CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208700Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`NDA 208700 (Resubmission)
`OPQ Integrated Quality Assessment final
`Review Date: 12/13/2017
`
`Dru ; Product
`-
`
`Route of Administration
`Rx/OTC Dis -
`l ed
`‘
`u licant
`
`US aent, if .
`
`. licable
`
`N/A
`
`Lutetium Lu 177 Dotatate / Lutathera
`370 MB - /n1L
`
`IV in'ection
`Rx
`Advanced Accelerator A lications
`
`Quality Review Data Sheet
`1. LEGAL BASIS FOR SUBMISSION: 505b2
`
`2. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs: See .revious IQA
`
`Table l Dru_ Master Files
`
`'WS
`
`TYPE
`
`ITEM
`
`REFERENCED
`
`STATUS
`
`DATE
`REVIEW
`COMPLETE
`
`REVIEWER
`
`——-EEE?E_
`
`Pea Krier.Ph-D-
`KrishnakaliGhosh. Ph-D-
`
`& FDA 483
`
`Project/Manager Gk Ph)
`
`”Iliao Vu/Steven Kinsley
`
`OMPT/CDER/OPQ/OPRO/ORDP
`MI/RBPMBI
`
`Application Techmcal Lead
`Eldon E.Le11tzinger. PhD.
`ONDP/Branch VII/Division H
`Environmental Assessment
`John Amartey. Ph.D.
`ONDP/Branch VII/Division 11
`(EA)
`
`RECEIPT DATE
`
`Table 2 Documents
`DESCRIPTION
`
`Section/reviewer
`
`Resubmission
`
`7/26/2017
`
`Application + inspectional documents
`
`Krishna Ghosh/OPF
`
`

`

`1.
`
`Recommendations
`
`Executive Summary
`
`APPROVAL, based on CMC, Microbiology Product Quality and Facility Inspections
`
`A. Recommendation and Conclusion on Approvability
`N/A
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`N/A
`
`Summary of Quality Assessments
`II.
`BACKGROUND:
`
`The Drug Product is a ready—to—use radiopharmaceutical contained in a 30 mL single-use
`glass vial. The vial fits in a lead pig. The pig with the vial is placed in the
`(5x4)-
`m". The dosage
`form is a solution for intravenous infusion, at a strength of 370 MBq/mL (10 mCi/mL)
`“"0
`
`The shelf-life is 72 hours "“0
`
`A Complete Response Letter was issued 12/19/2016 listing multiple clinical issues, as well as
`deficiencies identified during inspection of the manufacturing facilities. Those facilities included
`‘Advanced Accelerator Applications (Meldola, Italy; Ivrea, Italy), and IDB Radiopharmacy B.V.,
`the Netherlands.
`
`A. Drug Substance [USAN Name] Quality Summary
`The Drug Substance is 177Lu-DOTA°-Tyr3-Octreotate, a radiolabeled peptide, and has the
`following molecular structure:
`
`, n
`~
`
`
`o ,4(
`0..
`
`N
`
`*
`no,c
`no ,.\
`x
`
`-0
`/ ».
`,
`
`
`M-\n
`
`,
`
`,,
`.1.
`
`.
`
`.
`
`x
`
`n
`._ ~
`0
`"" N
`0 °
`x " /
`a.
`4
`°
`O o’ ‘nn
`a S
`o
`°"
`0 .
`4
`-
`u
`,» // o
`-.
`" ma y"? N .-
`N01
`0 a u
`.v
`
`N"
`
`«u,
`
`7
`
`I
`
`The peptide sequence is d—Phe-Cys—Tyr—d—Trp-Lys-Thr-Cys-Thr (cyclo 2,7), containing 8 amino
`acids, and has a molecular weight of 1535.6 g/mol. There is a -S-S- disulfide linkage between the
`two Cys amino acids, connecting the two cysteine amino acids of the peptide together. DOTA is
`attached to the d-Phe end of the peptide through an amide linkage by utilizing one of the
`carboxylic acid groups in the ligand. and the free amino group of HzN-d-Phe-Cys-Tyr-d-Trp-Lys-
`Thr-Cys-Thr (cyclo 2,7). D-Trp“ and Lys5 each possesses a N-atom that can be protonated, and
`in NDA 208700, the counter-ion used is trifluoroacetate, two per peptide. Afier linking DOTA
`to the peptide, there are remaining 3 carboxylic acid groups and 3 ring N-atoms for binding to
`177Lu’“. The radiolabel (”7Lu3“) is bound within the DOTA cavity.
`
`The overall process for production of drug substance is as follows.
`
`M”
`
`(b) (4)
`
`

`

`
`
`B. Drug Product [Established Name] Quality Summary
`Product Vial composition consists of an a ueous solution containing 177Lu—DOTA"—Tyr3—
`Octreotate (370 MBq/mL
`), plus excipients (Acetic Acid,
`
`Sodium Acetate, Gentisic ACl
`DTPA an Sodium Chloride). Each vial will
`contain suflicient volume of solution 20.5 — 25.0 mL) to allow for delive of 7.4 GBq :I: 10% at
`time of injection. A dose of 7.4 GBq corresponds to 7.4 x 103 MBq, or
`mCi.
`
`CMC Product Quality:
`
`In the ori
`'
`submission, there were dru substance issues,
`
`
`
`All issues were resolved, and the
` final recommendation from CMC was approval.
`
`
`
`Microbiology Product Quality:
`Similarl , there were multi le Microbiolo
`
`Product
`
`
`
`
`All microbiological
`product quality issues were resolved, and there was an approval recommendation from
`microbiology. A determination was made that a review from Microbiology is not necessary,
`since a recommendation of approval had been made, based on Microbiology Product Quality
`(Peggy Kriger, email of 9/19/2017).
`
`Facilities Inspection Status:
`There were 3 manufacturing sites out of 6 recommended for withhold until correction of the 483
`observations are complete. All 483 issues have been addressed, and no re-inspection per the
`resubmission is needed — by determination of Krishnakali Ghosh, Ph.D. (OPQ/OPF/DIA/Bl). On
`
`

`

`review of the application (Krishna Gosh, OPQ/OPF/DIA/BI), including the inspectional documents
`and responses to the FDA 483, a determination was made (OPF) that there are no outstanding
`manufacturing or facility risks preventing the approval of the NDA.
`
`C. Summa
`
`of Dru Product Intended Use
`
`Pro . rieta! Name of the Dru_ Product
`Non Proprietary Name of the Drug Product
`
`Lutathera—
`(lnLu-DOTAo-Tyl3-Octreotate) solution for
`intraveneous infusion
`
`Non Pro rieta Name of the Dru_ Substance
`Proposed Indication(s) including Intended
`Patient Population
`
`177Lu-DOTAo-Tyl3-Oct1'eotate
`Treatment of somatostatin receptor positive
`gastroenteropancreatic neuroendocrine tumors
`(GEP—NETs) including foregut. midgut and hindgut,
`
`neuroendocrine tumors in adults
`
`D. Biopharmaceutics Considerations
`1. BCS Classification: N/A
`
`0 Drug Substance:
`0 Drug Product:
`
`2. Biowaivers/Biostudies:N/A
`
`0 Biowaiver Requests
`0 PK studies
`0 IVIVC
`
`E. Novel Approaches
`N/A
`
`F. Any Special Product Quality Labeling Recommendations
`N/A
`
`G. Life Cycle Knowledge Information (see Attachment A)
`N/A
`Risk Assessment — Drug Product
`From Initial Risk Identification
`
`(5x4)
`
`Comments“ Factors that can impact
`
`the CQA
`
`'
`
`'
`
`'
`
`Risk Mitigation
`Approach
`
`Final Risk
`Evaluation2
`
`Lifecycle
`Considerations!
`
`Based on CMC and Microbiology Product Quahty considerations. Nevertheless there was a
`recommendation for withhold on three sites during the original review of the NDA (after a PAI
`inspection was conducted at the sites) until there was a satisfactory response to an FDA 483 for
`these sites.
`
`2. Overall Risk Assessment continues to be Low (RPN < 25). based on no new CMC issues
`uncovered, along with the standing decision of approval by Microbiology Product Quality (no
`review of resubmission necessary). Additionally. based on a review of the application (Krishna
`Gosh. OPQ/OPF/DIA/BI) inspectional documents and responses to the FDA 483. a determination
`was made (OPF) that there are no outstanding manufacturing or facility risks preventing the
`approval of the NDA.
`
`Application Technical Lead: Eldon E. Leutzinger, Ph.D., CMC Lead
`
`E I d O n E .
`
`Digitally signed by Eldon E. Leutzinger -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA. ou:People,
`09234219200300.1001 .‘l :1 300054329,
`.
`_
`=Eldo E.L tzi
`-S
`LeutZI nger S 3:...9em.
`
`

`

`Eldon
`Leutzinger
`
`Digitally signed by Eldon Leutzinger
`Date: 12/14/2017 10:16:48AM
`GUID: 508da7210002a0781943eff6cc724d1f
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208700
`
`OPQ N208700 Integrated Quality Assessment
`Final
`
`Review Date:
`
`Lutathera/solution
`Dru Name/Dosae F01In
`Em_ 370 MB - lmL
`Route of Administlation
`Rx/OTC Dis n ensed
`
`
`
`US a_ent if a :licable
`
`N/A
`
`Advanced Accelerator A lications
`
`Quality Review Data Sheet
`
`1. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`2. RELATED/SUPPORTING DOCUMENTS:
`A. DMFs:
`
`
`
`11/17/2016
`
`John Amar’tey.
`Ph.D. (CMC)
`
`INIFs
`DATE
`REVIEW
`COMPLETE
`
`REVIEWER
`
` Table l Dru Master Files
`
`ITEM
`
`HOLDER
`
`REFERENCED
`
`(5X
`
`
`
`\0) l“) H
`
`(D) (4) 2
`
`10/23/2015
`
`Martin Haber.
`Ph.D.
`
`John Amartey.
`Ph.D. (CMC)
`
`
`
`During NDA John Amar’tey
`review
`Ph.D. (CMC)y
`
`
`
`The DMF #
`
`2Adequate. Adequate with Information Request. Deficient. or N/A (There is enough
`data in the application. therefore the DMF did not need to be reviewed)
`
`B. Other Documents: 1ND, RLD, or sister applications: N/A
`
`

`

`3. CONSULTS: N/A
`
`Quali Review Team
`
`Project/Manager m. Ph)
`
`A lication Technical Lead
`Laborato OTR
`ORA Lead
`
`OMPT/CDER/OPQ/OPRO/OR
`MIIRBPMBI
`
`Eldon Leutzin'er
`
`0NDP/Branch VII/Division II
`
`
`
`(EA)
`
`
`Table 2 Documents
`
`DESCRIPTION
`um RECEIPT DATE
`John Amartey. Ph.D.
`Original Submission
`0000
`03/31/2016)
`labeling —
`0021
`07/13/2016
`0023,. 0024
`08/05. 12/2016 IJ_—
`0028
`
`09/09/2016 _—
`
`Executive Summary
`
`I.
`
`Recommendations
`
`APPROVAL. pending satisfactory correction of the FDA 483 observations for three of six
`manufacturing sites.
`
`A. Recommendation and Conclusion on Approvability
`1. Summary of Complete Response issues
`
`Recommendations:
`
`CMC — Approval
`Microbiology — Approval
`Manufacturing facilities — Withhold
`
`All CMCIssues identified fm the IIIno substance and III“0 p1oduct, and the associated
`DMF’S
`on»are Iesohed. There are no
`issues
`based on an acceptable D\IF
`om held by
`(but) (reviewed by MaItin Haber, Ph.D.(”(0/123/201<)1n conjunction
`with NDA
`one ,the latter appr0\'ed
`
`Issues for IVIicrobiology are resolved, and their recommendation is approval. Remaining
`are multiple obsen-‘ations (FDA 483) regarding 3 out of 6 manufactun‘ng facilities. These 3
`sites are recommended for withhold. As indicated by KIishnakali Ghosh of OPQ/OPF,
`some of the corrective actions on the 483 obsewations will take until Jauualy to complete.
`During this cycle, we did not perform a drug product labeling review.
`
`

`

`Resolved
`
`Resolved
`
`Resolved
`
`Resolved
`
`
`
`Three manufacturing sites out of 6
`are recommended for withhold until
`correction of the 483 observations is
`complete
`
`Resolved (recommend Approval); see
`Microbiology Review (attached)
`
`Based on FDA 483 observations,
`there are 3 sites (10010 Colleretto
`Giacosa, Italy; 47014 Meldola, Italy;
`Baarle-Nassau, 5111 PV, the
`Netherlands) that will be withheld,
`due to inadequate responses to
`address the issues. Many of these
`issues involve microbiolo 3 .
`
`2. Action letter language, related to critical issues such as expiration date: N/A
`3. Benefit/Risk Considerations: see Risk Assesncnt at end of executive summary.
`
`

`

`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvahle
`N/A
`
`II.
`
`Summary of Quality Assessments
`
`INTRODUCTION:
`
`The Drug Product is a ready—to—use radiopharmaceutical. The aqueous solution of product is
`contained in a 30 mL single-use glass vial (far left-side in the following picture). The vial fits in
`one
`
`the lead pig shown in the center.
`
`The pig with the vial is placed in
`«no
`
`The dosage form is a solution for intravenous infusion,
`at a strength of 370 MBq/mL (10 mCi/mL)
`(but)
`
`one
`
`Vial composition consists of an aqueous solution containing 177Lu-DOTAo—Tyr3—Octreotate
`(3 70 MBq/mL
`(”(0), plus excipients (Acetic Acid, Sodium Acetate,
`Gentisic Acid,
`“"9 DTPA and Sodium Chloride). Each vial will contain sufficient
`volume of solution (20.5 — 25.0 mL) to allow for delivery of 7.4 GBq i 10% at time of injection.
`A dose of 7.4 GBq corresponds to 7.4 x 103 MBq. or 0”“) mCi.
`
`A. Substance [USAN Name] Quality Summary
`The Drug Substance is 17I'Lu—DOTAO—Tyr3—Octreotate, a radiolabeled peptide, and has the
`following molecular structure:
`
`The peptide sequence is d-Phe-Cys-Tyr-d-TIp-Lys-Thr-Cys-Thr (cyclo 2.7), containing 8 amino
`acids, and has a molecular weight of 1535.6 g/mol. There is a -S-S- disulfide linkage between the
`two Cys amino acids, connecting the two cysteine amino acids of the peptide together. DOTA is
`attached to the d—Phe end of the peptide through an amide linkage by utilizing one of the
`carboxylic acid groups in the ligand, and the free amino group of HzN-d-Phe—Cys-Tyr-d-Trp-Lys—
`Thr-Cys-Thr (cyclo 2.7). D-Trp4 and Lys5 each possesses a N-atom that can be protonated. and
`in NDA 208700. the counter-ion used is uifluoroacetate. two per peptide.
`
`After linking DOTA to the peptide. there are remaining 3 carboxylic acid groups and 3 ring N-
`atoms for binding to 177Lu”. The radiolabel (177Lu3‘) is bound within the DOTA cavity. The
`lanthanides can have large coordination numbers (up to 12), and thus mLu3+ will utilize all of its
`possible coordination sites to “bind” to all 4 ring N—atoms. and the 3 available carboxylic acid
`
`

`

`arms (O-atoms) of DOTA. As a result, the 177Lu3+ ion is well-buried in the complex, with the
`metal ion flanked by the 4 N-atoms (below plane of paper) and the 3 carboxylic acid groups
`(above plane). Because 177Lu3+ is engulfed by the ligand, it has important consequences for in
`vitro stability, and perhaps in vivo stability that are potentially of clinical significance.
`Since the
`3 carboxylic acid groups of DOTA are involved in binding to 177Lu3+, and none remaining. the
`complex carries no charge (+3 — 3 = 0). The molecular weight of "‘Lu- DOTAo-Tyr30cueofide
`is 1609.6.
`
`mm:
`
`Lutetium (Lu), a rare earth. is the last member of the lanthanide period. There are 35 isotopes
`of Lu. But, of these 35 isotopes, only l75Lu (stable) and 176Lu (3.78 x 1010 years) are naturally
`occurring (97.41% and 2.59% abundance, respectively).
`177Lu (the subiect isotope in Lutathera)
`is produced
`(no) Lutetium has an
`electronic configuration of [Xe]4f“5dl6s2, with a fully filled 4f-orbital. Lu” ion is formed b
`loss ofthe two 6s-electrons and one 5d-electron, and has an electronic configuration of [Xe]4tX1.
`Another prominent aspect of the lanthanide elements is the preponderance of the very stable +3
`oxidation state in their aqueous solution chemistry. Only for Sm, Eu and Yb is there an
`additional +2 oxidation state. The single oxidation state of Lu3+ translates to assurance of
`formation of a single molecular entity on complexation with an appropriate ligand (except
`for the possibility of stereoisomers). Lu is also strongly electropositive, meaning that Lu”
`will strongly attract electronegative ions (e.g., 0— and N—atoms of simple non—cyclic and
`multidentate ligands), providing the basis for complexation of 177Lu3+ with DOTA of
`DOTAO—Tyr3—0ctreotate.
`
`of 177Lu-DOTA"—T —0ctreotate
`Coordination Chemis
`With the 4f—orbital fully filled (7 orbitals x 2 electrons = 14 electrons) in Lu“, [Xe]4f“, there
`are no metal orbitals available for overlap with ligand orbitals. But, there is more.
`It is
`well-known that there is an energy dependence of atomic orbitals on atomic number. As the
`atomic number increases across the lanthanide period. the energy of the 4f-orbital decreases and
`crosses over that of the 55, 5d, 6s. 5p and 4d-orbitals. When Lu is reached, the energy of the 4f-
`orbital in Lu3+ lies underneath the energies of these orbitals. As a result, the 4f-orbital becomes
`buried within the electronic configuration. Consequently, the 4f—orbital is screened by the 5s,
`5d, 6s, 5p and 4d—orbital electrons. Due to the shape of the seven f—orbitals, and th_e
`screening of the 4f-orbitala the lobes of the 4f—orbitals do not stick out far enough to achieve
`good overlap with ligand orbitals for covalent bonding to occur: even for those lanthanides
`that have empg' f—orbitals.
`
`On both counts, chemical bonding in Lu3+—D0TAO—Tyr3—0ctreotate is necessarily ionic.
`Although ionic, the bonding in these complexes does not fit the classical definition of a
`“salt,” one that readily dissociates into ions in aqueous solution. Quite to the contrary,
`metal—ligand coordination complexes (charged and uncharged) exist as stable “discrete
`molecular entities,” with well-defmed geometry. That this is so for Luk-DOTA -T -
`Octreotate is based on a body of evidence from X-Ray Crystallography studies of similar metal-
`ligand complexes of a lanthanide family member (Gdy’), and their exceptional stability profiles.
`emulating that as if the bonding in these complexes met the definition of a covalent bond.
`
`RADIOPHARMACEUTICAL PRODUCTION:
`
`Drug Substance
`The manufacture of 177Lu-DOTAo-Tyr3-0ctreotide (Drug Substance) proceeds
`
`”mom
`
`6 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`BACTERIAL ENDOTOXINS – See Microbiology Review
`STERILITY – See Microbiology Review
`
`
`C. Summary of Drug Product Intended Use
`Lutathera
`Proprietary Name of the Drug Product
`Non Proprietary Name of the Drug Product None (ready-to-use solution for infusion)
`Lu-177- DOTA0-Tyr3-Octreotate
`Non Proprietary Name of the Drug
`Substance
`Proposed Indication(s) including Intended
`Patient Population
`Duration of Treatment
`
`For treatment of gastroenterpancreatic
`neuroendrocrine tumors (GEP-NET’s)
`Four administrations of 7.4 GBq, every 8
`weeks
`7.4 GBq
`None
`
`Maximum Daily Dose
`Alternative Methods of Administration
`
`D. Biopharmaceutics Considerations
`N/A
`E. Novel Approaches
`N/A
`F. Any Special Product Quality Labeling Recommendations
`N/A
`G. Process/Facility Quality Summary (see Attachment A)
`N/A
`H. Life Cycle Knowledge Information (see Attachment B)
`N/A
`
`
`Risk Assessment - Drug Product (Lutathera) – Based on CMC and Microbiology
`
`
`
`12
`
`(b) (4)
`
`

`

`From Initial Risk Identification
`
`Atanutel
`Radionuclidic
`
`Identity/purity
`
`Factors that can impact
`the CQA
`Purity and CMC quality
`omeu-DOTAO-Tyr3
`Octreotate
`(b) (0
`
`Initial Risk
`Ranking”
`25<RPN<60
`
`Risk Mitigation
`Approach
`Information provided
`to addressissues
`identifiedin
`0') (4)
`DMF W" and that
`provided per (h)(4)
`
`Final Risk
`Evaluation6
`
`Lifccycle
`Considerations]
`
`NComments**
`
`Radiochemical
`
`identity
`
`-Reference standard
`characterization
`
`-Analytical methods
`
`25<RPN<60
`
`Information provided
`to address issues
`identified
`
`Radiochemical
`
`purity
`
`-Precursor purityl
`-analytical methods
`
`25<RPN<60
`
`Information provided
`to address issues
`identified in W"
`DMF "m, and that
`per (5)(4)
`
`Chemical
`
`Purity
`
`Strength
`(mCi/mL)
`
`Appearance
`(reconstituted
`solution)
`
`-Precursor integrity.
`purity and quality2
`
`-Scale (RAD input)3
`
`25<RPN<60
`
`N/A
`
`25<RPN<60
`
`N/A
`
`-Quality of manufactured
`Lutathera
`
`25<RPN<60
`
`N/A
`
`pH
`
`-Fonnulation
`
`-Quality of manufactured
`Lutathera
`
`-Sensitivity of ligand
`structure
`0’)(4)
`
`in formulation
`
`Microbiology4
`
`All issues resolved
`
`(see microbiology
`review)
`
`(It) (4)
`
`M". Chemical purity
`DMF
`'maDMF (W)
`(6) (”is
`Information for the manufacture. purity and quality
`held by
`“M".which has been reviewed (Martin Haber Ph.D.. 10/23/2015) 1and determined
`acceptable
`(It)(”in conjunction with another NDA
`0”(0 for (NDA
`on»)
`(m4) approved
`Strength (mCi/mL) — RAD scale is determined by the range of radioactivity to be used with
`Lutathera.
`If the radiolabeling fails to meet expectation (RAD yield). the strength will be
`impacted — that it will meet expectations is validated through studies performed in the NDA.
`
`13
`
`

`

`4. Microbiology – see Microbiology Review (Peggy Kriger, Ph.D., 11/10/2016); RPN = 0 (after
`modification when applicable) x S x D.
`5. Overall Risk Assessment, RPN < 25 (low to negligible, based on resolution of all issues for
`CMC).
`
`
`Application Technical Lead: Eldon E. Leutzinger, Ph.D., CMC Lead
`
`
`
`
`
`
`
`
`
`
`14
`
`

`

`Eldon
`Leutzinger
`
`Digitally signed by Eldon Leutzinger
`Date: 11/18/2016 04:19:48PM
`GUID: 508da7210002a0781943eff6cc724d1f
`
`122 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`Product Background: Rolling submission, granted an Orphan Designation and a Fast
`Track review.
`
`MICROBIOLOGY
`
`NDA: 208700
`
`Drug Product Name/ Strength: Lutetium 177Lu dotatate (177Lu-DOTA0-Tyr3-Octreotate
`370 MBq/mL solution for infusion)
`
`Route of Administration: Intravenous
`
`Applicant Name: Advanced Accelerator Applications USA, Inc.
`
`Manufacturing Sites:
`Advance Accelerator Applications (Italy) srl
`Via Ribes 5, Colleretto Giacosa, TO, Italy, 10100
`
`Advance Accelerator Applications (Italy) srl
`Via Piero Maroncelli 40, Meldola, FC, Italy, 47014
`
`Method of Sterilization:
`
`W4)
`
`Review Summary:
`List Submissions being reviewed (table):
`
`Submit
`Received
`I
`Review Request
`I Assigned to Reviewer
`
`3/31/2016
`3/31/2016
`|
`N/A
`|
`N/A
`
`4/28/2016
`4/28/2016
`|
`N/A
`|
`4/28/2016
`
`5/18/2016
`5/18/2016
`|
`N/A
`|
`N/A
`
`8/05/2016
`8/05/2016
`|
`N/A
`|
`N/A
`
`9/27/2016
`9/27/2016
`|
`N/A
`|
`N/A
`
`Highlight Key Outstanding Issues from Last Cycle: None identified
`
`Concise Description Outstanding Issues Remaining: None identified
`
`Supporting/Related Documents: IND 77219 is referenced for the sterility testing timeframe.
`
`Relevant information in a meeting package was reviewed by P. Kriger (077219.doc, dated
`August 20, 2015). DMF
`00(4) is referenced
`
`. An LOA dated
`
`(hm
`(10(4) is provided.
`
`Remarks: The submission is in the eCTD format. Some tables were copied from the
`
`submission. The August 5, 2016 and September 27, 2016 amendments are referenced for the
`
`responses to information requests from CMC/Microbiology sent to the sponsor on July 21, 2016
`
`and September 19, 2016, respectively.
`
`The Submission is Recommended for Approval.
`
`0PQ-XOPQ—TEM-0001v03
`
`Page 1 of 22
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Note to reviewer: The subject drug product is a sterile, ready-to-use radiopharmaceutical
`
`Effective Date: 18 Feb 2016
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 2 of 22
`
`

`

`m3
`
`QUALITY ASSESSMENT
`
`""""‘
`hunk—nun- ‘
`
`
`
`P. 8 Stability
`
`P. 8.1 Stability Summary and Conclusion
`
`Proposed Expiry: 72 hours—
`
`P. 8.2 Post-Approval Stability Protocol and Stability Commitment
`
`The product stability specification is the same as for release (see above).
`
`-?—----
`
`Bacterial Endotoxins ---
`
`Note to reviewer: In the 9/27/2016 amendment response, the applicant did not chan e
`the stability information, which indicates that the sterility test is performed
`However, further clarification will not be re uested as the sterili
`test is 0
`
`[5ype!ormed
`
`once -fl.
`
`0PQ-XOPQ-TEM-0001v03
`
`Page 20 of 22
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT :10 m an» (we- ~41 am»
`
`Post Approval Stabilifl Commitment
`On—going stability will be conducted annually at each manufacturing facility on a single
`batch produced at the largest possible batch size
`(5)“)
`. These batches used as part of the on—going stability program may
`also be used as commercial batches.
`
`Reviewer’s Assessment: Acceptable
`
`P.8.3 Stability Data
`
`Microbial testing results are provided for 12 primary stability batches, which cover both
`manufacturing sites,
`(m4) and two possible batch sizes.
`(m4),
`endotoxins and sterility test results complied with the drug product specification.
`Reviewer’s Assessment: Acceptable
`
`R
`
`Regional Information
`
`Executed Batch Records
`
`Executed lots:
`
`Colleretto Giacosa
`o
`
`.
`
`0
`
`M" GBq batch size 8 Ci), Lot numbers:
`LT141118B-03, LT141119B-03, LT141124C-03
`"’"" GBq batch size 8 Ci), Lot numbers: LT141113A-03,
`LT141114A—03, LT141125B-03
`(m4) GBq batch size 8 Ci), Lot numbers: LT141119C-
`03, LT141121A—03, LT141127A—03
`
`Meldola
`0
`
`(mo GBq batch size :2} Ci), Lot numbers:
`LT150713A—06, LT150714A-06, LT150720A—06
`
`The batch records for both drug product manufacturing sites confirm that validated
`one were used for the
`
`manufacture of the exhibit batches.
`
`Reviewer’s Assessment: Acceptable
`
`Comparability Protocols
`
`Reviewer’s Assessment: No CP was included in the application.
`
`2. REWEW 0F COMMON TECHNICAL DOCUMENT — QUALITY (CTD-Q) MODULE 1
`
`2/1. Package Insert
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 21 of 22
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Storage temperature: below 25°C M", vial enclosed in the original plastic sealed, lead
`shielded container
`
`Route of administration: IV infusion
`
`Container: Single dose
`
`(hm Single-dose vial and discard unused
`portion is stated in the PI and on vial and container labels. Sterile solution is noted on the
`container label.
`
`Reviewer’s Assessment: Acceptable
`
`Post-Approval Commitments:
`
`Reviewer’s Assessment: N/A
`
`Lifecycle Management Considerations
`
`Reviewer’s Assessment: N/A
`
`List ofDeficiencies:
`
`The Division ofMicrobiology has no additional comments at this time.
`
`Primary Microbiology Reviewer Name and Date: Peggy Kriger, Ph.D., November 10, 2016
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 22 of 22
`
`Effective Date: 18 Feb 2016
`
`

`

`Erika
`Pfeiler
`
`Peggy
`Kriger
`
`Digitally signed by Erika Pfeiler
`Date: 11/14/2016 08:42 53AM
`GUID: 502d1da500002b6a73a00c0e0dff6e1d
`
`Digitally signed by Peggy Kriger
`Date: 11/14/2016 08:42 03AM
`GUID: 534c169d00067f29cedbaa415df21ba2
`
`

`

`Danae
`Christodoulou
`
`Digitally signed by Danae Christodoulou
`Date: 11/22/2016 04:35 59PM
`GUID: 5050dd27000012a4c69bfc70b47660b7
`
`