ANDA202153
`
`Microbiology Review #2
`
`Product Quality Microbiology Data Sheet
`
`A.
`
`1.
`
`2.
`
`3.
`
`4.
`
`TYPE OF SUBMISSION: Original Amendment.
`
`SUBMISSION PROVIDES FOR: Response to Agency's deficiency
`letter and T-cons held between this reviewer and the applicant.
`
`MANUFACTURING SITE:
`DRAXIMAGE, a division of DRAXIS Specialty Phaim aceuticals Inc.
`16751 TransCanada Highway
`Kirkland, Quebec, Canada, H9H 414
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: A Ruby-Fillm (Rubidium Rb 82) generator for
`IV administration of sterile, pyrogen-free Rubidium Chloride Rb 82
`4l the
`82RbCl) in 0.9% sodium chloride.
`'u''4b
`<1>>f
`(
`generator delivers a single dose ofNMT 60mCi and
`a maximum volume of 60mL per infhsion
`
`(b
`
`5.
`
`METHOD@) OF STERILIZATION:
`
`--6.
`
`PHARMACOLOGICAL CATEGORY: A positrnn emission
`tomography (PET) product indicated for assessing_!!gional mY£cai·dial
`4
`perfhsion
`11>><
`
`B.
`
`SUPPORTING/RELATED DOCUMENTS: None
`
`C. REMARKS: This is an electronic submission. The subject amendment provides
`responses to the microbiology deficiencies conveyed to the applicant in the
`Agency's Mai·ch 1, 2011 deficiency letter. A discrepancy between the initial
`submission and the 5/18/11 amendment ret arding the applicant's description of
`4 was noted by the
`~ generator
`the
`(bl <
`reviewer. Clafification was requested in T-cons lield on 7727/11, and 7/29/11
`1n"
`between this reviewer and the a
`licant. Additional sterility data
`was also requested, and the
`applicant was asked to reference and link SOPs for pai·ametric release in the
`release specification sheet, the CoA and batch release records. The requested
`info1mation was submitted in the 8/29/11 amendment.
`
`--__,.~~~---,.--,--~~-~~~,,-...,.-..-~-=--
`
`<1
`
`filename: 202153al.doc
`
`Reference ID: 3015952
`
`Page2
`
`577 of 1085
`
`

`

`ANDA202153
`
`Microbiology Review #2
`
`Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`B.
`
`Recommendation on Approvability -
`The submission is recommended for approval on the basis of
`sterility assurance.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable - NI A
`
`II.
`
`Summary of Microbiology Assessments
`
`A.
`
`Brief Description of the Manufacturing Processes that relate to
`111n4
`Product Quality Microbiology -
`>
`
`B.
`
`C.
`
`Brief Description of Microbiology Deficiencies -None identified.
`
`Assessment of Risk Due to Microbiology Deficiencies - No
`microbiology deficiencies were identified. The applicant
`demonstrates an adequate level of sterility assurance for the
`manufacturing process.
`
`III. Administrative
`
`A.
`
`B.
`
`C.
`
`Reviewer's Signature--------------
`
`Endorsement Block
`Microbiologist I Dupeh Palmer, Ph.D.
`Microbiology Team Leader/Lynne Ensor, Ph.D.
`
`CC Block
`cc: Field Copy
`
`Reference ID: 3015952
`
`Page 3
`
`578 of 1085
`
`

`

`
`ANDA 202153
`
`
`Product Quality Microbiology Assessment
`The subject amendment provides a response to the microbiology deficiencies conveyed to
`the applicant in the Agency’s March 1, 2011deficiency letter. The original deficiencies
`are italicized. Additionally, the amendment contains requested information submitted in
`the 8/29/11 amendment.
`
`Microbiology Review #2
`
`
`
`
`Reference ID: 3015952
`
`Page 4
`
`(b) (4)
`
`11 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`579 of 1085
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DUPEH G Palmer-Ochieng
`09/16/2011
`
`ELIZABETH T MCNEAL
`09/16/2011
`Checked file and submission links. All correct. Thos application in not in RFS.
`
`NEAL J SWEENEY
`02/28/2012
`
`LYNNE A ENSOR
`02/29/2012
`
`Reference ID: 3015952
`
`580 of 1085
`
`

`

`Product Quality Microbiology Review
`
`November 1, 2010
`
`
`
`ANDA: 202153
`
`Drug Product Name
`Proprietary: N/A
`Non-proprietary: Rubidium Chloride Rb 82 Generator
`
`
`Review Number: #1
`
`Dates of Submission(s) Covered by this Review
`Submit
`Received
`Review Request
`06/18/2010
`06/30/2010
`N/A
`
`Assigned to Reviewer
`10/29/2010
`
`
`Submission History (for amendments only): N/A
`
`Applicant/Sponsor
`Name:
`
`Draximage
`Address:
`16751 Trans Canada Highway,
`
`
`
`Kirkland, Quebec, Canada H9H 4J4
`
`U.S. Agent: Kendle International Inc.
`
`
`
`7361 Calhoun Place Suite 500
`
`
`
`Rockville, MD 20855-2765
`
`Representative: Hari Nagaradona, Director Regulatory Affairs
`Telephone:
`(301) 838-3120
`
`
`Name of Reviewer: Dupeh Palmer Ph.D.
`
`
`Conclusion: The submission is not recommended for approval on the
`basis of sterility assurance.
`
`
`Reference ID: 2882025
`
`581 of 1085
`
`

`

`ANDA202153
`
`Microbiology Review #1
`
`Product Quality Microbiology Data Sheet
`
`A.
`
`1.
`
`2.
`
`3.
`
`4.
`
`TYPE OF SUBMISSION: Original ANDA
`
`SUBMISSION PROVIDES FOR: Initial marketing of a sterile drug
`product/PET chug product application.
`
`MANUFACTURING SITE:
`DRAXIMAGE, a division of DRAXIS Specialty Phannaceuticals Inc.
`167 51 Trans Canada Highway
`Kirkland, Quebec, Canada, H9H 4J4
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: A Ruby-FillTM (Rubidium Rb 82) generator for
`IV administration of sterile, pyrogen-free Rubidium Chloride Rb 82
`82RbCl) in 0.9% sodium chloride.
`111><" the
`(
`aenerator delivers a sin le dose ofNMT 60mCi and
`lbH'I
`f
`1
`.
`. ft
`6ff4l
`.
`a maxrmum vo ume o 60mL per m IS10n
`\04
`
`5.
`
`METHOD S OF STERILIZATION:
`
`--6.
`
`PHARl\ilACOLOGICAL CATEGORY: A positron emission
`tomography (PET) product indicated for assessincr regional m~cardial
`perfusion
`11>11.oJ
`
`B.
`
`SUPPORTING/RELATED DOCUMENTS: None
`
`C.
`
`REMARKS: This is an electronic submission.
`
`filename: 202153.doc
`
`Reference ID: 2882025
`
`Page2
`
`582 of 1085
`
`

`

`ANDA202153
`
`Micl'obiology Review #1
`
`Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability - The submission is not
`recommended for approval on the basis of sterility assurance.
`Specific comments and deficiencies ai-e provided in the "Product
`Quality Microbiology Assessment" and "List of Microbiology
`Deficiencies and Comments" sections.
`
`B.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable - NI A
`
`II.
`
`Summary of Microbiology Assessments
`
`A.
`
`Brief Description of the Manufacturing Processes that relate to
`Product Quality Microbiology-
`(bJ(ll
`
`B.
`
`C.
`
`Brief Description of Microbiolo
`recrardin the
`
`Deficiencies - Questions
`(llf
`
`validation studies.
`
`Assessment of Risk Due to Microbiology Deficiencies - The
`safety risk associated with the microbiology deficiencies is
`considered moderate.
`
`III. Administrative
`
`A.
`
`B.
`
`c.
`
`Reviewer's Signature--------------
`
`Endorsement Block
`Microbiologist I Dupeh Palmer, Ph.D.
`Microbiology Team Leader/Lynne Ensor, Ph.D.
`
`CC Block
`cc: Field Copy
`
`Reference ID: 2882025
`
`Page 3
`
`583 of 1085
`
`

`

`ANDA 202153
`
`Micl'obiology Review #1
`
`Product Quality Microbiology Assessment
`
`P
`P .1
`
`DRUG PRODUCT
`Description of the Composition of the Drug Product
`• Description of drug product -
`
`4 generator that produces
`The proposed product consists of a
`(bl<
`Rb-82 by the decay of Strontium-821Sr), ana an accesso1y elution
`system for eluting 82RbCl Injection containing 82RbCl in 0.9% sodium
`chloride.
`
`Proposed maximum commercial batch size: A maximum of1~f generators
`are manufactured per batch.
`
`• Drug product composition - (Folder m3, 32-body-data, 32-drng-prod,
`32pl-desc-comp, p. 2 of3).
`
`All components used in the manufacturing of 82RbCl injection are
`presented in the following table.
`
`Tnble P.1 - 1:
`
`l ngr!'diL•nts
`"SrCI,
`
`Sodium Chloride
`
`Lisi· of components of t be dosage fo1·m, their function, r efrr e11ce to qnnlity sta11dai•d, and amount 011
`Der-unit basis
`
`Qualit y Standard O uant ilx_n_cr ucnentlor
`(b)•r-
`~
`House
`llouse
`
`USP / Ph. Eur.
`
`10114
`
`Ingredient funcl'ion
`Scarting Ma1crial
`(bf('JJ~1an11ic Acid Adsorbent
`
`(6f('4
`
`-• At calibrnhon time
`
`• Description of container closure system - (Folder m3, 32-body-data, 32-
`dtug-prod, 32p7-cont-closure, p. 4 of 85).
`
`A diagram of the Ruby-Fill'™ (Rubidium Rb 82) generator colmnn was
`provided. Com onents of the column are shown in the table below and
`include
`1t1>T4
`
`13 Pages tiave oeen Wittitiela in Full as 84 {CCI/TS) immeaiately following ttiis page
`
`Reference ID: 2882025
`
`Page4
`
`584 of 1085
`
`

`

`ANDA 202153
`
`
`
`
`
`Microbiology Review #1
`
`
`REVIEW OF COMMON TECHNICAL DOCUMENT-
`QUALITY (CTD-Q)
`MODULE 1
`
`A.
`
`PACKAGE INSERT
`
`oC; Route of administration: IV; Container:
`Storage temperature:
`Single dose administered with additive free 0.9% Sodium Chloride
`Injection. Due to the short half-life of Rb-82, most of the radioactivity in
`the eluate decays within
` minutes from the end of elution.
`
`
`2.
`
`Acceptable
`
`
`
`
`
`Reference ID: 2882025
`
`
`
`
`Page 18
`
`
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`585 of 1085
`
`

`

`ANDA202153
`
`Microbiology Review #1
`
`3.
`
`LIST OF MICROBIOLOGY DEFICIENCIES AND
`COMMENTS:
`
`ANDA: 202153
`
`APPLICANT: Draximage
`
`DRUG PRODUCT : Rubidium Chloride Rb 82 Generator
`
`Microbiology Deficiencies:
`
`1. Regardin validation studies conducted
`
`(ti)(4
`
`(a) Please rovide data summaries from
`
`studies with perfonnance dates.
`
`(b) Please state the manufacturer, genus/species of the endotoxin used in challenge
`studies, and provide endotoxin recove1y results including results for positive
`controls.
`
`(c) Please rovide all acceptance criteria associated with successful
`validation rnns.
`- - - - -
`
`(till.ii
`
`2. The endotoxin dose, at the proposed endotoxin specification of NMT ~l EU/mL
`and the maximum adult dose of <bll.il MBq indicated in the package labeling,
`exceeds the Agency's limit of 175 EU/dose for injected radiophannaceuticals.
`Please revise the endotoxin specification for the drng product to confo1m to the
`Agency's 175 EU/dose limit and provide the appropriate documentation to reflect
`the change (e.g. finished product specification and stability protocol, endotoxin test
`validation data summa1y, and any suppo1iing exhibit batch endotoxin test data).
`
`3. Data to support parametric release of the drng product are not provided. Please
`provide data to support parametric release of the drng product. Alternatively, the
`sterility release specification could be revised to comply with 21 CFR 211.165 (a)
`which states:
`
`Sec 211 .165 Testing and release for distribution.
`(a) For each batch of drug product, there shall be appropriate laborat01y
`determination of satisfaction conformance to final specifications for the drug
`product, including identity and strength of each active ingredient, prior to release.
`Where sterility and/or pyrogen testing are conducted in specific batches of short(cid:173)
`lived radiopharmaceuticals, such batches may be released prior to completion of
`sterility and/or pyrogen testing, provided such testing is completed as soon as
`possible.
`
`Reference ID: 2882025
`
`Page 19
`
`586 of 1085
`
`

`

`
`
`
`Microbiology Review #1
`
`
`ANDA 202153
`
`
`Please clearly identify your amendment to this facsimile as “RESPONSE TO
`MICROBIOLOGY DEFICIENCIES”. The “RESPONSE TO MICROBIOLOGY
`DEFICIENCIES” should also be noted in your cover page/letter.
`
`
`Sincerely yours,
`
`
`
`
`
`
`
`
`{See appended electronic signature page}
`
`Lynne A. Ensor, Ph.D.
`Microbiology Team Leader
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`
`
`
`Reference ID: 2882025
`
`
`
`
`Page 20
`
`
`
`587 of 1085
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DUPEH G Palmer-Ochieng
`12/22/2010
`
`ELIZABETH T MCNEAL
`12/22/2010
`Checked file and submission link. Both correct.
`
`LYNNE A ENSOR
`01/03/2011
`
`Reference ID: 2882025
`
`588 of 1085
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202153Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`589 of 1085
`
`

`

`NDA
`
`Submission Date
`
`Brand Name
`Formulation
`OCP Reviewer
`OCP Team Leader
`OCP Division
`OND Division
`Applicant
`Submission Type
`
`
`
`
`
`Clinical Pharmacology Review
`202-153
`December 28, 2015 (SDN 30)
`May 3, 2016 (SDN 33)
`July 25, 2016 (SDN 44)
`RUBY-FILL (rubidium Rb 82 generator)
`For intravenous administration
`Christy S John, Ph.D.
`Gene M. Williams, Ph.D.
`Division of Clinical Pharmacology V
`Division of Medical Imaging Products
`Jubilant Draximage, Inc.
`Resubmission/Class 2
`
`Dosing regimen
`
`Indication
`
`
`
`Rubidium Rb 82 chloride injection is a radioactive
`diagnostic agent indicated for Positron Emission
`Tomography (PET) imaging of the myocardium under
`rest or pharmacologic stress conditions to evaluate
`regional myocardial perfusion in adult patients with
`suspected or existing coronary artery disease
`
`
`Reference ID: 3993384
`
`1
`
`(b) (4)
`
`590 of 1085
`
`

`

`
`Table of Contents
`1 Executive Summary……………………………………………………………………..2
`1.1
`Recommendations……………………………………………………………….2
`1.2
`Post-Marketing Requirements and Commitments………………………………2
`1.3
`Summary of Clinical Pharmacology Findings…………………………………..2
`2 Question Based Review…………………………………………………………………4
`2.2 General Clinical Pharmacology ………………………………………………...4
`3 Detailed Labeling Recommendations…………………………………………………....5
`
`EXECUTIVE SUMMARY
`
` 1
`
`
`
`
`The current NDA is a re-submission of a 505(b)(2) NDA that received a complete response (CR)
`on December 18, 2014. The CR letter was issued due to deficiencies in clinical (human factors
`study and training materials) and chemistry and manufacturing controls (CMC). The prior NDA
`was not reviewed by clinical pharmacology because of the similarity of the product and proposed
`package insert to those of the referenced approved product, Cardiogen. The current submission is
`being reviewed because labeling negotiations for the current NDA resulted in the applicant
`suggesting that section 2 Dosage and Administration of their package insert deviate from that
`of Cardiogen.
`
`The proposed package insert changes are supported by literature publications and broadly
`consistent with the guidelines of professional societies. In principle, we find them acceptable.
`
`1.1
`
`The re-submission is approvable from a clinical pharmacology perspective.
`
`Labeling Recommendations
`
`Our recommendations for the package insert appear in Section 3 DETAILED LABELING
`RECOMMENDATIONS.
`
`1.2
`
`We have no recommendations for PMRs or PMCs.
`
`1.3
`
`No clinical or clinical pharmacology studies were conducted by the applicant. The reference drug
`for the current 505 (b) (2) NDA is Cardiogen. The Cardiogen package insert recommends a dose
`of 1480 MBq (40 mCi), with a range of 1110-2220 MBq (30-60 mCi), and an upper limit of
`2220 MBq (60 mCi).
`
`
`Recommendations
`
`Post-Marketing Requirements and Commitments
`
`Summary of Clinical Pharmacology Findings
`
`
`Reference ID: 3993384
`
`2
`
`591 of 1085
`
`

`

`Rather than duplicating the Cardiogen package inse1i, the applicant proposes weight-based
`dosing. To suppo1i their proposal, the applicant conducted a MED LINE database search for the
`period of 111/2007 to 6/29/2016. Of the 36 pe1iinent aiiicles, studies, 12 studies used weight(cid:173)
`based dosing (3-10 MBq/kg) with a mid-range of activity 24 mCi and a range 16-32 mCi. There
`were 16 studies using weight-based dosing which did not provide the dose, the mean activity
`administered in these studies was 44 mCi, and the lowest administered dose was 20 mCi. Eight
`studies used fixed dosing with a mid-range activity of 44 mCi and the lowest administered dose
`was 15 mCi. None of the 36 studies included comparisons between two or more doses.
`
`The applicant 's proposal to base recollllllendations on cmTent clinical use as identified by
`literature aiiicles and the judgment of professional societies is reasonable. The proposal includes
`a dose range sufficiently wide to allow institutions with 2D-imaging cameras to dose within the
`package inse1i recommendations. At the same time, those with 3D-imaging cameras can choose
`lower doses that ai·e within the package inse1i range. As coupling the dose with the imaging
`technology is cunently rejected, we agree with the proposal to give a broad dose range. We also
`agree with the use of weight-based dosing, as it is suppo1ied by the clinical use data and will
`minimize llllilecessaiy radiation exposure.
`
`SIGNATURES
`
`Reviewer: Christy S John, Ph.D.
`Division of Clinical Phaimacology V
`
`Team Leader: Gene Williams, Ph.D.
`Division of Clinical Phaimacology V
`
`Cc: DMIP: PM F. Lutterodt.; MTL I. Krefting; MOM. Fedowitz, I. Krefting
`DCPV: DDD B . Booth; DD A. Rahman
`
`Reference ID: 3993384
`
`3
`
`592 of 1085
`
`

`

` 2
`
`
`
`QUESTION-BASED REVIEW
`
`
`2.2 GENERAL CLINICAL PHARMACOLOGY
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`
`The reference drug for the current 505 (b) (2) NDA is Cardiogen. The Cardiogen package insert
`recommends a dose of 1480 MBq (40 mCi), with a range of 1110-2220 MBq (30-60 mCi).
`
`No clinical studies were conducted by the applicant.
`
`Rather than duplicating the Cardiogen package insert, the applicant proposes weight-based
`dosing. To support their proposal, the applicant conducted a MEDLINE search for the period of
`1/1/2007 to 6/29/2016. Of the 36 pertinent articles, 12 studies used weight-based dosing (3-10
`MBq/kg; 0.081-0.27 mCi/kg) with a mean activity of 24 mCi and a range 16-32 mCi. There were
`16 studies using weight-based dosing which did not provide the dose, the mean activity
`administered in these studies was 44 mCi, and the lowest administered dose was 20 mCi. Eight
`studies used fixed dosing with a mean activity of 44 mCi, and a lowest administered dose of 15
`mCi. None of the 36 studies included comparisons between two or more doses.
`
`The applicant presents data showing that from 2002 to 2016 there was a trend of decreasing
`administered radioactivity (Figure 1).
`
`
`
`Figure 1. Administered radioactivity (mCi) versus time (calendar year); each data point is a
`literature study, vertical lines are ranges within the study, points in gray area not included in
`dotted trend line.
`
`
`
`
`
`
`
`Reference ID: 3993384
`
`4
`
`593 of 1085
`
`

`

`Reviewer 's Comment
`A fonnal meta-analysis for efficacy was not conducted by the applicant. The applicant's implicit
`reasoning is that the widespread use of lower dosing is evidence that lower doses provide
`adequate efficacy.
`
`The decrease in dose across time that the applicant presents coincides with the introduction of
`3D PET imaging equipment. 3D acquisition can allow greater resolution, thus allowing equi(cid:173)
`effective imaging at lower radioactivity doses.
`
`The applicant's proposal to base recommendations on cmTent clinical use identified from
`literature aiticles and the judgment of professional societies is reasonable. The proposal includes
`a dose range sufficiently wide to allow those with 2D-imaging cameras to dose within the
`package inse1t recommendations. At the same time, those with 3D-imaging cameras can choose
`the lower doses that are within the package inse1t range. As coupling the dose with the imaging
`technology is cunently rejected, we agree with the proposal to give a broad dose range. We also
`agree with the use of weight-based dosing, as it is suppo1ted by the clinical use data and will
`minimize unnecessa1y radiation exposure.
`
`3
`
`DETAILED LABELING RECOMMENDATIONS
`
`The package inse1t proposed in the July 25, 2016 submission, together with our recommended
`edits, appears below as Table 1.
`
`Reference ID: 3993384
`
`5
`
`594 of 1085
`
`

`

`Table 1. Packa2e Insel't
`Reviewel''s Recommended
`_____ A_ pplicant's Pl'op._o_s_e_d____
`!bT~ ~.2 !Recommended Dose and
`Administt'ation Instt'uctions
`
`Comment [WGMl ]: Sectionmmberchanged
`!bTC4} to 2 2 due to re-arrangemeot of other
`elements of section 2 by Medical Officer
`
`J
`
`• The re.commended weight-based dose
`of Rb 82 to be administered per rest or
`stress component of a PET myocardial
`perfilsion imaging (MPI) procedure is
`10-30 Megabecquerels
`between
`(MBq)/kg
`[0.27-0.81
`millicuries
`(mCi)/kg].
`
`• Do not exceed a single dose of 2220
`MBq (60 mCi).
`• Use the lowest dose necessary to obtain
`adequate cardiac visualization and
`individualize the weight-based dose
`on multiple
`factors,
`depending
`including, patient weight,
`imaging
`equipment and acquisition type used to
`perfonn the procedure. For example,
`3D imaging acquisition may require
`doses at
`the
`lower end of
`the
`recommended range compared to 2D
`imaging.
`
`6
`
`Reference ID: 3993384
`
`595 of 1085
`
`

`

`•
`
`• Administer the single dose at a rate of
`15 - 30 mL/minute through a catheter
`inserted into a large peripheral vein; do
`not exceed an infusion volume of 60
`mL.
`Instruct patients to void as soon as a
`study is completed and as often as
`possible thereafter for at least one hour.
`available
`activity
`• The maximum
`(delivery limit) will decrease as the
`[see Dosage and
`generator ages
`Administration (2.8)].
`
`
`
`
`
`
`2.3 Image Acquisition Guidelines
`
`For Rest Imaging:
`• Administer a single (“rest”) rubidium
`Rb 82 chloride dose;
`imaging 60-90 seconds after
`• Start
`completion of the infusion of the rest
`dose and acquire
`images for 3-7
`minutes.
`
`
`
`
`
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`
`
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`
`
`
`
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`
`
`7
`
`Reference ID: 3993384
`
`(b) (4)
`
`596 of 1085
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`For Stress Imaging:
`the study 10 minutes after
`• Begin
`completion of the resting dose infusion,
`to allow for sufficient Rb 82 decay;
`• Administer a pharmacologic stress
`agent in accordance with its prescribing
`information;
`the
`of
`administration
`• After
`pharmacologic stress agent, administer
`the second dose of Rb 82 at the time
`interval according to the prescribing
`information of
`the pharmacological
`stress agent;
`imaging 60-90 seconds after
`• Start
`completion of the stress rubidium Rb
`82 chloride dose infusion and acquire
`images for 3-7 minutes.
`
`
`
`
`
`
`
`
`For Both Rest and Stress Imaging:
`is
`time
`If a
`longer
`circulation
`•
`anticipated (e.g., in a patient with
`severe
`left ventricular dysfunction),
`start imaging 120 seconds after the rest
`dose.
`• Acquisition may be started immediately
`post-injection if dynamic imaging is
`needed.
`
`
`
`8
`
`
`
`
`
`
`Reference ID: 3993384
`
`(b) (4)
`
`597 of 1085
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTY S JOHN
`09/30/2016
`
`GENE M WILLIAMS
`09/30/2016
`I concur with the recommendations
`
`Reference ID: 3993384
`
`598 of 1085
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`

`

`DIVISION OF BIO EQUIV ALEN CE REVIEW
`
`202153*
`Rubidium Chloride Rb-82 Generator (Ruby-Fill®)
`NIA** (Generator ofj lbH(j mCi of Strontium 82 (Sr 82))
`
`- .
`
`,
`
`Jubilant Draxlmage Inc.
`16751 TransCanada Highway
`Kirkland, Quebec, Canada
`H9H 4J4
`
`Hari Nagaradona
`INC Research, LLC ***
`7361 Calhoun Place, Suite 500
`Rockville, MD 20855-2765
`
`301 -296-1370
`301 -838-3182
`
`6/1812010
`
`NIA
`
`Rong Wang, Phaim.D., Ph.D.
`
`NA
`
`!I
`Generator o[
`NA
`
`16
`
`ff4j mCi Sr 82
`
`I ANDA No.
`
`Dl'llg Product Name
`
`Strength(s)
`Applicant Name
`
`Addr ess
`
`Applicant's Point of Contact
`
`Contact' s Telephone Number
`
`Contact's Fax Number
`Original Submission Date(s)
`Submission Date(s) of
`Amendment(s) Under Review
`Reviewer
`
`Study Number (s)
`Study Type (s)
`Sh·ength (s)
`
`Clinical Site
`
`Clinical Site Address
`
`Analy tical Site
`Analytical Site Add1·ess
`
`NA
`NA
`
`NA
`
`ADEQUATE
`
`I OUTCOME DECISION
`* As advised by the Agency, the cmTent submission was converted from an Abbreviated New Dmg
`Application (ANDA) under section 505 G) to a New Drug Application (NDA) under Section 505 (b) (2) of
`the statute. The OGD retains limited authority to approve 505(b)(2) applications and NDA 202153 was
`2
`dete1mined to be one of those applications 1
`• Therefore, NDA 202153 is being reviewed by the Office of
`•
`Generic Dmgs (OGD).
`** In the Orange Book, the strength is listed as NIA for the RLD product.
`***According to the Fonn-356h submitted on 111712013.
`
`1 Note: Details please also see the internal email com111m1ications within OGD in section 4 Appendix in the
`cutTent review.
`2 DARRTS: ANDA 202153; EDR submission on 1/1712013; Cover Letter.
`
`Reference ID: 3252475
`
`Page 1 of 18
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`

`

`1
`
`EXECUTIVE SUMMARY
`
`This application which was initiall submitted as an Abbreviated New Drng AEplication
`(bJl4
`ANDA,
`
`for tlie test proauct, Rulllilium Clilonae Ro 82 Generator,
`'u"" mCi of Sr-82 at calibration time. The reference listed drng (RLD) product is
`'""c-ru-·d"""i-ogen-82® (rnbidium chloride Rb 82 Generator), 90-150 mCi of Sr-82 at calibration
`time, manufactured by Bracco Diagnostic, Inc. (NDA 019414, approved on 12/29/1 989).
`
`According to the internal meeting minutes dated 11/16/2012 3
`, the generic applicant for
`ANDA 202153 proposed different 'condition of use' in the label for the test product
`(Infusion Rate and Maximum Volume to be administered) compru·ed to the RLD product.
`Due to differences in the drng products' labeling, the Office of Generic Drngs (OGD)
`considered that the test product is NOT eligible for approval under section 505 G) of the
`statute. Additionally, on December 12, 2012, the Office of New Drng Quality
`Assessment (ONDQA) completed its initial quality assessment on the test product, in
`response to the consult re uest from the OGD's Division of Chemistry. The ONDQA
`1
`4
`reviewer
`> <
`raised safety concerns for the different infusion rate proposed for the test product
`(Ruby-Fill®) from the RLD product (Cru·diogen-82®). As advised by the Agency, the
`fom then resubmitted the application to the OGD as a New Drng Application (NDA)
`under section 505 (b) (2)1 (for details please also see section 4 Appendix). According to
`the email sent by Thomas Hinchliffe from OGD, NDA 202153 will still be reviewed by
`OGD.
`
`<1
`
`Rubidium Chloride Rb 82 Generator (Ruby-Fill) contains Sr 82 chloride adsorbed onto
`hydrous 14 stannic oxide in a column. Elution of the generator column with 0.9% Sodium
`Chloride rn·ection USP produces the final product, Rubidium Chloride Rb 82 rn·ection
`USP.
`4
`(llJl
`
`The Division of Bioequivalence I (DBI) has
`------~------------------------
`reviewed the component and composition of the final product. The final product
`Rubidium Chloride Rb 82 rn· ection USP solution administered to a atient by infusio p:
`
`contams tlie active mgreaient, rn6iaium clilorlcle
`0.9% sodium chloride .
`
`3 DARRTS: ANDA 202153; DOAN, DATT 11116/2012 NIA 11/ 16/2012 FRM-MINUTES-Ol (Intemal
`Meeting Minutes) Original-I (Unknown) Archive
`
`Reference ID: 3252475
`
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`

`

`
`
`
`
`
`
` 2
`
`TABLE OF CONTENTS
`
`
`1 Executive Summary ................................................................................................................................ 2
`2 Table of Contents .................................................................................................................................... 3
`3 Submission Summary.............................................................................................................................. 4
`3.1 Drug Product Information ................................................................................................................ 4
`3.2 PK/PD Information .......................................................................................................................... 4
`3.3 OGD Recommendations for Drug Product ...................................................................................... 5
`3.4 Contents of Submission.................................................................................................................... 7
`3.5 Formulation...................................................................................................................................... 7
`3.6 Waiver Request(s)............................................................................................................................ 7
`3.7 Formulation...................................................................................................................................... 7
`3.8 Deficiency Comments.................................................................................................................... 10
`3.9 Recommendations.......................................................................................................................... 10
`3.10 Comments for Other OGD Disciplines .......................................................................................... 12
`4 Appendix............................................................................................................................................... 13
`5 Outcome Page ....................................................................................................................................... 18
`Completed Assignment for 202153 ID: 15909 ............................................................................................. 18
`
`
`Reference ID: 3252475
`
`Page 3 of 18
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`

`

`3
`
`SUBMISSION SUMMARY
`
`3.1
`
`Drug Product Information 4
`
`Test Product
`
`R eference P1·oduct
`
`Rubidium Chloride Rb 82 Generator,f
`
`lb){~ mCi of Sr 82 (Ruby-Fill®)
`
`Cardiogen-82® (rnbidium chloride Rb-82 Generator) , 90-150 mCi of
`Sr 82
`
`RLD Manufactw·er
`
`Bracco Diagnostics Inc.
`
`NDA No.
`
`RLD Approval Date
`J
`Indication
`
`019414
`
`December 29, 1989
`
`CardioGen-82® is a closed system used to produce rnbidium chloride
`Rb 82 for intravenous injection use. Rubidium chloride Rb 82 injection
`is a radioactive diagnostic agent indicated for Positron Emission
`Tomography (PE1) imaging of the myocardium under rest or
`pha.tmacologic stress conditions to evaluate regional myocardial
`perfusion in adult patients with suspected or existing coronary arte1y
`disease.
`
`3.2
`
`PK/PD Information5
`
`Bioavailability
`
`Food Effect
`
`Tmax
`
`Metabolism
`
`Excretion
`
`Intrnvenous, therefore 100%.
`
`Not applicable for I.V. injection
`
`Not indicated in the mug label
`
`Not indicated in the mug label
`With a physical half-life of 75 seconds, Rb-82 is ve1y rapidly converted
`by radioactive decay into trace amount of stable Kr-82 gas, which is
`passively expired by the lungs. Renal and hepatic excretion is not
`anticipated to play an essential role in Rb-82 elimination, although some
`of the Rb-82 dose may be excreted in the urine prior to radioactive
`decay.
`
`Half-life
`
`Drng Specific Issues (if any)
`
`The physical half-life ofRb-82 is 75 seconds.
`Black Box Warning
`
`WARNING: UNINTE1'1DED STRONTIUM-82
`STRONTIUM-85 (Sr-85) RADIATION EXPOSURE
`
`(St·-82) AND
`
`Unintended radiation exposure occurs when the levels of Sr-82 or Sr-85
`in the rnbidium Rb 82 chloride iitjection exceed specified lllnits
`
`Pe1f01m 2enerator eluate tests:
`
`\Off(
`
`I
`
`4 Orange Book, Seat-di Te1m: rnbidium, last accessed on 1/22/2013.
`5 Thugs@ FDA, Search term: rnbidium; Label info1mation, last access 1122/2013
`
`Reference ID: 3252475
`
`Page 4of 18
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`

`

`\D}\.I
`
`1Dm '
`
`3.3
`
`OGD Recommendations for Drug Product
`
`Numbe1· of studies recommended:
`
`NIA-Waiver Request
`
`Analytes to measu re
`(in
`plasma/serum/blood):
`
`NA
`
`Source of most 1·ecent None available from OGD.
`However, FDA's draft Guidance- FDA Oversight of PET Dmg Products -
`recommendations:
`Questions and Answers, issued Febmary 2012 is available @
`http://www.fda.gov/downloads/Dmgs/GuidanceComplianceRegulato1y information
`/Guidances/UCM290024.pdf
`
`Reference ID: 3252475
`
`Page 5of 18
`
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`

`

`Summal'y of OGD OI'
`DBE History
`(for· details, see
`Appendix 4.2) :
`
`As of 1/22/2013, the OGD has received only one control coITespondence related to
`Rubidium Rb 82 generator, which was submitted by Draximage on 6/ 12/2008. The
`control coITespondence was requesting a type C meeting with