CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`214324Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSMENT
`
`NDA 214324
`TYVASO (Treprostinil) Dry Powder Inhaler,
`16 mcg, 32 mcg, 48 mcg, 64 mcg
`
`Integrated Quality Review # 2
`
`Recommendation: Approval
`
`RO
`
`Applicant
`
`United Therapeutics Corp.
`
`Submissions (s) Reviewed
`
`NDA214324 (Class I Resubmission)
`
`Quality Review Team
`
`
`ONDP/DNDPIII/NDPB5
`
`DISCIPLINE|REVIEWER|BRANCH/DIVISION
`Drug Substance
`ONDP/DNDAPI/NDB3
`Drug Product/Environmental
`ONDP/DNDPII/NDPB5
`Assessment (EA)
`
`Process and Facility Alexander Gontcharov|OPQ/OPMA/DPMAITII/PMB7
`PamChteee|"ONDPDBEBS
`
`Akm Khairuzzaman
`
`Galerie|OPROTDRDPAT
`
`Application Technical Lead (ATL)
`
`Link for Integrated Quality Review # 1:
`https://darrts.fda.gov/darrts/ViewDocument?documentId=090140af8061de0c&showAsPdf=true
`
`1|Page
`
`Reference ID: 4929518
`
`

`

`QUALITY ASSESSMENT
`Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From the chemistry, manufacturing, and controls (CMC) perspective, NDA 214324is
`recommended for approval. Aspart of this action, an expiration period of 18 monthsfor the
`product, when refrigerated at controlled temperature of 2°C to 8°C (36°F to 46°F) in the
`commercial packaging is granted. The drug product in unopened blister cards/strips is permitted to be
`stored up to 5 weeks at room temperature.
`
`B. Recommendation on Post-Marketing Commitments (PMCs), Agreements, and/or Risk
`ManagementSteps, if Applicable
`
`None.
`
`Il.
`
`Background, and Quality Assessment Summary
`
`This is the second integrated quality assessment for this NDA, which specifically addresses the
`facility related issues that were communicated to the Applicant, United Therapeutics Corporation
`via a complete response (CR)letter dated 10/15/2021. The Agency issued a CR because of an
`official action indicated (OAI) classification for the drug substancetesting facility,
`On 12/23/2021, the Applicant resubmitted the NDA (class I resubmission). The
`resubmitted NDA indicated withdrawal of the
`©) and its replacement with two
`alternate drug substancetesting facilities, namely,
`() (4)
`(4) and United Therapeutics Corporation, Silver Spring, MD. These two newfacilities
`will now beresponsible to conduct the drug substancetesting for © content, endotoxin, and
`microbiallimits. All these three compendial (USP) tests and their methods were appropriately
`transferred. The tests were conducted on the new drug substancebatchesat these newtesting sites.
`The testing data demonstrated acceptable results. The office of Pharmaceutical Manufacturing
`Assessment (OPMA/OPQ) has recommendedapproval for these newly listed facilities. Therefore,
`the complete response issues are now adequately resolved from quality perspective and the NDA is
`now recommended for approval.
`
`(0) (4)
`
`A. Drug Substance Quality Summary
`
`The revised information regarding the drug substance testing provided in this NDA resubmissionis
`found to be adequate by the drug substance reviewer(please see link below). The updated analytical
`testing information andbatch data from the new
`®) contenttesting site,
`"OM
`is also found to be acceptable. Stability data support a retest period of) months
`for the Treprostinil drug substance whenstored in
`4). For
`details, refer to the drug substance review chapters via the links provided below:
`Review # 1: https://panorama.fda.gov/document/view?ID=60faf56900105cfd102fb56e641a3915
`Review # 2: NDA 214324Treprostinil Resub DJJ review (fda.gov)
`
`B.1. Product Design, and Release Specification: There is no change in product design andrelease
`specification. For details, refer to the first integrated quality assessmentvia the link provided on page
`lof this review.
`
`2|Page
`
`Reference ID: 4929518
`
`

`

`QUALITY ASSESSMENT
`
`B.2. Manufacturing: The details of manufacturing processandits controls are provided in DMF #
`4) The DMF hasbeen reviewed and found to be adequate to support this NDA.Please referto
`the drug product manufacturing review chapter via the link provided below:
`https://panorama.fda.gov/task/view?ID=613f5211001f11f930b4b0dac4e0d7c8
`
`B.3. Microbiological Aspects: Please refer to the first integrated quality assessmentvia the link
`provided below:
`https://darrts.fda.gov/darrts/ViewDocument?documentId=090140af8061de0c&showAsPdf=true
`
`B.4. Biopharmaceutics Aspects: Not relevant for this drug product. Please refer to the
`biopharmaceutics memovia the link provided below.
`https://panorama.fda.gov/document/view?ID=6 1 2cfae70007d877404348 14e7a82037
`
`B.5. Container Closure System: There is no change in the container closure system. Please referto
`the first integrated quality assessmentvia the link provided below:
`https://darrts.fda.gov/darrts/ViewDocument?documentId=090 140af8061deOc&showAsPdftrue
`
`B.6. Product Stability, Expiration Date & Storage Conditions. The Applicant’s proposed shelf
`life of 18 months with recommendedstorage condition of 2°C to 8°C (36°F to 46°F) is acceptable.
`The drug product in unopenedblister cards/strips is permitted to be stored up to 5 weeks at room
`temperature. . Fordetails, refer to the first integrated quality assessmentvia the link provided below:
`https://darrts.fda.gov/darrts/ViewDocument?documentId=090140af8061de0c&showAsPdf=true
`
`C. Assessment of Manufacturing Facilities: As indicated below (Panoramafacility status: Overall
`Manufacturing Inspection Recommendation (fda.gov)), the office of Pharmaceutical Manufacturing
`Assessment (OPMA) has recommendedapprovalforall the facilities listed in this NDA
`resubmission..
`
`(b) (4)
`
`The details of facility review for this NDA resubmission can be foundvia the links provided below:
`Review # 1: https://panorama.fda.gov/document/view?ID=6 1 4a7 1cd00f15ea352c925622ae847ff
`Review # 2 (NDA-resubmission):
`https://panorama.fda.gov/task/view?ID=6 1 ddbfb20013e823a019fbeSaa7bc463
`
`3|Page
`
`Reference ID: 4929518
`
`

`

`QUALITY ASSESSMENT
`
`D. The applicant has claimed categorical exclusion from the environmental assessment requirements
`under 21 CFR Part 25.31(b) on the basis that no extraordinary circumstances exist under 21 CFR
`25.15(d) that would warrant preparation of an environmental assessment. The applicant’s claim of
`categorical exclusion is acceptable.
`
`E. OPQ's all labeling recommendations are reflected in the most recent version of the product
`labeling.
`
`OVERALL ASSESSMENT AND SIGNATURES
`
`Application Technical Lead (ATL) Assessment and Signature:
`
`Based on integrated quality review by the Office of Pharmaceutical Quality (OPQ), manufacturing
`facilities-related deficiencies are now adequately resolved. Therefore, from an OPQ perspective,
`this NDA is recommended for approval.
`
`Date: 2022.01.31 08:03:50 -05'00"
`
`Akm Khairuzzaman, Ph.D.
`A lication Technical Lead ATL
`ONDP/DNDPIII/NDPB5S
`
`Akm
`fm
`KhairuzZaman -S
`
`Digitally signed by Akm Khairuzzaman -S
`DN: C=US, 0=U.S.Government,ou=HHS,
`ou=FDA, ou=People,
`0.9.2342.19200300.100.1.1=2000423292,
`«nakmratruzzaman-s
`
`4|Page
`
`Reference ID: 4929518
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`AKM KHAIRUZZAMAN
`01/31/2022 08:19:37 AM
`OPQ Team Recommends an Approval for this NDA
`
`MOHAN K SAPRU
`01/31/2022 10:33:54 AM
`
`Reference ID: 4929518
`
`

`

`QUALITY ASSESSMENT
`
`NDA 214324
`TYVASO(Treprostinil) Dry Powder Inhaler,
`16 mcg, 32 mcg, 48 mcg, 64 mcg
`
`Integrated Quality Review
`Recommendation: A Complete Response (CR)
`
`TYVASO(Treprostinil) DPI™ / Dry PowderInhaler
`Drug Name/Dosage Form
`[Strength=|0g, 32 meg, 48 me, OF meg
`
`Rx/OTCDispensed
`Applicant
`
`United Therapeutics Corp.
`
`Submissions (s) Reviewed
`
`NDA 214324, andall the submitted CMC amendments
`
`DISCIPLINE
`
`Quality Review Team
`REVIEWER
`
`BRANCH/DIVISION
`
`Akm Khairuzzaman
`
`ONDP/DNDAPI/NDB3
`ONDP/DNDPIII/NDPBS5
`
`
`
` an Adequate
`
`Drug Substance
`Drug Product/Environmental
`Assessment (EA)
`
`Process and Facility Alexander Gontcharov|OPQ/OPMA/DPMAIII/PM
`B7
`ONDP/DB/BB3
`OPRO/ DRBPMI
`
`Biopharmaceutics
`RBPM
`
`Parnali Chatterjee
`Grafton Adams
`
`Application Technical Lead (ATL)
`
`Akm Khairuzzaman
`
`ONDP/DNDPIII/NDPBS
`
`Quality Review Data Sheet
`
`ITEM
`REFERENCED
`
`STATUS
`
`DATE OF
`REVIEW
`COMPLETED
`9/15/2021
`
`COMMENTS
`
`Reviewsare in
`Panorama
`submitted by
`different OPQ
`sub-offices
`
`Other Documents:
`Type B Pre NDAwritten responses, dated November19, 2020
`Type C meeting minutes, dated December 17, 2019
`Type C meeting minutes preliminary comments, dated January 06, 2019
`Type B Pre-NDA meeting written response, dated July 28, 2017
`
`1|Page
`
`Reference ID: 4872189
`
`

`

`QUALITY ASSESSMENT
`
`I. Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`Based on integrated quality review by the Office of Pharmaceutical Quality (OPQ), manufacturing
`facilities-related deficiencies remain currently unresolved because ofan official action indicated
`(OAI) for the drug substancetesting facility,
`a ((
`uy
`resulting in ‘withhold’ recommendation for the facility. Therefore, from an OPQ perspective, this
`NDAis not deemed ready for approval in its present form until the above-mentionedfacility related
`issue is resolved. As such, OPQ recommends a Complete Response (CR) action from a product
`quality perspective.
`
`B. Recommendation on Post-Marketing Commitments (PMCs), Agreements, and/or Risk
`ManagementSteps, if Applicable
`
`None.
`
`II.
`
`Background, and Quality Assessment Summary
`
`The applicant, United Therapeutics Corporation, has sought U.S. marketing approval for TYVASO
`(Treprostinil) Dry PowderInhaler in accordance with Section 505(b)(1) of the Federal Food, Drug,
`and Cosmetic Act. Treprostinil is a prostacyclin analogue. Its major pharmacologic actions are
`direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition ofplatelet
`aggregation. The drug productis a drug-device combination product which is comprised of single-
`use cartridges containing a dry powderformulation of treprostinil inhalation powder (Tyvaso
`DPI™)at 16, 32, 48, or 64 mcgoftreprostinil per cartridge and a small, portable, reusable, breath-
`powered, dry powderinhaler. This combination productis a change in dosage form for treprostinil
`from a solution for oral inhalation (Tyvaso® [treprostinil] Inhalation Solution, NDA 022387) to a
`dry powderfor oral inhalation. All CMC information on this new drug product formulation of
`treprostinil is referenced to DMF (#
`©® The DMFhas been reviewedbydifferent disciplines
`within the Office of Pharmaceutical Quality (OPQ) and foundto be acceptable. The proposed
`control strategies for the drug product manufacturing are adequate to ensure consistent drug product
`quality regarding identity, assay, purity, dissolution, content uniformity,
`©@microbial
`content, and stability. The proposed 18-monthshelf life is supported by sufficient stability data and
`found to be acceptable. Whileall of the listed facilities were found to be acceptable, note that one of
`the facilities (drug substance testing laboratory) is currently on “withhold”status.
`
`A. Drug Substance Quality Summary
`
`Treprostinil is a small molecule and has been well characterized using state-of the-art methods with
`regard to its structure and physicochemical characteristics. The drug substance reviewer concluded
`that the manufacturing process of the drug substance has been described in sufficient detail and the
`proposedspecification is adequate. Analytical methodsto control the quality of the drug substance
`are adequate. Stability data support retest of {} monthsfor the Treprostinil drug substance when
`
`z|Page
`
`Reference ID: 4872189
`
`

`

`
`
`stored in
`chaptervia the link provided below:
`https://panorama.fda.gov/document/view?ID=60faf56900 1 05cfd102fb56e641a3915
`
`©® Please refer to the drug substance review
`
`B.1. Product Design, and Release Specification:
`
`The drug product is a drug-device combination product which is comprised of single-use cartridges
`containing a dry powderformulation of treprostinil inhalation powder (Tyvaso DPI™)at 16, 32, 48,
`or 64 mcg oftreprostinil per cartridge and a small, portable, reusable, breath-powered, dry powder
`inhaler. All chemistry, manufacturing, and control (CMC) information on this new drug product
`formulation of treprostinil is referenced to DMF #
`©@® The DMFhas been reviewed and found
`to be adequate to support this NDA.Please refer to the drug product review chaptervia the link
`provided below:
`https://panorama.fda.gov/document/view?ID=6 13f43d6001d52c212db4661928f7dea
`
`B.2. Manufacturing: The manufacturing process andits controls information are provided in the
`DMF# ©® The DMFhas been reviewed and found to be adequate to support this NDA.Please
`refer to the drug product manufacturing review chaptervia the link provided below:
`https://panorama.fda.gov/task/view?ID=613f5211001f11f930b4b0dac4e0d7c8
`
`B.3. Microbiological Aspects: The drug product is adequately controlled for inclusion of
`microbiological testing in the drug product specification. Please refer to the microbiology review
`chapter (provided under the DMF #
`®©® via the link provided below:
`https://panorama.fda.gov/task/view?ID=5bc9573700Secff95a53bdacbced50d2
`
`B.4. Biopharmaceutics Aspects: Not relevant for this drug product. Please refer to the
`biopharmaceutics memovia the link provided below.
`https://panorama.fda.gov/document/view?ID=6 1 2cfae70007d877404348 1 4e7a82037
`
`B.5. Container Closure System: Treprostinil Inhalation Powderis packed into a single dose
`cartridge cup and sealed byalid. The cartridge cups and lids are made of
`Thefilled cartridges are packagedinto blisters {© sealed with aluminum lid. Each blister card
`contains seven (7) blisters strips separated by perforations for a total of 28 cartridges. The cartridge
`cup
`
`containing the inhalation powderis inserted into the inhalation device prior to administration. he productstability data indicate suitability of the proposed container closure
`
`the intended use. All CMC information regardingthe container closure system is
`system for
`provided under the DMF # © which is found to be adequate to support this NDA.
`
`
`
`B.6. Product Stability, Expiration Date & Storage Conditions. The applicant provided data from
`stability studies from eight (8) registration batches stored in the intended commercial packaging
`under long-term conditions (S°C + 3°C) for up to 12 months, and accelerated conditions (25°C +
`2°C/60% RH) for 6 months. Additional stability data including in-usestability and stress condition
`stability data were also provided. Note that all stability data and associated reports are provided in
`the DMF #
`©® which has been found to be adequate to support this NDA.All these stability
`data indicate no changesin the drug product with respect to any of the quality attributes. Therefore,
`
`3|Page
`
`Reference ID: 4872189
`
`

`

`| QUALITY ASSESSMENT | ea
`|
`
`the applicant’s proposed shelf life of 18-month with recommended storage condition of 5°C is
`acceptable.
`
`C. Assessment of Manufacturing Facilities: The office of Pharmaceutical Manufacturing
`Assessment (OPMA)has recommended a “Withhold” under the overall manufacturing
`
`recommendation for this NDA as follows (copied from Panorama facility status).
`
`Note that only one particular facility listed above (ie.,)=) has OAT
`classification due to compliance issue. This particular facility is a testing laboratory for the drug
`substance. All other listed facilities are GMP compliant. The facility review can be foundvia the link
`provided below: _
` bALLIJO.// VAI GALI. 1
`
`D. The applicant has claimed categorical exclusion from the environmental assessment requirements
`under 21 CFR Part 25.31(b) on the basis that no extraordinary circumstances exist under 21 CFR
`25.15(d) that would warrant preparation of an environmental assessment. The applicant’s claim of
`categorical exclusion is acceptable.
`
`E. OPQ's all labeling recommendations are reflected in the most recent version of the product
`labeling.
`
`4|Page
`
`Reference ID: 4872189
`
`

`

`QUALITY ASSESSMENT
`
`OVERALL ASSESSMENT AND SIGNATURES
`
`Application Technical Lead (ATL) Assessment and Signature:
`
`Basedonintegrated quality review by the Office of Pharmaceutical Quality (OPQ), manufacturing
`facilities-related deficiencies remain currently unresolved because of an official action indicated
`(OAI)classification for the drug substancetesting facility,
`ooo
`©)Therefore, from an OPQ perspective, this NDA is not deemed ready for approval in
`its present form until the above-mentionedfacility’s OAI status is changed to GMP complaint. As
`such, OPQ recommends a Complete Response (CR) action from a product quality perspective
`along with the following CR deficiency.
`
`CR Deficiency for the Applicant:
`
`oan for
`©® facility (
`During a recent inspection of the
`this application, our field investigator conveyed deficiencies to the representative of the
`facility. As a result of this inspection, FDA hasclassified this facility as Official Action
`Indicated (OAT) on
`®™® for drug CGMP.Satisfactory resolution of these
`deficiencies is required before this application may be approved.
`
`Date: 2021.10.14 10:39:54 -0400'
`
`Akm Khairuzzaman, Ph.D.
`Application Technical Lead (ATL
`ONDP/DNDPII/NDPBS5
`
`eeene
`Akm
`SOO=2000423292,
`e
`Kh a l fuZZa mM a al -S cn=Akm Khairuzzaman -S
`
`5|Page
`
`Reference ID: 4872189
`
`

`

`Signature Page 1 of 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This is a representation of an electronic record that was signed
`
`
`
`
`
`
`
`
`
`electronically. Following this are manifestations of any andall
`
`
`
`
`
`
`electronic signatures for this electronic record.
`
`
`
`/s/
`
`
`
`
`
`
`AKM KHAIRUZZAMAN
`
`
`
`10/14/2021 10:46:50 AM
`
`
`
`
`
`
`
`
`
`
`
`
`
`Updated IQA. A Complete Response (CR) is recommended from OPQ duetofacility issue.
`
`
`
`
`
`
`MOHAN K SAPRU
`
`
`10/14/2021 10:52:38 AM
`
`
`
`Reference ID: 4872189
`
`
`
`
`
`

`

`QUALITY ASSESSMENT
`
`NDA 214324
`TYVASO(Treprostinil) Dry Powder Inhaler,
`16 mcg, 32 mcg, 48 mcg, 64 mcg
`
`Integrated Quality Review
`Recommendation: A Complete Response (CR)
`
`TYVASO(Treprostinil) DPI™ / Dry PowderInhaler
`Drug Name/Dosage Form
`[Strength=|0g, 32 meg, 48 me, OF meg
`
`Rx/OTCDispensed
`Applicant
`
`United Therapeutics Corp.
`
`Submissions (s) Reviewed
`
`NDA 214324, andall the submitted CMC amendments
`
`DISCIPLINE
`
`Quality Review Team
`REVIEWER
`
`BRANCH/DIVISION
`
`Akm Khairuzzaman
`
`ONDP/DNDAPI/NDB3
`ONDP/DNDPIII/NDPBS5
`
`
`
` ahi Adequate
`
`Drug Substance
`Drug Product/Environmental
`Assessment (EA)
`
`Process and Facility Alexander Gontcharov|OPQ/OPMA/DPMAIII/PM
`B7
`ONDP/DB/BB3
`OPRO/ DRBPMI
`
`Biopharmaceutics
`RBPM
`
`Parnali Chatterjee
`Grafton Adams
`
`Application Technical Lead (ATL)
`
`Akm Khairuzzaman
`
`ONDP/DNDPIII/NDPBS
`
`Quality Review Data Sheet
`
`ITEM
`REFERENCED
`
`STATUS
`
`DATE OF
`REVIEW
`COMPLETED
`9/15/2021
`
`COMMENTS
`
`Reviewsare in
`Panorama
`submitted by
`different OPQ
`sub-offices
`
`Other Documents:
`Type B Pre NDAwritten responses, dated November19, 2020
`Type C meeting minutes, dated December 17, 2019
`Type C meeting minutes preliminary comments, dated January 06, 2019
`Type B Pre-NDA meeting written response, dated July 28, 2017
`
`1|Page
`
`Reference ID: 4865581
`
`

`

`QUALITY ASSESSMENT
`
`I. Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`Based on integrated quality review by the Office of Pharmaceutical Quality (OPQ), manufacturing
`facilities-related deficiencies remain currently unresolved because ofan official action indicated
`(OAI) for the drug substancetesting facility,
`a ((
`uy
`resulting in ‘withhold’ recommendation for the facility. Therefore, from an OPQ perspective, this
`NDAis not deemed ready for approval in its present form until the above-mentionedfacility related
`issue is resolved. As such, OPQ recommends a Complete Response (CR) action from a product
`quality perspective.
`
`B. Recommendation on Post-Marketing Commitments (PMCs), Agreements, and/or Risk
`ManagementSteps, if Applicable
`
`None.
`
`II.
`
`Background, and Quality Assessment Summary
`
`The applicant, United Therapeutics Corporation, has sought U.S. marketing approval for TYVASO
`(Treprostinil) Dry PowderInhaler in accordance with Section 505(b)(1) of the Federal Food, Drug,
`and Cosmetic Act. Treprostinil is a prostacyclin analogue. Its major pharmacologic actions are
`direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition ofplatelet
`aggregation. The drug productis a drug-device combination product which is comprised of single-
`use cartridges containing a dry powderformulation oftreprostinil inhalation powder (Tyvaso
`DPI™)at 16, 32, 48, or 64 mcgoftreprostinil per cartridge and a small, portable, reusable, breath-
`powered, dry powderinhaler. This combination product is a change in dosage form for treprostinil
`from a solution for oral inhalation (Tyvaso® [treprostinil] Inhalation Solution, NDA 022387) to a
`dry powderfor oral inhalation. All CMC information on this new drug product formulation of
`treprostinil is referenced to DMF (#
`©® The DMFhas been reviewedbydifferent disciplines
`within the Office of Pharmaceutical Quality (OPQ) and foundto be acceptable. The proposed
`control strategies for the drug product manufacturing are adequate to ensure consistent drug product
`quality regarding identity, assay, purity, dissolution, content uniformity,
`©@microbial
`content, and stability. The proposed 18-monthshelf life is supported by sufficient stability data and
`found to be acceptable. Whileall of the listed facilities were found to be acceptable, note that one of
`the testing facilities (drug substance testing laboratory) is currently on “withhold”status.
`
`A. Drug Substance Quality Summary
`
`Treprostinil is a small molecule and has been well characterized using state-of the-art methods with
`regard to its structure and physicochemical characteristics. The drug substance reviewer concluded
`that the manufacturing process of the drug substance has been described in sufficient detail and the
`proposedspecification is adequate. Analytical methodsto control the quality of the drug substance
`are adequate. Stability data support retest of {monthsfor the Treprostinil drug substance when
`stored in
`ae
`
`z|Page
`
`Reference ID: 4865581
`
`

`

`
`
`B.1. Product Design, and Release Specification:
`
`The drug product is a drug-device combination product which is comprised of single-use cartridges
`containing a dry powder formulation of treprostinil inhalation powder (Tyvaso DPI™)at 16, 32, 48,
`or 64 mcgoftreprostinil per cartridge and a small, portable, reusable, breath-powered, dry powder
`inhaler. All chemistry, manufacturing, and control (CMC) information on this new drug product
`formulation of treprostinil is referenced to DMF #|© The DMFhas been reviewed and found
`to be adequate to support this NDA. Pharmaceutical development studies adequately support the
`formulation design, including excipient selection and excipient levels. No human/animal-origin
`excipients are used in the formulation. The drug product contains the drug substance and other
`inactive ingredients namely, fumaryl diketopiperazine,
`
`
`
`
`
`The productrelease specification, involving testing ofall the productcritical quality attributes
`(CQAs), is adequate to ensure the consistent product quality such as appearance, identification,
`assay, related compound, uniformity ofdosage unit, aerodynamic particle size distribution,
`uniformity of delivered dose, foreign particulate matter,==“, and microbiallimits. All
`analytical methodsusedare validated. A risk assessment regarding levels of elemental impurities in
`the drug product have been assessed and foundto be acceptable. A risk assessment of
`contamination in Treprostinil Inhalation Powder wasalso conducted and the risk was found to be
`very low/negligible.
`
`B.2. Manufacturing: Theas processandits conte information canine
`
`
`
`The DMF
`
`
`wasfound to be adequate from manufacturing process and control perspective by the reviewerto
`support this NDA.
`
`B.3. Microbiological Aspects: The drug productis adequately controlled for inclusion of
`microbiological testing in the drug product specification.
`
`B.4. Biopharmaceutics Aspects: Not relevant for this drug product.
`
`B.5. Container Closure System: Treprostinil Inhalation Powderis packed into a single dose
`cartridge cup and sealed by a lid. The cartridge cups and lids are made of
`Thefilled cartridges are packagedinto blisters (™ sealed with aluminum lid. Eachblister card
`contains seven (7) blisters strips separated by perforations for a total of 28 cartridges. The cartridge
`a| Page
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` system for
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`the intended use. All CMC jnformtion regarding the container closure system is
`provided under the DMF #|__®which is found to be adequate to support this NDA.
`
`B.6. Product Stability, Expiration Date & Storage Conditions. The applicant provided data from
`stability studies from eight (8) registration batches stored in the intended commercial packaging
`under long-term conditions (5°C + 3°C) for up to 12 months, and accelerated conditions (25°C +
`2°C/60% RH) for 6 months. Additional stability data including in-use stability and stress condition
`stability data were also provided. Notethatall stability data and associated reports are provided in
`the DMF #|© which has been found to be adequate to support this NDA.All thesestability
`data indicate no changesin the drug product with respect to any of the quality attributes. Therefore,
`the applicant’s proposedshelf life of 18-month with recommendedstorage condition of 5°C is
`acceptable.
`
`C. Assessment of Manufacturing Facilities: The office of Pharmaceutical Manufacturing
`Assessment (OPMA)has recommendeda “Withhold” underthe overall manufacturing
`
`recommendation for this NDA as follows (copied from Panorama facility status).
`
`Note that only one particular facility listed above (ie,7) has OAT
`classification due to compliance issue. This particular facility is a testing laboratory for the drug
`substance. All other listed facilities are GMP compliant.
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`QUALITY ASSESSMENT
`
`D. The applicant has claimed categorical exclusion from the environmental assessment requirements
`under 21 CFR Part 25.31(b) on the basis that no extraordinary circumstances exist under 21 CFR
`25.15(d) that would warrant preparation of an environmental assessment. The applicant’s claim of
`categorical exclusion is acceptable.
`
`E. OPQ's all
`labeling.
`
`labeling recommendations are reflected in the most recent version of the product
`
`OVERALL ASSESSMENT AND SIGNATURES
`
`Application Technical Lead (ATL) Assessment and Signature:
`
`Date: 2021.09.30 11:39:37 -04'00"
`
`Based on integrated quality review by the Office of Pharmaceutical Quality (OPQ), manufacturing
`facilities-related deficiencies remain currently unresolved becauseofan official action indicated
`(OAD)classification for the drug substancetesting facility,
`os)
`©)Therefore, from an OPQ perspective, this NDA is not deemed ready for approval in
`its present form until the above-mentionedfacility’s OAI status is changed to GMP complaint. As
`such, OPQ recommends a Complete Response (CR) action from a product quality perspective
`along with the following CR deficiency.
`
`CR Deficiency for the Applicant:
`©®for this
`©facility (
`During a recent inspection ofthe
`application, ourfield investigator conveyed deficiencies to the representative of thefacility.
`Satisfactory resolutionof these deficiencies is required before this application may be approved.
`
`.
`Akm Khairuzzaman, Ph.D.
`Application Technical Lead (ATL)
`ONDP/DNDPIII/NDPB5
`
`Digitally signed by Akm Khairuzzaman-S
`DN: c=US, o=U.S. Government,ou=HHS,
`A km
`ee0.9.2342.19200300.100.1.1=2000423292,
`Khairuzzaman -S cr-akm khairuzzaman-s
`
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`
`
`This is a representation of an electronic record that was signed
`
`
`
`
`
`
`
`
`
`electronically. Following this are manifestations of any andall
`
`
`
`
`
`
`electronic signatures for this electronic record.
`
`
`
`/s/
`
`
`
`Signature Page 1 of 1
`
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`AKM KHAIRUZZAMAN
`
`
`
`
`09/30/2021 11:45:28 AM
`
`
`
`
`
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`
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`OPQ Team has recommended a Complete Response (CR) due to pending facility related issue
`
`
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`
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`MOHAN K SAPRU
`
`
`
`09/30/2021 11:48:14 AM
`
`
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`Reference ID: 4865581
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`
`
`CHAPTER IV: LABELING
`IQA NDA Assessment Guide Reference
`
`
`1.0 PRESCRIBING INFORMATION
`Assessment of Product Quality Related Aspects of the Prescribing Information:
`
`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`Items
`
`Information Provided
`in the NDA
`
`Assessor’s
`Comments
`
`Product Title in Highlights
`Proprietary name
`Established name(s)
`
`TYVASO DPI™
`Treprostinil inhalation
`powder for oral
`inhalation use
`oral inhalation
`Route(s) of administration
`Dosage Forms and Strengths Heading in Highlights
`Summary of the dosage
`Inhalation powder for
`form(s) and strength(s)
`oral inhalation use.
`in metric system.
`16 mcg, 32 mcg, 48
`mcg, and 64 mcg
`NA
`
`For injectable drug products
`for parental administration,
`use appropriate package type
`term (e.g., single-dose,
`multiple-dose, single patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`package.
`Special instructions for
`product preparation (e.g.,
`reconstitution and resulting
`concentration, dilution,
`compatible diluents, storage
`conditions needed to maintain
`the stability of the
`reconstituted or diluted
`product)
`
`Available dosage form(s)
`
`Acceptable
`Acceptable
`
`Acceptable
`
`Acceptable
`
`
`Acceptable
`
`Acceptable
`
`Acceptable
`
`Separate labeling/
`package insert has been
`provided that includes
`step-by-step instruction
`(along with picture) on
`how to remove the drug
`filled cartridges from the
`blister pack and insert
`into the inhalation device
`prior to use. This is also
`subject to further review
`by the labeling
`reviewers.
`Inhalation powder for
`oral inhalation use
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 1
`
`Effective Date: February 1, 2019
`
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`

`

`Strength(s) in metric system
`If the active ingredient is a
`salt, apply the USP Salt
`Policy per FDA Guidance
`
`Acceptable
`Not applicable
`Not applicable, not a salt Acceptable
`
`
`1.2.3 Section 11 (DESCRIPTION)
`Items
`Information Provided
`in the NDA
`
`TYVASO DPI™
`(treprostinil) inhalation
`powder, for oral
`inhalation use
`Inhalation powder, for
`oral inhalation use
`Not a salt (NA)
`
`Assessor’s
`Comments
`
`Acceptable
`
`
`Acceptable
`
`Acceptable
`
`DESCRIPTION section
`Proprietary and established
`name(s)
`
`Dosage form(s) and route(s)
`of administration
`If the active ingredient is a
`salt, apply the USP Salt
`Policy and include the
`equivalency statement per
`FDA Guidance.
`List names of all inactive
`ingredients. Use USP/NF
`names. Avoid Brand names.
`For parenteral injectable
`dosage forms, include the
`name and quantities of all
`inactive ingredients. For
`ingredients added to adjust
`the pH or make isotonic,
`include the name and
`statement of effect.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`volume of absolute alcohol
`Statement of being sterile (if
`applicable)
`Pharmacological/ therapeutic
`class
`Chemical name, structural
`formula, molecular weight
`If radioactive, statement of
`important nuclear
`characteristics.
`Other important chemical or
`
`Provided
`
`Acceptable
`
`Not a parenteral product
`
` Acceptable
`
`Not Applicable
`
`Acceptable
`
`Not a sterile product
`
`Acceptable
`
`Prostacyclin mimetic
`
`Acceptable
`
`Provided
`
`Acceptable
`
`Not Applicable
`
`Acceptable
`
`None
`
`Acceptable
`
`OPQ-XOPQ-TEM-0001v06 Page 2 Effective Date: February 1, 2019
`
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`

`physical properties (such as
`pKa or pH)
`Remove statements that
`may be misleading or
`promotional (e.g.,
`“synthesized and developed
`by Drug Company X,”
`“structurally unique
`molecular entity
`
`None present
`
`Acceptable
`
`
`1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
`
`
`Items
`
`Information Provided
`in the NDA
`HOW SUPPLIED/STORAGE AND HANDLING section
`Available dosage form(s)
`Inhalation powder, for
`oral inhalation use
`Not applicable
`Each card contains 7
`blister strips separated
`by perforations for a total
`of 28 cartridges
`The cartridges are color-
`coded, purple for 16
`mcg, dark blue for 32
`mcg, light blue for 48
`mcg, and light green for
`64 mcg. Each cartridge
`is marked with “Tyvaso
`DPI” and the
`corresponding dosage
`strength of “16 mcg”, “32
`mcg”, “48 mcg”, or “64
`mcg”
`Not an injectable drug
`product
`
`Assessor’s
`Comments
`
`Acceptable.
`
`Acceptable
`Acceptable
`
`Acceptable
`
`