CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`204485Orig1s000
`CHEMISTRY REVIEW(S)
`
`
`

`
`Memorandum
`
`NDA #
`Date:
`Product Name:
`Company Name:
`Subject:
`
`204-485 (Division of Cardiovascular and Renal Products)
`18-Oct-2013, Resubmission
`Vasostrict“‘ (vasopressin injection, USP)
`Par Sterile Products, LLC
`Overall OC Recommendation
`Updated Drug Product Specification (Amendment 28-Mar-2014)
`Updated Labeling (Amendment 28-Mar-2014)
`
`Overall Recommendation
`
`Pursuant the overall Acceptable OC Recommendation issued on 04-Apr-2014
`(refer to attachment to this Memo), the overall quality recommendation is for “approval”.
`
`Updated Drug Product Sgcification
`The applicant has provided the following updated drug product specification.
`
`Revised Release and Shelf Life Drug Product Specification
`
`00215
`
`A3mI.vialcomaininga A3mI.vialcontaining
`clear. colorless to
`a clear, colorless to
`practically colorless
`practically colorless
`S0lllIlDlL_ essentially flee
`of visible -~-
`'culates
`
`‘
`
`2.5 — 4.5
`Not - licable
`
`
`
`The UV spectrum of the
`peak in the sample
`matches the vasopressin
`- «
`in standard
`
`
`
`Not Applicable
`
`Description
`
`pH
`Volume inContainer
`Identification (HPLC)
`
`
`
`tionProducts
`-
`-_a
`Total 9
`Particulate Matter
`07020
`(USP €788“ Method I)
`
`Bacteriallindotoxin
`60570
`
`
`Stuili
`
`
`Evaluation: Adequate. The firm has revised the limits for several test parameters in the shelf-life and release
`specifications to make both specifications identical except for the levels of Total Degradation Products that are
`different. In the release specification, revision of the pH and Assay acceptance criteria was made, and in the
`shelf-life specifications the revision of the acceptance criteria for Assay and for chlorobutanol was made. The
`limits for Assay comply with the USP requirements in both sets of the specifications. All revisions in the shelf-life
`and release specifications are acceptable.
`
`Structured Product Labeling (SPL)
`The applicant has provided the updated Product Data Elements (PDE) in the Structured Product Labeling (SPL)
`text.
`
`Evaluation: Adequate.
`
`Reference ID: 3485674
`
`

`
`
`Carton/Container Labels
`The applicant has removed the word “synthetic” from the drug product container and carton labels, as requested.
`Acceptable.
`
`Recommendation and Conclusion on Approvability
`NDA 204-485 for Vasostrict™ (vasopressin injection, USP), 20 units /ml, is recommended for
`APPROVAL from a Chemistry, Manufacturing and Controls standpoint. The drug substance DMF
` remains adequate. Based on the drug product stability data, the 12-month expiration dating period
`is recommended for drug product stored in the proposed container/closure system at the recommended
`storage condition, between 15°C and 25°C (59°F and 77°F)”. The overall Acceptable OC
`recommendation for drug substance and drug product facilities is issued on 04-Apr-2014.
`
`
`
`Reference ID: 3485674
`
`(b) (4)
`
`

`
`Attachment
`
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`
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`1. sous
`Q ueuveu
`K. SRIIVASACIMR
`
`o-uni anon--union:
`
`FDA CDER S
`ESTABIJSI-IENT EVALUATION REQUEST
`SUMMARY REPORT
`
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`
`PAR STERLE Paooucrs
`1 urren woman awe D alto Fl.
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`vnsosnucr
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`vnsoraessn nxcnou
`cause Ia-e.
`P-III-III-hr. Do-UIF-I-: IIIIIEII: SIIIIUIII
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`Pmuuuouny nu
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`run lander
`
`(Ir-22)
`
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`
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`aomomo
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`
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`
`3017004403
`
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`PEIDIIG
`PEIDIIG
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`venous
`PEIDNG
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`on no-nav-am by EES_PROD
`on Isnov-mus
`by EES_PRoD
`onnwanzou byEEs_Pnoo
`on as-oeezm by EES_PROD
`on 29-Dec-2912
`by ES_PROD
`on 23-Oct-2012
`by Ess_PRoo
`on n-ocr.2m2 by Es_PRoo
`
`
`
`FNIS-EMEMEREEASETESIER
`O%'lRG.1ESTI$lA%TORV
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`KN-S‘lBlI.EAP|BVCl$CAL5VNIl£SS
`
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`
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`
`Reference ID: 3485674
`
`

`
`Attachment (Cont’d)
`
`R . IIITHJ SI'A‘I'$ 4%7I7flI
`
`DRJ6S|E'I’A%REE§‘I'E.S'I'EI
`
`EséggsggErEgg
`
`Xlfljz
`
`Xlfljz
`
`Reference ID: 3485674
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LYUDMILA SOLDATOVA
`04/08/2014
`
`OLEN M STEPHENS
`04/08/2014
`
`Reference ID: 3485674
`
`

`
`
`
`NDA 204-485
`
`Vasostrict TM(vasopressin injection, USP)
`
`Par Sterile Products, LLC
`
`Lyudmila N. Soldatova, Ph. D.
`Office of New Drug Quality Assessment
`for
`
`Division of Cardiovascular and Renal Products
`
`Review of Chemistry, Manufacturing, and Controls
`
`Reference ID: 3472444
`
`

`
`
`
`Table of Contents
`
`Table of Contents ................................................................................................... ..2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations .................................................................................................................... ..7
`
`A. Recommendation and Conclusion on Approvability ..................................................................... .. 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................. .. 7
`
`II. Summary of Chemistry Assessments....................................................................................... ..7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ........................................................... .. 7
`
`B. Description of How the Drug Product is Intended to be Used........................................................ .. 8
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... .. 8
`
`III. Administrative......................................................................................................................... ..8
`
`A. Reviewer’s Signature...................................................................................................................... .. 8
`
`B. Endorsement Block......................................................................................................................... ..9
`
`C. CC Block ........................................................................................................................................ ..9
`
`Chemistry Assessment ...........................................................................................I0
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ..... ..10
`
`S DRUG SUBSTANCE [Namc. Manufacturer] ................................................................................ ..
`
`P DRUG PRODUCT [Name, Dosage form] ............................................................................... .. N/A
`
`A APPENDICES ......................................................................................................................... .. N/A
`
`R REGIONAL INFORMATION ................................................................................................ .. N/A
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................. ..N/A
`
`A. Labeling & Package Insert ....................................................................................................... ..N/A
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .............................................. .. N/A
`
`III.
`
`List Of Deficiencies To Be Communicated ..................................................................... ..36
`
`Reference ID: 3472444
`
`

`
`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 204-485
`
`2. REVIEW #1 2
`
`3. REVIEW DATE: 18-March-2014
`
`4. REVIEWER: Lyudmila N. Soldatova
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`N/A
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! sf Reviewed
`
`Document Date
`
`Reference ID: 3472444
`
`Page 3 of 38
`
`

`
`
`
`Chemistry Review Data Sheet
`
`Resubmission
`
`Amendment
`
`Amendment
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`1 8-OCT-2013
`
`05-MAY-201 3
`
`23—DEC-201 3
`25-FEB-2014
`
`25-FEB-20 14
`
`04—MAR-20 14
`
`06-MAR—20 14
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`JHP Pharmaceuticals LLC
`
`Address:
`
`Morris Corporate Center 2
`One Upper Pond Road
`Building D, 3"‘ Floor
`Parsippany, NJ 07054
`
`Representative:
`
`Gerald G. Vasquez, Manager Regulatory Affairs
`
`Telephone:
`
`973-658-3551
`
`8. DRUG PRODUCT NAlVIE/CODE/TYPE:
`
`a) Proprietary Name: Pitressin® Injection
`b) Non-Proprietary Name (USAN): Vasopressin Injection, USP
`c) Code Name/# (ONDC only): N/A
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 7
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Treatment of vasodilatory shock, including
`post—cardiotomy shock and septic shock.
`
`I 1. DOSAGE FORM:
`
`Sterile solution (injection)
`
`Reference ID: 3472444
`
`Page 4 of 38
`
`

`
`FPACD
`,
`E ,
`
`CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`""“5—“
`
`12. STRENGTI-I/POTENCY:
`
`1 ml/vial (20 pressor units)
`
`13. ROUTE OF ADMINISTRATION: Intravenous Infusion
`
`14. Rx/OTC DISPENSED:
`
`x Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM ):
`SPOTS product — Form Completed
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name: Cyclo (1-6) L-Cysteinyl-L—Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-
`Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide.
`
`Molecular Formula: C451-I55N15O12S2
`Molecular Weight:
`1084.23
`
`2
`
`I
`
`3
`
`4
`
`5
`
`(I
`
`7
`
`R
`
`9
`
`90®@@@@@@ —
`
`sAs
`
`17. RELATEDISUPPORTING DOCUMENTS:
`
`A. DMFS:
`
`TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE‘
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`II ‘i "
`
`Adequate
`
`Review #2
`12-Feb-2014
`
`Drug
`substance
`
`Reference ID: 3472444
`
`Page 5 of 38
`
`

`
`
`
`Chemistry Review Data Sheet
`
`M HI
`
`“Mr
`
`‘'’’w
`
`3
`
`Adequate
`
`N/A
`
`Containerl
`closure
`
`
`
`‘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 relevant revision since last review
`4 — Sufficient infomiation 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:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`N/A
`
`18. STATUS:
`
`ONDC:
`
`CONSULTSI CMC
`
`RELATED
`REVIEWS
`
`RECOMNIENDATION
`
`DATE
`
`EES
`
`Pharm/Tox
`
`Bio 0
`
`E
`
`DMEPA
`
`DMEPA
`
`Pendin
`
`Approvable
`A roval
`
`Proprietary name,
`Vasostrict is acceptable
`Container & Carton
`Labels: Acceptable
`
`1 0-Apr-20 1 3
`1 5-Mar-201 3
`
`06-Feb-20 1 4
`
`Office of Com u liance
`
`Rama Dwivedi, Ph.D.
`
`Elsbeth Chikhale, Ph.D.
`
`Janine Stewart, Pha1m.D.
`
`27-Feb-2014
`
`Janine Stewart, Pharm.D.
`
`Microbiology
`
`Methods Validation
`
`Acceptable
`
`['11>>
`
`Categorical Exclusion is
`'4 anted
`
`Approval
`
`As per this
`Review
`
`Lyudmila Soldatova, Ph.D.
`
`1 -May-20 1 3
`
`Lyudmila Soldatova, Ph.D.
`
`08-Apr-2013
`03-Dec-2013
`
`Erika Pfeiler, Ph.D.
`
`Reference ID: 3472444
`
`Page 6 of 38
`
`

`
`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 204-485
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`NDA 204-485 for Vasostrictm (Vasopressin injection, USP), 20 units /ml, is
`recommended for APPROVAL from a Chemistry, Manufacturing and Controls
`"W
`standpoint pending the overall OC recommendation. The drug substance DMF
`remains adequate. Based on the drug product stability data, the 12-month expiration
`dating period is recommended for drug product stored in the proposed container/closure
`system at the recommended storage condition, between 15°C and 25°C (59°F and
`77°F)”.
`The overall OC recommendation for drug substance and drug product facilities is
`currently pending.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`
`Risk Management Steps, if Approvable
`
`None as per this review.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Refer to the Review #1 dated 09-May-2013 for this NDA regarding the description of the Drug
`Product and Drug Substance.
`The NDA received a complete response action in the first cycle of NDA primarily due to CMC
`deficiencies. In this NDA resubmission, the applicant has provided response to the deficiencies
`outlined in the CR Letter and an information request issued on 07-Feb-2014 during this review
`cycle. The response to these information requests addressed all CMC issues, and no more
`unresolved deficiencies remain.
`
`The major issues in this NDA submission were: the acceptance criterion for Assay in the shelf-
`life specifications, the lack of the stability data for the proposed product without overages, and
`the expiration period. The other issues related to several impurities/degradants were resolved
`based on the adequate responses.
`Regarding the limits for Assay in the shelf-life specifications, JI-IP has updated the drug product
`specification from
`M” to 90.0% - 110.0% ofVasopressin Units, which is consistent
`with USP monograph for Vasopressin Injection. In the resubmitted NDA, the applicant has
`provided the 12- month stability data for three primary stability batches produced without the
`overages that were stored at the long term (25°C/ 65% RH), intermediate (3 0°C/ 75% RH), and
`accelerated (40°C/ 75% RH; 3-month data) conditions. The recommended storage condition is:
`between 15°C and 25°C (59°F and 77°F). The statistical evaluation of the 12-month stability
`
`Reference ID: 3472444
`
`Page 7 of 38
`
`

`
`
`
`Executive Summary Section
`
`data for primary stability batches without overages concluded that 13 months of expiration
`period could be granted. This expiry period is limited primarily due to the failure of Assay to
`comply with the acceptance criteria of
`M”. Due to significant changes at the accelerated
`conditions after 3 month and out—of—spec stability data for assay at 12 months of storage at the
`intennediate conditions, the expiry cannot be extrapolated as per ICH QIE. As a result, a 12
`months expiration dating period can be granted for drug product. It should be noted that the
`applicant was advised to explore the possibility of storage the product at 5°C. JHP has provided
`the 9-month stability data for three batches stored at 5°C that demonstrates that the drug product
`without overages is more stable at the refrigerated condition, as was expected for this peptide
`product. However, in response to advice, the applicant clarified that “given that the drug product
`is kept in rapid-use settings such as the ICU or ambulances, a room temperature shelf life is
`needed”, and rejected the option of storage of the product at the refrigerated condition.
`The applicant, JHP Pharmaceuticals, LLC has changed their name to Par Sterile Products, LLC.
`Regarding the drug substance, Dl\/IF mm remains Adequate; the Dl\/IF holder has provided the
`adequate response to the Information Request in the Review #1 for this DI\/IF.
`An overall acceptable OC recommendation for drug substance and drug product facilities is
`currently pending.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Vasost1ict® (vasopressin injection, USP), was developed by JHP Phannaceuticals, LLC. for the
`Treatment of vasodilatory shock, including post-cardiotomy shock and septic shock.Dilute
`Vasostrict® in normal saline (0.9% sodium chloride) or 5% dextrose in water 035W) prior to use.
`Discard unused diluted solution after 18 hours at room temperature or 24 hours under
`refrigeration.
`For post-cardiotomy shock, start with a dose of 0.03 units/minute. For septic shock, start with a
`dose of 0.01 units/minute. Ifthe target blood pressure response is not achieved, titrate up by
`0.005 units/minute at 10-15 minute intervals. The maximum dose for post-cardiotomy shock is
`0.1 units/minute and for septic shock 0.07 units/min. After target blood pressure has been
`maintained for 8 hours without the use of catecholamines, taper Vasostrict® by 0.005
`units/minute every hour as tolerated to maintain target blood pressure.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`NDA 204-485 is recommended for APPROVAL from CMC standpoint pending the overall OC
`recommendation. The NDA received a complete response action in the first cycle of NDA; the
`deficiencies listed in the CR Letter have been resolved in the resubmitted NDA. The drug
`substance DIVIF M” remains Adequate. An overall acceptable OC recommendation for drug
`substance and drug product facilities is currently pending.
`
`III. Administrative
`
`A. Reviewer’s Signature
`.4gadond¢7Z. Soldatow:
`
`Reference ID: 3472444
`
`Page 8 of 38
`
`

`
`£ 273
`
`I
`
`.
`
`B. Endorsement Block
`
`CHEMISTRY REVIEW
`
`Executive Summaiy Section
`
`J 1;?R
`
`I.
`
`E
`
`.
`
`Lyudmila Soldatova, Ph.D./XX-FEB-2014
`Chemist:
`CMC Branch Chief: Olen Stephens, Ph.D.
`CMC Lead:
`Kasturi Srinivasachar, Ph.D.
`
`C. CC Block
`
`Quality Project Manager: Yvonne Knight
`Clinical Project Manager: Nguyen Quynh
`
`
`
`Reference ID: 3472444
`
`Page 9 of 38
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LYUDMILA SOLDATOVA
`03/18/2014
`
`OLEN M STEPHENS
`03/18/2014
`
`Reference ID: 3472444
`
`

`
`
`
`NDA 204-485
`
`Pitressin® Vasopressin Injection, USP
`
`JHP Pharmaceuticals, LLC
`
`Lyudmila N. Soldatova, Ph. D.
`Office of New Drug Quality Assessment
`for
`
`Division of Cardiovascular and Renal Products
`
`Review of Chemistry, Manufacturing, and Controls
`
`Reference ID: 3305797
`
`

`
`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations .................................................................................................................... ..7
`
`A. Recommendation and Conclusion on Approvability ..................................................................... .. 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps, if Approvable ................................................................................................. .. 7
`
`II. Summary of Chemistry Assessments....................................................................................... ..7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ........................................................... .. 7
`
`B. Description of How the Drug Product is Intended to be Used........................................................ .. 8
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... .. 9
`
`III. Administrative......................................................................................................................... ..9
`
`A. Reviewer’s Signature ...................................................................................................................... .. 9
`
`B. Endorsement Block......................................................................................................................... .. 9
`
`C. CC Block ........................................................................................................................................ .. 9
`
`Chemistry Assessment ...........................................................................................l0
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ..... .. 10
`
`S DRUG SUBSTANCE [Name. Manufacturer] ............................................................................ .. 10
`
`P DRUG PRODUCT [Name, Dosage form] .................................................................................. .. 18
`
`A APPENDICES ............................................................................................................................ .. 50
`
`R REGIONAL INFORMATION ................................................................................................... .. 50
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ................................ ..5l
`
`A. Labeling & Package Insert .......................................................................................................... .. 51
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. .. 52
`
`III.
`
`List Of Deficiencies To Be Communicated ..................................................................... ..53
`
`Reference ID: 3305797
`
`

`
`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 204-485
`
`2. REVIEW #1 1
`
`3. REVIEW DATE: 01-MAY-2013
`
`4. REVIEWER: Lyudmila N. Soldatova
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`N/A
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; sf Reviewed
`Original
`Amendment
`
`Amendment
`
`Document Date
`26-SEP-2012
`01-FEB-2013
`
`19-FEB-2013
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`JHP Pharmaceuticals LLC
`
`Address:
`
`Morris Corporate Center 2
`One Upper Pond Road
`Building D, 3" Floor
`Parsippany, NJ 07054
`
`Representative: Gerald G. Vasquez, Manager Regulatory Affairs
`
`Reference ID: 3305797
`
`Page 3 of 57
`
`

`
`
`
`Chemistry Review Data Sheet
`
`Telephone: 973-658-3551
`
`8. DRUG PRODUCT NAIVIE/CODE/TYPE:
`
`a) Proprietary Name: Pitressin® Injection
`b) Non-Proprietary Name (USAN): Vasopressin Injection, USP
`c) Code Name/# (ONDC only): N/A
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 7
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Treatment of Vasodilatory shock, including
`post-cardiotomy shock and septic shock.
`
`11. DOSAGE FORM:
`
`Sterile solution (injection)
`
`12. STRENGTH/POTENCY:
`
`1 ml/vial (20 pressor units)
`
`13. ROUTE OF ADMINISTRATION: Intravenous Infusion
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`l5. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM [:
`SPOTS product — Fonn Completed
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Reference ID: 3305797
`
`Page 4 of 57
`
`

`
`
`
`Chemistry Review Data Sheet
`
`Chemical Name: Cyclo (1-6) L-Cysteinyl-L, Tyrosil-L, Phenylalanyl-L-Glutaminyl-L-
`Asparaginyl-LCysteinyl-L-Propyl-L-Arginyl-L-Glycineamide
`
`Molecular Formula: C45H55N15O12S2
`
`Molecular Weight: 1084.23
`
`I
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`®@@@@@@@@ -
`
`17. RELATED/SUPPORTIIEG DOCUMENTS:s
`
`A. DMFS:
`
`DATE
`
`
`
`REFERENCE‘)
`
`CODE‘
`
`STATUS2
`
`‘
`
`Inadequate
`
`3
`3
`
`Adequate
`Adequate
`
`|
`|
`|
`|
`Ll
`
`REVIEW
`COMPLETED
`
`COMMENTS
`
`Pending upon
`response to
`
`Deficiency
`
`Letter
`
`Drug
`substance
`
`' 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 relevant revision since last review
`4 — Sumcient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`Reference ID: 3305797
`
`Page 5 of 57
`
`

`
` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`N/A ——
`
`18. STATUS:
`
`ONDC:
`
`RELATED
`
`REVIEWS
`
`RECONINIENDATION
`
`DATE
`
`REVIEWER
`
`08-JAN-2013
`
`2013
`
`‘ M
`
`ethods Validation
`
`Pending
`
`
`
`Review
`
`Lyudmila Soldatova, Ph.D.
`
`OCP
`EA
`
`Pendin ‘ Peter Hinderlin, Ph.D.
`Categorical Exclusion is
`1-MA -2013
`Lyudmila.Soldatova, Ph.D.
`u anted
`
`Microbiology
`
`Approval
`
`08-APR-2013 Erika Pfeiler, Ph.D.
`
`Reference ID: 3305797
`
`Page 6 of 57
`
`

`
`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 204-485
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`NDA 204-485 for Vasopressin Injection, USP cannot be approved in its current form
`from the CMC standpoint. The approval is contingent upon satisfactory resolution of
`the drug substance DIVIF
`"W deficiencies, and drug substance and drug product
`deficiencies summarized in the IR Letter dated 07-Mar-2013.
`
`The Overall Acceptable OC recommendation for drug substance and drug product
`manufacturing facilities was made on 08-Jan-2013.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None as per this review.
`
`H. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The JI-IP Pharmaceutical’s currently marketed product Pitressin® (vasopressin injection) is the
`same product initially manufactured and marketed by Parke-Davis for over 100 years, as per
`applicant’s statement. The therapeutic indication is a treatment of vasodilatory shock, including
`postcardiotomy shock and septic shock. The original formulation contained
`"M"
`
`he drug product Pitressin® (vasopressin injection) proposed in this NDA
`submission is a drug product without overages. The dosage fonn is a sterile solution for
`injection/intravenous administration. The strength of the Pitressin is 20 pressor rmits/ml that
`corresponds to 0.0377 mg vasopressin/ml. The 1 ml of drug product Pitressin contains a 0.5% of
`preservative chlorobutanol in water for injection and acetic acid for pH adjustment. The
`excipients used in the formulation are USP/NF grade including acetic acid. The pH is a critical
`parameter in the Pitressin formulation; in the pH range of 3.4 — 3.6, the vasopressin acid salt is
`relatively stable in water, and degradation accelerates at the pH that is above and below this
`range. Antimicrobial effectiveness of chlorobutanol has been established in accordance with USP
`<51>, and it was found acceptable according to evaluation by Microbiology reviewer. The
`container closure system consists of a 3 ml “M Type I USP glass vial with a
`stopper and
`"'"'" cap. The confirmatory photostability study
`confirmed that the current market packaging provide adequate photo-protection. The
`microbiological evaluation of the container/closure integrity was performed by Microbiology
`Reviewer, and it was found adequate. Compatibility study demonstrated that Pitressin appears to
`
`D) (4!
`
`Reference ID: 3305797
`
`Page 7 of 57
`
`

`
`
`
`Executive Summary Section
`
`be incompatible with 5% dextrose as diluent/intravenous solution; it is reflected in the Package
`Insert. Pitressin is manufactured by
`“M
`'"""'. The sterility assurance of the
`drug product after manufacturing and maintenance of sterility over the shelf-life is evaluated in
`the Microbiology Review.
`M“
`However, the release and shelf-life specification are different from each other, and
`different from those provided in the USP Monograph for Vasopressin Injection (except for pH
`limit at shelf-life); these include pH, assay, impurities and chlorobutanol content; also, the shelf-
`life limits for some impurities are very high. The applicant was requested in the IR letter to
`resolve this issue. The batch analysis for three commercial size registration batches demonstrate
`compliance of all test results with the proposed specifications; the drug product produced both
`with and without overages utilizes the same manufacturing process. The three-month primary
`stability data (long-term, intermediate and accelerated) have been submitted for 2 batches in the
`upright and inverted configurations, and the two-month data are for the third batch. Supportive
`stability data (9-24 months long-term, 12-month intermediate, and 6-month accelerated stability
`data) for representative historical commercial drug product manufactured with overages are
`provided. The additional 9-month stability data should have been submitted by mid-cycle review
`time. The accelerated studies will only be carried out for 3 months since the product is known to
`be unstable with assay and impurities going out of specification limits under these conditions.
`The applicant claims the (G3 months expiration dating period based on all available stability data.
`The provided 2-3 months stability data for primary stability batches are not sufficient to grant the
`expiration date for drug product Pitressin.
`"M for information on the drug substance
`The sponsor is referencing
`"M DMF
`Vasopressin. The original DNIF
`""" was reviewed by this reviewer, and it was found to be
`currently Inadequate: IR was sent to DMF holder. Vasopressin is a polypeptide hormone having
`the properties of causing the contraction of vascular and other smooth muscles, and of
`antidiuresis (neurohypophyseal antidiuretic hormone). At
`‘W’ Vasopressin is obtained
`by synthesis. The partial information on drug substance is provided m the submitted NDA. The
`proposed specification for Vasopressin are based on the USP monograph but this set of tests and
`limits is not sufficient for release of Vasopressin API. Additional tests and limits should be
`included in the specification; this request was included in the IR letter. In addition, deficiencies
`were identified for analytical methods used by drug product manufacturer, JHP Pharmaceuticals,
`to test the drug substance. The batch analysis of the Batches VPl00l and VPl002-l complies
`with the limited drug substance specifications by JHP. However, comparison of the CoAs of
`these batches issued by
`"wand by JHP demonstrates discrepancy in the test results for assay
`and for total impurities; the IR letter includes this issue as well.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The subject of the NDA is Pitressin® (Vasopressin injection), being developed by JHP
`Pharmaceuticals, LLC. for the Treatment of vasodilatory shock, including post-cardiotomy shock
`and septic shock.
`
`Reference ID: 3305797
`
`Page 8 of 57
`
`

`
`
`
`Executive Summary Section
`
`Proposed Pitressin Administration
`
`Pitressin® should be diluted to a concentration of .1 unit/mL to 1.0 unit/mL with normal saline
`
`
`(0.9% sodium chloride) for intravenous administration. Pitressin® is inco
`atible with 5%
`dextrose (l_)5 E 1 and this diluent should NOT be used to dilute Pitressin®. Discard unused
`diluted solution after 18 hours at room temperature or 24 hours under refiigeration.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`NDA 204-485 cannot be approved as submitted from the CMC stan oint. The outstanding
`issues that need to be resolved include deficiencies in the DMF
`, the drug substance and
`drug product deficiencies in the submitted NDA summarized in the IR Letter, and insuflicient
`amount of stability data for primary stability batches for granting the expiration dating period.
`
`III. Administrative
`
`A. Reviewer’s Signature
`.49admd¢ 72. Saldatoaa
`
`B. Endorsement Block
`
`Lyudmila Soldatova, Ph.D./01-MAY-2013
`Chemist:
`CMC Branch Chief: Ramesh K. Sood, Ph.D.
`CMC Lead:
`Kasturi Srinivasachar, Ph.D.
`
`C. CC Block
`
`Quality Project Manager: Teshara Bouie
`Clinical Project Manager: Nguyen Quynh
`
`
`
`Reference ID: 3305797
`
`Page 9 of 57
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LYUDMILA SOLDATOVA
`05/08/2013
`
`RAMESH K SOOD
`05/09/2013
`
`Reference ID: 3305797
`
`

`
` Initial Quality Assessment
`Branch I
`
`
`
` OND Division: Division of Cardiovascular and Renal Products
` NDA:
`
` 204485
` Applicant:
` JHP Pharmaceuticals, LLC
`
` Letter Date: Sep 25, 2012
` Stamp Date: Sep 26, 2012
` PDUFA Date: July 26, 2013
`