`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205029Orig1s000
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`NDA 205029
`
`Epinephrine Injection
`1 mg/mL
`
`Belcher Pharmaceuticals
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`
`Office of New Drug Quality Assessment
`
`Submission Date : 29—JAN—2014
`
`PDUFA Goal Date: 28—JUL—2014
`
`NDA 205029
`
`Epinephfine Injection, 1.0 mg/mL
`
`Page 1
`
`Reference ID: 3541427
`
`

`

` CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205029
`
`2. REVIEW #2 3
`
`3. REVIEW DATE: 10-July—2014
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`IND-
`
`Document Date
`
`01-Feb-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; 3) Reviewed
`NDA 205029 SD#9
`
`NDA 205029(SD#10)
`NDA 205029(SD#11)
`NDA 205029(SD#12)
`
`Document Date
`29-JAN—2014
`
`l3—JU N—2014
`01-JUL-2014
`09—JUL—2014
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Belcher Pharmaceuticals
`
`Representative:
`
`Mihir Taneja
`Vice President,
`Regulatory Affairs & Compliance
`6911 Bryan Dairy Road
`Largo, FL 33777 USA
`
`Telephone:
`
`(727) 471-0850 Ext 250
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 2
`
`Reference ID: 3541427
`
`

`

` CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name (USAN): Epinephrine
`c) Code Name/# (ONDQA only): N/A
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 7
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50, 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Cardiology, Septic Shock
`
`ll. DOSAGE FORM:
`
`Injection
`
`12. STRENGTH/POTENCY:
`
`1.0 mg/mL (1: 1000)
`
`13. ROUTE OF ADMINISTRATION: Intravenous
`
`14. Rx/OTC DISPENSED:
`
`
`X
`
`Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 3
`
`Reference ID: 3541427
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`l. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`Chemical Name(s):
`1. Chemical Name: (R)-1-(3,4-dihydroxyphenyl)—2-methylaminoethanol 1,2-
`Benzenediol, 4-( l -hydroxy—2-(methylamino )ethyl)-, (R)- (- )-3,4-
`Dih drox - IX - meth lamino :- eth 1 -be
`1 alcohol
`
`
`
`CH-CHZ-NH-CH3
`
`| O
`
`H
`
`Synonym: (-)-Adrenaline
`
`i-i— Bimihrine
`
`CAS-No: 51 - 43 — 4
`
`Molecular Formula: C9H13NO3
`
`Molecular Mass: 183.20
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DATE
`
`TYPE
`
`HOLDER
`
`ITEM
`REFERENCED CODE
`
`1
`
`2
`
`STATUS
`
`REVIEW
`COMPLETE
`
`COW/IENTS
`
`3. Bhamidipan'
`
`D 06/24/2014
`
`4 l.-
`
`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")
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 4
`
`Reference ID: 3541427
`
`

`

` CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`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
`
`_I '
`
`‘
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED
`
`RECOMMENDATION
`
`REVIEWS
`
`ot a licable
`
`‘ cceptable
`0t applicable
`Notappncable
`
`un-07-2014
`
`Steven
`
`Methods Validation
`
`ot requested. The methods are
`conventional and do not qualify
`for internal validation by FDA
`labs
`
`7
`
`’1 is acceptable Aug-07-2013
`
`—Cate ° orical Exclusion u anted
`Microbiology
`5'
`
`15-Feb-2013
`
`19. ORDER OF REVIEW (OGD Only)
`
`The application submission(s) covered by this review was taken in the date order of
`
`receipt.
`Yes
`No
`If no, explain reason(s) below:
`Not Applicable
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 5
`
`Reference ID: 3541427
`
`

`

`
`
`Chemistry Assessment Section
`
`Chemistry Review for NDA 205029
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA 205029 for Epinephrine Injection 1mg/mL, USP from Belcher Pharmaceuticals is
`recommended for approval from CMC perspective. Oflice of Compliance has provided an overall
`acceptable recommendation for manufacturing and testing facilities for this NDA.
`
`Note: Please refer to Quality Reviews filed for this NDA in DARRTS on Aug-21-2013 and Oct—03-
`2013 for complete details.
`B.
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`None applicable .
`
`II. Summary of Chemistry Assessments
`A.
`Description of the Drug Product(s) and Drug Substance(s)
`Review Cycle#l :The proposed drug product, Epinephrine Injection 1 mg/mL (1:1000) USP is an
`injectable sterile solution for the treatment ofseptic shock. The sponsor, Belcher Pharmaceuticals, met
`with the Agency and agreed to submit the NDA for the proposed indication (septic shock) for a
`literature based review without conducting any new clinical studies. While Epinephrine injection
`was marketed as an unapproved drug at the time Belcher Pharmaceuticals submitted their original
`NDA, Division of Pulmonary, Allergy and Rheumatology Products (DPARP) has subsequently
`approved NDA 204200 Adrenalin (Epinephrine) injection , 1 mg/mL (l : 1000) USP submitted by JH
`Pharmaceuticals for treatment of allergic reactions and anaphylactic shock in Dec 2012. The
`proposed drug product in this NDA contains 1 mg/mL of Epinephrine base equivalent as a sterile
`solution with 1 ml of the solution filled in 2 ml Type I (USP) clear glass ampoule. The on]
`
`
`excipients in the product are sodium chloride tonici
`h drochloric acid (for
`
`Theman actunn
`
`
`
`
`The specification provided for the drug
`product is essentially the same as in USP for epinephrine injection. The only addition is a
`
`
`specification for the related substance,
`Batch analysis data have been submitted for 3
`commercial batches manufactured between 2004 and 2007. Stabili
`data were
`rovided for 4 full
`
`
`
` Appearance, assay,
`and particulate matter were
`tested at every time point whereas sterility and endotoxins were tested annually. Based on the
`
`scale batches manufactured with
`
`
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 6
`
`Reference ID: 3541427
`
`

`

`
`
`not include evaluation of the drug product for
`the applicant’s response that a minimum of
`end of proposed commercial manufacturing process with
`with the current manufacturing process is considered not justified. In addition, the analytical
`methods employed for assay and degradation products were considered not adequately validated to
`ensure the drug product quality characteristics at release and on stability. A Complete Response
`letter was sent to the Applicant with CMC deficiency items on 4-Oct-2013.
`
`at release or during storage. Based on
`of E in brine was observed at the
`
` However, batch analysis and stability data presented did
`
`
`
`Review cle# 2
`
`esubmission : The dru
`
`
`
`
`and included acceptance
`specification was revised for assay to
`
`at release and on stability respectively.
`limits of no more than - and
`The HPLC analytical method employed for assay and related substances was adequately revised.
`Additional] , description and validation results of chiral HPLC method employed for quantitation
`of
`content were provided. Stability data for one batch of drug product manufactured
`with revised formulation and manufacturing process stored at lon term storage conditions (25°C) up
`
`to 9 months were provided. Based on the levels of* observed on stability, the
`Applicant proposed a shelf-life of- for the drug product.
`
`sed commercial manufacturin
`
`The ro
`rocess which consists of
`
`
`
`is considered acceptable.
`
`
`lacks adequate scientific
`It was noted that the proposed drug product shelf-life of
`justification since stability data presented are limited to nine months for one batch in the
`resubmission. Stability data submittedm the original NDA (three batches manufactured with -
`manufactured at
`
`
`
`
`oval based on changes to the
`The NDA is recommended for
`
`
`manufacturing process and formulation reducing the level of
`impurity in the final
`
`dru
`roduct, which should provide reduced risk to the patient. The stability data for a single batch
`show the drug product maintains the critical quality attributes up to 12 months and
`hence a shelf-life of 12 months for the drug product is recommended. Following a discussion of
`limited stability data during the Teleconference held on July 2nd 2014, the Applicant submitted the
`following information to the NDA(SD#12 dated 09-JUL-2014)
`
`The Applicant has agreed to submit long term stora e stabili
`
`for expiration dating extension ofthe drugproducth.
`
`data for three commercial batches
`
`The Applicant revised the drug product s
`
`total impurities/degradants (includinga) at release and on stability
`
`ification to include appropriate acceptance limits for
`
`Drug Substance:
`
`NDA 205029
`
`Epinephrine Injection, 1.0 mg/mL
`
`Page 7
`
`Reference ID: 3541427
`
`

`

`
`
`Chemistry Assessment Section
`
`The drug substance, epinephrine, commonly known as adrenaline is a white to almost white
`crystalline powder which is practically insoluble in water, ethanol or methylene chloride but is soluble
`in HCl. It is an endogenous hormone and neurotransmitter. Epine hrine has one chiral center and is a
`pure enantiomer with the R configuration. It is manufactured by
`'
`
`
`by am and all CMC information is cross-reference
`
`o
`
`s
`
`pecifications for
`a equa e to support this NDA for an injectable dosage form.
`been eeme
`epinephrine are rovided in the NDA based on the USP monograph with the addition of tests for
`residual solvents
`and bacterial endotoxins. Batch anal sis data have been provided for 2
`
`representative ba c es. was stated that DMF holder,F has assigned a retest
`period of- based on stability data submitted to the
`.
`
`B.
`
`Description of How the Drug Product is Intended to be Used
`
`consisting of 1 mg/mL of
`Epinephrine Injection 1 mg/mL (1:1000) USP is a sterile solution
`Epinephrine base e
`'valent and one ml of the solution is filled in 2 ml Type I (USP clear
`ass
`
`ampomefi The ampomefi are packed in
`
`g
`e
`cardboard-box contarns 10 ampo es 0 Eprnephrine Injection .
`oxes. Eac
`cardboar
`product is diluted further in saline for intravenous administration.
`The recommended storage
`conditions for the drug product are:
`
`“Store at room tefirature, between 20°C and 25°C i68° and 77°F—
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation
`
`This NDA 205029 for Epinephrine Injection, 1 mg/mL (1:1000) USP is approvable based on the
`evaluation of
`quality information submitted in the resubmission. The
`to osed commercial
`manufacturin
`rocess which consists of
`
`and manufacturing
`is acceptable because the
`changes in this resubmission assure adequate L-epinephrine is present in the drug product to assure
`clinical efficacy while minimizing drug product impurities that were present with the previous
`process. However, based on limited stability data submitted in the resubmission, a shelf-life of 12
`months is recommended for the drug product.
`
`III. Administrative
`
`A. Reviewer’s Signature
`B. Endorsement Block
`
`Chemist Name/Date: Shastli Bhamidipati, Ph.D.
`Chemistry Team Leader Name/Date: Kasturi Srinivasachar, Ph.D.
`Project Manager Name/Date: R. Forlney
`C. CC Block
`
`NDA 205029
`
`E in brine In'ection 1.0m mL
`
`Pa e8
`
`Reference ID: 3541427
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHASTRI P BHAMIDIPATI
`07/11/2014
`
`OLEN M STEPHENS
`07/14/2014
`
`Reference ID: 3541427
`
`

`

`
`
`CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`NDA 205029
`
`(Epinephrine) Injection
`1 mg/mL
`
`Belcher Pharmaceuticals
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`
`Office of New Drug Quality Assessment
`
`Submission Date : 04—DEC—2012
`
`PDUFA Goal Date: 04—OCT—2013
`
`NDA 205029
`
`m" (Epinephrine) Injection, 1.0 mg/mL
`
`Page 1
`
`Reference ID: 3383944
`
`

`

` CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205029
`
`2. REVIEW #2 2
`
`3. REVIEW DATE: 03-Oct-2013
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`IND-
`
`Document Date
`
`01-Feb-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; s! Reviewed
`
`NDA 205029 Original Submission
`NDA 205029 SD#7
`
`Document Date
`
`04-DEC-2012
`08-MAR-2013
`
`7. NANIE & ADDRESS OF APPLICANT:
`
`Name: Belcher Pharmaceuticals
`
`6911 Bryan Dairy Road
`Address; Largo,FL33777 USA
`
`NDA 205029 - Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3383944
`
`Page 2
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Mihir Taneja
`Vice President,
`Regulatory Affairs & Compliance
`6911 Bryan Dairy Road
`Largo, FL 33777 USA
`
`Representative:
`
`Telephone:
`
`(727) 471-0850 Ext 250
`
`8. DRUG PRODUCT NAIVIE/CODE/I'YPE:
`
`a) Proprietary Name: -
`b) Non-Proprietary Name (USAN): Epinephrine
`c) Code Name/# (ONDQA only): N/A
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 7
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50, 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Cardiology, Septic Shock
`
`1]. DOSAGE FORM:
`
`Injection
`
`12. STRENGTH/POTENCY:
`
`1.0 mg/mL (1: 1000)
`
`13. ROUTE OF ADMMSTRAHON: Intravenous
`
`l4. Rx/OTC DISPENSED:
`
`
`X
`
`Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`NDA 205029 - Epinephrine) Injection, 1.0 mglmL
`Reference ID: 3383944
`
`Page 3
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`l. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`Chemical Name(s):
`1. Chemical Name: (R)-l-(3,4-dihydroxyphenyl)—2-methylaminoethanol 1,2-
`Benzenediol, 4-( l -hydroxy—2—(methylamino )ethyl)-, (R)- (- )-3,4-
`Dih drox - Di - meth lamino neth l-be lalcohol
`
`
`
`CH-CHZ-NH-CH3
`
`| O
`
`H
`
`Synonym: (-)-Adrenaline
`
`i-i- Bimihrine
`
`CAS-No: 51 - 43 — 4
`
`Molecular Formula: C9H13NO3
`
`Molecular Mass: 183.20
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`HEM
`
`DATE
`
`REFERENC CODEl
`ED
`
`STATUS2
`
`REVIEW
`COMPLETED
`
`COMMENTS
`
`W 07/15/2013
`
`E.En; und
`
`TYPE
`
`HOLDER
`
`El
`
`
`
`‘ Action codes for DMF Table:
`1 — DMF Reviewed
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Typc 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3383944
`
`Page 4
`
`

`

` CHENIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`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:
`
`DESCRIPTION
`
`APPLICATION NUMBER
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED
`REVIEWS
`
`EES
`
`Methods Validation
`
`RECONINIENDATION
`
`DATE
`
`REVIEWER(S)
`
`Not a licable ——
`Acceptable
`Oct—03-2013
`Christina Capacci—
`Daniel
`
`Not a licable ——
`Not applicable ——
`Not requested. The methods are
`conventional and do not qualify for
`internal validation b FDA labs
`
`StevenD—onald
`
`is acceptable
`"
`’
`DMEPA
`_ Cate orical Exclusion
`anted
`Microbiology
`Recommended approval
`
`A—ug-07—2013Kim—berlyDe Fronzo
`
`
`Feb15-2013
`
`19. ORDER OF REVIEW (OGD Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`If no, explain reason(s) below:
`
`NDA 205029 - Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3383944
`
`Page 5
`
`

`

`
`
`Executive Summary Section
`
`Chemistry Review for NDA 205029
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA 205029 for- (Epinephrine) Injection lmg/mL USP from Belcher Pharmaceuticals
`is not recommended for approval from CMC perspective due to significant issues in regards to
`quality of the drug product resulting from the proposed commercial manufacturing process. A list
`of CMC deficiencies and recommendations are provided at the end of this Executive summary.
`The Office of Compliance has provided overall acceptable recommendation for manufacturing
`and testing facilities for this NDA ( see Attachment).
`
`Note: Please refer to Quality Review filed for this NDA in DARRTS on Aug-21-2013 for
`complete details.
`B.
`Recommendation on Phase 4 (Post-Marketing) Commitments,
`Agreements, and/or Risk Management Steps, if Approvable
`None applicable .
`
`II. Summary of Chemistry Assessments
`A.
`Description of the Dru Product(s) and Drug Substance(s)
`The proposed drug product,
`(Epinephrine) Injection 1 mg/mL (1:1000) USP is an
`injectable sterile solution for file treatment of septic shock. Currently, Epinephrine injection is
`marketed as an unapproved drug and the sponsor , Belcher Pharmaceuticals, agreed at the pre-
`NDA meeting to a literature based review to support the proposed indication was considered
`sufficient in lieu of clinical studies. The drug product contains 1 mg/mL of Epinephrine base
`equivalent and 1 ml of the solution is filled in 2 ml Type I (USP) clear
`ass ampoule. The only
`exci ients in the product are sodium chloride (tonicity agent),
`h drochloric acid for
`
`
`
`
`
`
`The specification provided for the drug product is essentially the same as in
`USP for
`inephrine injection. The only addition is a specification for the related substance,
`
`Batch analysis data have been submitted for 3 commercial batches manufactured
`
`between 2004 and 2007. Stabili data were
`rovided for 4 full scale batches manufactured with
`
` Appearance, assay,
`and particulate matter were tested at every
`
`
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3383944
`
`Page 6
`
`

`

`
`
`Executive Summary Section
`
`time point whereas sterility and endotoxins were tested annually. Based on the stability data , the
`applicant proposed an expiration datin of
`for the
`roduct. The
`roduct is
`
`recommended to be stored at
`
`
`
`However, batch analysis and stability data presented did
`
`
`
`not mc 11
`ev nation 0
`e
`g product for
`at release or during storage. Based
`
`on the applicant’s response that a minimum of
`of E ine hrine was observed
`at the end of
`to osed commercial manufacturing process with
`with the current manufacturing process is considered not justified. In
`addition, the analytical methods employed for assay and degradation products were considered
`not adequately validated to ensure the drug product quality characteristics at release and on
`stability.
`
`Drug Substance:
`
`The drug substance, epinephrine, commonly known as adrenaline is a white to almost white
`crystalline powder which is practically insoluble in water, ethanol or methylene chloride but is
`soluble in HCl. It is an endogenous hormone and neurotransmitter. Epinephrine has one chiral
`center and is a ure enantiomer with the R configuration.
`It is manufactured by
`
`
`DMF
`
`DMF has been rev1ew numerous times and the most recent review dated 15-
`
`by aq and all CMC information is cross-referenced to
`
`q in
`
`
`concludes that it is adequate to support an NDA for an injectable dosage form.
`Jul—2013
`Specifications for epinephrine are provided in the NDA based on the USP monograph with the
`
`addition oftests for residual solvents- and bacterial endotoxins. Batch analfiis data
`
`stated that DMF holder,
`have been provided for 2 representative batches. It was
`e DIvIF.
`has assigned a retest period of- based on stability data submitted to
`the Office of Compliance has put the Epinephrine HCl drug substance manufacturing
`However,
`site in- on a “withhold” status.
`
`B.
`
`Description of How the Drug Product is Intended to be Used
`
`Epinephrine Injection 1 mg/mL (1:1000) USP is a sterile solution consisting of 1 mg/mL of
`Epinephrine base e uivalent and one ml of the solution is filled in 2 ml Type I (USP clear
`ass
`
`ampoulei. The ampoules— are packed infi
`
`cardboard boxes. Each cardboard-box contains 10 ampoules of Epinephrine Injection . The drug
`product is diluted further in saline for intravenous administration. The recommended storage
`conditions for the drug product are:
`
`“Store atroom temirature, between 20°C and 25°C i68° and 77°F—
`
`Basis for Approvability or Not—Approval Recommendation
`C.
`The recommendation for non-approvability of this NDA 205029
`for - (Epinephrine)
`Injection is based on the evaluation of quality information submitted in the original application
`and the su
`rtin documents. The ro sed commercial manufacturin
`rocess which consists
`
`ofj in considered notjustified. In addition, the analytical methods employed for assay
`
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3383944
`
`Page 7
`
`

`

`
`
`Executive Summary Section
`
`and degradation products were considered not adequately validated to ensure the drug product
`quality characteristics at release and on stability.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemist Name/Date: Shastli Bhamidipati, Ph.D.
`Chemistry Team Leader Name/Date: Kasturi Srinivasachar, Ph.D.
`Project Manager Name/Date: R. Fortney
`C. CC Block
`
`
`
`NDA 205029
`
`Reference ID: 3383944
`
`(Epinephrine) Injection, 1.0 mg/mL
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHASTRI P BHAMIDIPATI
`10/03/2013
`
`RAMESH K SOOD
`10/03/2013
`
`Reference ID: 3383944
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`NDA 205029
`
`(Epinephrine) Injection
`1 mg/mL
`
`Belcher Pharmaceuticals
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`
`Office of New Drug Quality Assessment
`
`Submission Date : 04—DEC—2012
`
`PDUFA Goal Date: 04—OCT—2013
`
`NDA 205029
`
`“m (Epinephrine) Injection, 1.0 mg/mL
`
`Page 1
`
`Reference ID: 3360751
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205029
`
`2. REVIEW #: l
`
`3. REVIEW DATE: 20-Jan-2013
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`IND-
`
`Document Date
`
`01-Feb-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; s! Reviewed
`
`NDA 205029 Original Submission
`NDA 205029 SD#7
`
`Document Date
`
`04-DEC-2012
`08-MAR-2013
`
`7. NANIE & ADDRESS OF APPLICANT:
`
`Name: Belcher Phannaceuticals
`
`_
`6911 Bryan Dairy Road
`Address Largo,FL33777 USA
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Mihir Taneja
`Vice President,
`
`Representative:
`
`Regulatory Affairs & Compliance
`6911 Bryan Dairy Road
`Largo, FL 33777 USA
`
`Telephone:
`
`(727) 471-0850 Ext 250
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: -
`b) Non-Proprietary Name (USAN): Epinephrine
`c) Code Name/# (ONDQA only): N/A
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 7
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50, 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Cardiology, Septic Shock
`
`1]. DOSAGE FORM:
`
`Injection
`
`12. STRENGTH/POTENCY: 1.0 mg/mL (1 : 1000)
`
`13. ROUTE OF ADMINISTRATION: Intravenous
`
`l4. Rx/OTC DISPENSED:
`
`
`X
`
`Rx
`
`OTC
`
`15. SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 3
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`1. CHEMICAL NANIE, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name(s):
`1. Chemical Name: (R)-l -(3,4-dihydroxyphenyl)—2-methylaminoethanol 1,2-
`Benzenediol, 4-( l -hydroxy-2—(methylamino )ethyl)-, (R)- (-)--3,4-
`
`H
`
`CH -CH2-NH-CH3
`
`| O
`
`Synonym: (-)-Adrenaline
`
`i-i— Eiineihrine
`
`CAS-No: 51 - 43 — 4
`
`Molecular Formula: C9H13NO3
`Molecular Mass: 183.20
`
`17. RELATED/SUPPORTING DOCUMENTS:
`A. DMFs:
`
`DATEWM COMPLETED
`
`
`
`07/15/2013
`
`E.En; und
`
`‘ 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
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 4
`
`

`

`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`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:
`
`_I 7'
`
`APPLICAHON NUMBER
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED
`REVIEWS
`
`RECONINIENDATION
`
`DATE
`
`REVIEWER(S)
`
`Methods Validation
`
`Recommended 3. uroval =—Steven Donald
`
`Not applicable ——
`Final Recommendation endin , ——
`Not a licable ——
`Not applicable ——
`Not requested. The methods are
`conventional and do not qualify for
`internal validation by FDA labs
`
`
`DMEPA
`_ Cate
`
`'
`
`'
`
`
`
`is acce table A-—u-07-2013 Kim—bedDe Fronzo
`
`19. ORDER OF REVIEW (0013 Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`Ifno, explain reason(s) below:
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 5
`
`

`

`
`
`Executive Summary Section
`
`Chemistry Review for NBA 205029
`The Executive Summa
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`(Epinephrine) Injection 1mg/mL USP from Belcher Pharmaceuticals
`This NDA 205029 for
`is not recommended or approval from CMC perspective due to significant issues in regards to
`quality of the drug product resulting from the proposed commercial manufacturing process. A list
`of CMC deficiencies and recommendations are provided at the end of this Executive summary.
`Additionally, the Oflice of Compliance has not provided a final recommendation as to the
`acceptability of manufacturing and testing facilities for this NDA.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments,
`B.
`Agreements, and/or Risk Management Steps, if Approvable
`None applicable .
`
`II. Summary of Chemistry Assessments
`A.
`Description of the Dru Product(s) and Drug Substance(s)
`The proposed drug product,
`(Epinephrine) Injection 1 mg/mL (121000) USP is an
`injectable sterile solution for the treatment of septic shock. Currently, Epinephrine injection is
`marketed as an unapproved drug and the sponsor , Belcher Pharmaceuticals, agreed at the pre-
`NDA meeting to a literature based review to support the proposed indication was considered
`sufficient in lieu of clinical studies. The drug product contains 1 mg/mL of Epinephrine base
`equivalent and 1 ml of the solution is filled in 2 ml Type I (USP) clear glass ampoule. The only
`exci ients in the product are sodium chloride (tonicity agent),
`h drochloric acid for
`
`
`
`
`
`
`e injection. The only addition is a specification for the related substance,
`Batch analysis data have been submitted for 3 commercial batches manufactured
`between 2004 and 2007. Stabili
`data were
`rovided for 4 full scale batches manufactured with
`
`
`
`
` Appearance, assay, an part1c ate matter were teste at every
`
`time point whereas sterility and endotoxins were tested annually. Based on the stability data , the
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 6
`
`

`

`
`
`Executive Summary Section
`
`roduct. The
`for the
`applicant proposed an expiration datin of
`recommended to be stored at
`
`
`However, batch analysis and stability data presented did
`
`
`
`gproduct forflame orduring storage. Based
`e
`ev nation0
`not111011
`
`on the applicant’s response that a minimum of
`at the end of
`to osed commercial manufacturing process Mh
`
`with the current manufacturing process is considered not justified. In
`addition, the analytical methods employed for assay and degradation products were considered
`not adequately validated to ensure the drug product quality characteristics at release and on
`stability.
`
`of E in brine was observed
`
`Drug Substance:
`
`The drug substance, epinephrine, commonly known as adrenaline is a white to almost white
`crystalline powder which is practically insoluble in water, ethanol or methylene chloride but is
`soluble in HCl. It is an endogenous hormone and neurotransmitter. Epinephrine has one chiral
`center and is a me enantiomer with the R configuration. It is manufactured by
`in
`by a— and all CMC information is cross-referenced to
`This DMF has been reviewed numerous times and the most recent review dated 15-
`
`DMF
`
`concludes that it is adequate to support an NDA for an injectable dosage form.
`Jul-2013
`Specifications for epinephrine are provided in the NDA based on the USP monograph with the
`addition of tests for residual solvents- and bacterial endotoxins. Batch anal sis data
`have been provided for 2 representative batches. It was
`stated that DMF holder,
`has assigned a retest period of- based on stability data submitted to the DMF.
`the Office of Compliance has put the Epinephrine HCl drug substance manufacturing
`However,
`site in- on a “withhold” status.
`
`B.
`
`Description of How the Drug Product is Intended to be Used
`
`Epinephrine Injection 1 mg/mL (1:1000) USP is a sterile solution consisting of 1 mg/mL of
`Epinephrine base e
`'valent and one ml of the solution is filled in 2 ml Type I (USP clear
`s
`ampoule
`. The ampoules— are packed in
`cardboard boxes. Each cardboard-box contains 10 ampoules of Epinephrine Injection . The drug
`product is diluted further in saline for intravenous administration. The recommended storage
`conditions for the drug product are:
`
`“Store at room tefirature, between 20°C and 25°C i68° and 77°F—
`
`Basis for Approvability or Not-Approval Recommendation
`C.
`The recommendation for non-approvability of this NDA 205029
`for - (Epinephrine)
`Injection is based on the evaluation of quality information submitted in the original application
`and the su
`rtin documents. The to osed commercial manufacturin
`rocess which consists
`
`
`
`ofj in considered notjustified. In addition, the analytical methods employed for assay
`
`
`NDA 205029 - (Epinephrine) Injection, 1.0 mg/mL
`Reference ID: 3360751
`
`Page 7
`
`

`

`
`
`Executive Summary Section
`
`and degradation products were considered not adequately validated to ensure the drug product
`quality characteristics at release and on stability.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemist Name/Date: Shastri Bhamidipati, Ph.D.
`Chemistry Team Leader Name/Date: Kasturi Srinivasachar, Ph.D.
`Project Manager Name/Date: R. Fortney
`C. CC Block
`
`Original NDA 205029
`DNP a-[FD-l lO)/NDA Division File
`DNP(HFD-110)/CSO/R. Fortney
`ONDQA/DNDQAI/Chemist/S. Bhamidipati
`ONDQA/DNDQAI /Lead/K.Srinivasachar
`ONDQA/DNDQAI RPM/T. Bouie
`ONDQA/DNDQAI /Branch Chief/R. Sood
`
`
`
`NDA 205029
`
`(Epinephrine) Injection, 1.0 mg/mL
`
`Page 8
`
`Reference ID: 3360751
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHASTRI P BHAMIDIPATI
`08/21/2013
`
`RAMESH K SOOD
`08/21/2013
`
`Reference ID: 3360751
`
`

`

`PRODUCT QUALITY — BIOPHARMACEUTICS
`
`FILING REVIEW
`
`NDA Number
`
`205029
`
`Submission Date
`
`12/4/12
`
`Product name _eneric name of the active
`Dosa _e form and stren_ 11
`Route of Administration
`
`«on ( ' inc u hrine) In'ection
`Solution for In'ection — 1 m. 061' mL
`IV infusion
`
`A . licant
`Clinical Division
`
`Belcher Pharmaceuticals LLC
`Division of Cardiovascular and Renal Products
`
`
`
`T p e of Submission
`Bio n harmaceutics Reviewer
`
`Ori - inal NDA — 505(b)(2)
`Elsbeth Chikhale. Ph.D.
`
`Bio n harmaceutics Team Leader
`
`An elica Dorantes. Ph.D.
`
`The following parameters for the ONDQA‘s Product Quality-Biophannaceutics filing checklist are
`necessary in order to initiate a full biophalmaceutics review (i.e.. complete enough to review but may
`have deficiencies).
`
`0NDQA—BIOPHARMACEUTICS
`A. INITIAL OVERVIEW OF THE NDA APPLICATION FOR FILING
`
`_-m_mm—
`I _dissolution data?
`2.
`Is the dissolution test part of the
`x
`NA
`DP speCIficatIons?
`
`3.
`
`4.
`
`Does the application contain the
`dissolution method development
`report?
`
`Is there a validation package for
`the analytical method and
`dissolution methodol0o ?
`
`Does the a