CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 87
`
`MICROBIOLOGY REVIEW! S!
`
`
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 87
`
`MICROBIOLOGY REVIEW! S!
`
`
`
`Product Quality Microbiology Review
`
`23 March 2009
`
`NBA:
`
`-
`
`22—387/N-000
`
`Drug Product Name
`Tyvaso.
`Proprietary:
`treprostinil sodium.
`Non-proprietary:
`Drug Product Priority Classification: S.
`
`Review Number:
`
`'
`
`1.
`
`Dates of Submissiongs! Covered by this Review
`Letter
`Stamp
`Review Request
`
`08 JUL 2008
`30 JUN 2008
`27 JUN 2008
`N/A
`29 OCT 2008
`29 OCT 2008
`N/A
`29 JAN 2009
`29 JAN 2009
`N/A
`25 FEB 2009
`25 FEB 2009
`“Previously assigned to another microbiology reviewer.
`
`‘
`
`Asmgned to
`Rev1ewer
`07 OCT 2008)::
`N/A
`N/A
`N/A
`
`Applicant/Sponsor
`Name:
`Address:
`
`Representative:
`Telephone:
`
`'
`
`United Therapeutics Corp.
`One Park Dr.
`Suite 400
`
`Research Triangle Park
`NC 27709
`Dean Bunce
`919-485—8350
`
`Name of Reviewer:
`
`John W. Metcalfe, Ph.D.
`
`Conclusion:
`
`Recommend approval.
`
`
`
`Microbiology Review #1
`NDA 22-387/N-000
`
`
`Product Quality Microbiology Data Sheet
`
`A.
`
`B.
`
`C.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`TYPE OF SUBMISSION: Original NDA.
`
`SUBMISSION PROVIDES FOR: A new drug product.
`
`MANUFACTURING SITE:
`
`Catalent Pharma Solutions (formerly Cardinal Health)
`2200 Lake Shore Dr.
`
`Woodstock, IL 60098
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY:
`
`> Solution for inhalation in _/ ampules to be administered via
`portable ultrasonic nebulizer.
`> 0.6 mg/mL.
`
`METHOD(S) OF STERILIZATION:
`\
`
`‘rx—
`
`[1(4)
`
`PHARMACOLOGICAL CATEGORY: The subject drug product is
`indicated for the treatment of pulmonary arterial hypertension.
`
`SUPPORTING/RELATED DOCUMENTS: None.
`
`REMARKS:
`
`-
`
`The application is submitted electronically in the CTD format.
`
`An Initial Quality Assessment was performed by the ONDQA PAL on 23 July
`2008. The IQA identified the lack of a test method and acceptance criterion for
`-——-——~
`in the drug product as a critical review issue and posed the
`questions as to whether this is acceptable.
`
`31(4)
`
`Reviewer’s Comment
`
`Since the subject drug product is a solution for inhalation, a test method and
`acceptance criterion for
`2% ‘
`is not required.
`
`The following information request was provided to the applicant regarding
`sterility assurance issues on 16 October 2008:
`A sterility assurance review of NDA 22-3 87 is on-going. Please provide
`the following information, or reference to its location in the subject
`submission:
`
`> Data sets from the container closure integrity studies.
`> A narrative describing the environmental microbiological monitoring
`program which includes information regarding the sampling and
`testing methods, incubation conditions, alert and action limits and
`
`-—————__——___—____—____
`
`Page 2 of 14
`
`
`
`NDA 22-387/N-000
`
`Microbiology Review #1
`
`routine production monitoring frequency.
`Data sets demonstrating the .
`-~-:~ ability to retain a
`microbial challenge from the subject drug product.
`Data sets supporting the holding periods listed in Module 3.2.P.3.5 of
`
`the subject submission.
`process simulation procedures,
`A narrative describing the
`acceptance criteria and actions to be taken following a failed ,—
`.— . Include the frequency at which process simulations are
`performed, and data sets in support of the manufacture of the subject
`drug product at the Catalent Pharma Solutions manufacturing facility.
`
`33(4)
`
`The applicant amended the NDA on 29 October 2008 with the container closure
`
`integrity and .
`: validation studies. A second information request
`was forwarded to the applicant on 17 November 2008 reminding the applicant of
`the 3 bulleted items in the original information request which were not addressed
`in the applicant’s 28 October 2008 amendment. The applicant amended the
`application with responses to the second microbiology information request on 29
`January 2009 and on 25 February 2009. The applicant responses to these requests
`for information are summarized and reviewed in appropriate sections of this
`review.
`
`3(4)
`
`File Name: N022387Rl .doc
`
`Page 3 of l4
`
`
`
`NDA 22-387/N—000
`
`Microbiology Review #1
`
`m»
`Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability —— NDA 22-387/N-000 is
`recommended for approval on the basis of product quality
`microbiology.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable — Not applicable.
`
`II.
`
`Summary of Microbiology Assessments
`
`A.
`
`B.
`
`C.
`
`Brief Description of the Manufacturing Processes that relate to '
`Product Quality Microbiology — The bulk drug solution is
`
`I 53(4)
`
`Brief Description of Microbiology Deficiencies ~ There are no
`microbiology deficiencies identified.
`
`Assessment of Risk Due to Microbiology Deficiencies — Not
`applicable.
`
`I III.
`
`Administrative
`
`A.
`
`Reviewer's Signature
`
`
`
`John W. Metcalfe, Ph.D.
`
`B.
`
`
`Endorsement Block
`
`Stephen Langille, Ph.D.
`
`C.
`
`CC Block
`N/A '
`
`M P
`
`age 4 of 14
`
`
`
`l 9 Page(s) Withheld
`
`lo Trade Secret / Confidential (b4)
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld Track Number: Microbiology Review Section-
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`John Metcalfe
`3/23/2009 10:00:56 AM
`MI CROBIOLOGI ST
`
`Stephen Langille
`3/24/2009 10:26:39 AM
`MI CROB IOLOGI ST
`
`
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