Withheld in Full as B4(CCI/
`TS) Immediately Following this Page
`
`

`

`Wendy
`Wilson- Lee
`
`Digitally signed by Wendy Wilson- Lee
`Date: 7/09/2018 04:14:14PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Reference ID: 4409052
`
`
`