CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

210828Orig1s000

PRODUCT QUALITY REVIEW(S)

NDA 210828 OPQ Integrated Quality Assessment final

Review Date: April 25, 2019 Drug Product [68Ga]-DOTATOC Strength 0.5 – 4 mCi/mL (18.5 – 148 MBq) Route of Administration IV injection Rx/OTC Dispensed Rx Applicant University of Iowa Hospital & Clinics (UIHC PET Imaging Center) US agent, if applicable N/A

Quality Review Data Sheet 1. LEGAL BASIS FOR SUBMISSION: 505(b)(2)

2. RELATED/SUPPORTING DOCUMENTS: A. DMFs:

Table 1 Drug Master Files (DMFs)

DMF # TYPE HOLDER ITEM REFERENCED STATUS

DATE REVIEW

COMPLETE REVIEWER

II

II

Acceptable

Acceptable

11/09/2018

11/09/2018; 4/12/2019

John Amartey, Ph.D.

John Amartey, Ph.D., CMC Ghadiali Alifiya, Ph.D., Microbiologist

B. Other Documents: IND 70,663 (Molecular Insight Pharmaceuticals, Inc.)

3. CONSULTS: N/A

Quality Review Team DISCIPLINE REVIEWER BRANCH/DIVISION

Drug Substance John Amartey, Ph.D. ONDP/Branch VI/Division II Drug Product John Amartey, Ph.D. ONDP/Branch VI/Division II Microbiology Alifiya Ghadiali, Ph.D. OPQ/OPF/Microbiology

Facility Krishna Ghosh, Ph.D. OPQ/OPF/DIA/B1 Project/Manager (R.Ph) Anika Lalmansingh OMPT/CDER/OND/ODEIV/DMIP

Application Technical Lead Eldon E.Leutzinger, Ph.D. ONDP/Branch VII/Division II Environmental Assessment

(EA) John Amartey, Ph.D. ONDP/Branch VII/Division II

(b) (4) (b) (4)

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(b) (4)

Table 2 Documents DOCUMENT RECEIPT DATE DESCRIPTION Section/reviewer

Original & IR’s as detailed in primary reviews

3.2.S and 3.2.P John Amartey

Executive Summary I. Recommendations

APPROVAL from the CMC drug product quality, Microbiological product quality perspectives, and Facilities

For the Action Letter, the following statement should be included: “We acknowledge your proposed comparability protocol which will be submitted in a prior approval supplement (PAS), post-approval. Include in the PAS comparative batch data .”

(b) (4)

(b) (4)

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

II. Summary of Quality Assessments

CONCISE SUMMARY OF ISSUES AND ASSESSMENTS: ♦ DRUG SUBSTANCE PRECURSOR - DOTATOC PEPTIDE

Category Issue Totality of information on structure, synthesis, controls, stability provided in NDA (no DMF)

None identified

ASSESSMENT: information provided by - determined to adequately support the NDA

♦ DRUG SUBSTANCE / DRUG PRODUCT: Category Issue

Reference Standard for None identified Drug Substance (natGa-DOTATOC,

sourced from ASSESSMENT: information to support authenticity and characterization is satisfactory Quality

(b) (4)

One major issue: Controls (74-day letter #10).

There were 4 lesser important issues (74-day

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

letter #7, #8, #9 and #11). ASSESSMENT: 74-day letter issue #10 and all others (#7, #8, #9 and #11) for quality controls are resolved with response of September 25, 2018

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Stability Lack of data for inverted vials of drug product in 6 of the registration batches that provides an account of any retention of 68Ga-DOTATOC by the container walls/closure (adsorbed/absorbed) after product extraction, conveyed in IR comments subsequent to 74-day letter (IR-1, #5).

ASSESSMENT: issue resolved with iTLC data provided in the responses

♦ DRUG PRODUCT Category Issue

Production are employed for (b) (4)

(b) (4)use in the (74-day letter #2) and (b) (4)

module (74-day letter #3) necessitating explanation, since the

In their 6 validation batches, the radioactivity scale is seen to be suboptimal necessitating resolution (74-day letter #5). In such batch studies, it is customary to employ the highest radioactivity expected for use with radiopharmaceuticals to establish real-world production performance capability.

conveyed to the applicant as (IR-1, #1 to #4). There were other issues conveyed as (74-day letter #1, #12, #13)

(b) (4)

(b) (4)

ASSESSMENT: all issues conveyed in 74-day letter (#1, #2, #3, #5, #6, #12, #13) and IR-1 (#1 - # 5) are satisfactorily resolved. . Microbiology All issues resolved. Information in DMF acceptable

information to support the proposed post-approval change In

(b) (4)(4/12/2019). There is a non-hold comment for additional

essence, this comment directs the applicant to refer to FDA guidance PET drugs (CGMP) and USP <823> Positron Emission Tomography Drugs. The applicant facility (UIHC-PET Imaging Center) was found compliant, based on a PAI inspection conducted from 6/27-28/2018 and 7/2/2018. There was a one item FDA 483 for inadequate quality procedures related to final product release, supplier’s qualification and audit trail review of HPLC analysis by the QC lab. The firm’s response to the FDA 483 was found acceptable on review. The recommendation by OPF/DAI B3 is adequate (2/20/2019).

Facilities

of the final product. Joint with these issues is the observation

(74-day letter #6).

(b) (4)

(b) (4)

Subsequent to these 74-day letter issues, there were other lesser important issues that ranged from

These issues were

(b) (4)

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♦ DRUG PRODUCT / LABELING: Category Issue

Structure of Drug Substance

N/A

ASSESSMENT: no issues were identified regards determination of structure (methodology, reference standard and data analysis/conclusion) Labeling Missing drug preparation description in package insert –

Structure for 68Ga-DOTATOC in Figure 1 of package insert is incorrect.

ASSESSMENT: both issues are resolved. The incorrect structure was revised. For the missing drug preparation, there is concurrence with the applicant – description not needed, because the drug is provided to users as a “ready-to-use” product.

(b) (4)

(b) (4)

A. Drug Substance [USAN Name] Quality Summary The Drug Substance (chemical entity accounting for action of the drug) is 68Ga-DOTATOC, a 68Ga(III) labeled peptide (Edotreotide). The peptide (Edotreotide) is also known as DOTA0­Phe1-Tyr3-octreotide. A USAN name is absent for 68Ga-DOTATOC, but that for the peptide is Edotreotide (otherwise DOTATOC). Hence, another name for the drug substance is 68Ga­Edotreotide, or 68Ga-DOTA0-Phe1-Tyr3-octreotide. Its molecular formula is C65H92

68GaN14O18S2, with molecular weight of 1489.65 g/mol.

Chemistry: (68Ga-DOTATOC). The molecular weight (1489.65) is that with the gallium mass for the isotope (6831Ga), (Element No. 31 in Group 13 (IIIa) of the Periodic Table) and n = 37 neutrons. There is a S-S disulfide bond bridging Cys2 and Cys7, and has the following structure as depicted in the NDA/CMC section):

It is comprised of a completely defined peptide portion with the location of the S-S disulfide bond and an attached DOTA chelate labeled with 68Ga3+. The “Ga-DOTA moiety” is defined from the standpoint of (1) where DOTA is linked to the peptide, and (2) the location of the Ga3+ in DOTA0-Phe1-Tyr3-octreotide.

Perspectives on Structure of 68Ga-DOTA0-Phe1-Tyr3-octreotide (68Ga­DOTATOC) - by ATL: Despite the simplistic portrayal of the “complex” portion in the above structural representation of 68Ga- DOTA0-Phe1-Tyr3-octreotide, Ga3+ does not have a passive existence within the DOTA cavity, nor does the complex exist as it appears, a kind of salt form [(+3) + 3(-1) = 0]. Rather, Ga3+ interacts with the ring N-atoms and carboxylic acid groups in a way consistent with the definition of both a chelate (after the Greek word for “claw”) [Cotton and Wilkinson, Advanced

4

Inorganic Chemistry] and a coordination entity [IUPAC]. Chelation is the “formation or presence of bonds (or other attractive interactions) between two or more separate binding sites within the same ligand and a single central atom” [IUPAC]. As such, a chelate is a class of coordination entity [IUPAC: an assembly consisting of a central atom (usually metallic) to which is attached a surrounding array of other atoms (ligands)]. In this context, Nat,68Ga- DOTA0-Phe1­Tyr3-octreotide is best described as a metal-ligand coordination entity, where the central atom is a metal cation. Aside from the peptide portion that belongs solely to organic chemistry, the coordination details in the “Gd-DOTA moiety” falls within the domain of the Coordination Complexes or Coordination Compounds of inorganic chemistry and is best understood and treated from that perspective. Because the details of this coordination structure are central to establishing stability and other physicochemical properties and plays influential roles within the Critical Quality Attributes (CQA’s), the author of this Executive Summary provides in the following a proper framework with which to understand that structure and the part it plays in the aforementioned.

Within the framework of the definitions, the important point associated with these entities is that the interaction type and strength of binding within the coordination sphere depends on the nature of the metal cation and the ligand, and often the role of the metal cation is overlooked. As it is in this case, Ga3+ is not just any metal cation, but one that is distinguished by possessing a pseudo inert gas (electronic) configuration, playing a defining role in determining the nature of the interaction with ligand atoms (explained later).

By virtue of the well-defined polydentate ligand and binding strength within the coordination sphere, Nat,68Ga-DOTA0-Phe1-Tyr3-octreotide is a discrete molecular entity with a defined stoichiometry. The geometry in the coordinate structure has not been determined as part of the

(b) (4)characterization studies by (or the applicant in the NDA). However, there is a work­around this absence. Conceptually, Ga-DOTA0-Phe1-Tyr3-octreotide can be thought of as a derivative of Ga-DOTA. In that regard, it turns out that the structure of such substance (Ga-DOTA) has been established by single crystal X-Ray Crystallography [Vojtech Kubicek, et.al., Inorg. Chem., 2010, 49, (23), pp. 10960-10969]. In the structure of Ga-DOTA, Ga3+ cation binds to all 4 ring N-atoms of DOTA and two of its carboxylic acid groups in an octahedral coordination structure. This forms a scientifically sound basis for predicting the geometric structure of Nat,68Ga-DOTA0-Phe1-Tyr3-octreotide as following suit to that for Ga-DOTA.

♦ Location of 68Ga3+ in the Structure: The above depiction for the structure of 68Ga-DOTA0-Phe1-Tyr3-octreotide from the NDA appears to have been taken directly from the COA for reference standard (

(b) (4)

NatGa-DOTA0-Phe1­Tyr3-octreotide) from That Ga3+ is associated with DOTA and resides within the DOTA cavity (shown above), as opposed to some non-specific binding site, can be drawn from some of

(b) (4)the evidence presented in the COA. characterization information from the COA capitalizes on MS (for molecular weight and stoichiometry) and HPLC (for purity). Coordination of Ga3+ within the DOTA cavity is supported by certain electronic effects seen in

(b) (4)the FT-IR spectrum, but the latter is not interpreted by (will be discussed later).

Strengthening the assumptions and augmenting the evidence from FT-IR (COA by are insights drawn from structure studies on Ga-DOTA [Kubicek, Inorg. Chem reference above

(b) (4)

] that in my learned opinion serve as an appropriate model for NatGa-DOTA0-Phe1-Tyr3-octreotide (and all DOTA-containing molecules), thus providing a (1) scientifically sound basis for the positional assignment of Nat,68Ga3+ in DOTATOC peptide. As well, these studies discussed in the 2010 paper provide (2) insight on the coordination structure in Nat,68Ga-DOTATOC.

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♦ Coordination Structure: Conceptually, NatGa-DOTA0-Phe1-Tyr3-octreotide can be considered as a derivative of Ga-DOTA. Single crystal X-Ray Crystallography of Ga-DOTA showed that Ga3+ binds to the 4 ring N-atoms of DOTA and two of its carboxylic acid groups in an octahedral structure [Kubicek]. By virtue of the relationship to Ga-DOTA, the coordination structure in NatGa-DOTA0-Phe1-Tyr3-octreotide is expected (would be predicted) to follow suit. 68Ga-DOTA0-Phe1-Tyr3-octreotide is also expected to follow suit by virtue of the fact that isotopes of the same element possess identical chemistry.

♦ The pivotal role of 68Ga3+ cation: As some background, Ga is a post-transition element (Group III), [Ar]3d104s24p1, in the same Group as Al in the Periodic Table and shares some similar chemical properties. Its aqueous chemistry is predominantly that of the +3-oxidation state (Ga3+), formed on losing one electron from the 4p-orbitals, and two electrons from the 4s-orbitals, in that order, leaving [Ar]3d10. Unpacking this configuration, it can be rewritten as [Ne]3s23p63d10 . The 3s,3p,3d-shell is a closed valence shell containing 18 electrons, instead of 8 (as for an inert gas), making it a pseudo inert gas configuration. As would be expected, there are consequences of a closed valence shell, similar to an inert gas, rendering the Ga3+ cation very stable. That means Ga3+ cannot coordinate with a ligand by accepting an electron pair from a ligand atom and forming a shared-electron pair bond in the quantum mechanical sense. However, a nuance kicks in with the pseudo inert gas configuration, resulting in Ga3+ expressing great polarizing power. Pseudo inert gas configurations are described in the inorganic chemistry literature as providing relatively poor shields for the excess positive charge of the nucleus in a positive monatomic ion (such as in Ga3+). The result of poor electric-field shielding renders the large positively-charged field of Ga3+, with its small ionic radius, more effective in penetrating through to better polarize the electron cloud(s) of the atoms of a ligand.

The effect of the intense field of a small cation of large nuclear charge to distort the charge distribution of a neighboring anion and increase the interaction above that of Coulombic attraction (Kazimierz Fajans) is well-known in inorganic chemistry. The smaller the cation and more highly charged, the more distortion will occur (after Fajans), strengthening the interaction. With Ga3+, this strengthening (Fajans) of interactions with a ligand is enhanced by increased polarization through the pseudo inert gas configuration. As well, the stability of the DOTA-entity will be further enhanced through the well-known chelate effect, [Cotton and Wilkinson, Advanced Inorganic Chemistry], created by formation of multiple insipient chelate rings.

Ga3+ cation organizes these ligand atoms/arms around itself using the mechanisms just described. It belies any notions of absence of capability for strong bonding when as an element it does not possess the necessary electronic structure for electron-pairing. Despite absence of the typical bonding criteria possessed by the d-block elements, the coordinating ability of Ga3+

creates conditions that set up its DOTA entities as discrete molecular entities.

Significance of Ga3+ cation and its isotope with mass number 68 in radiolabeling of DOTA-peptides (by ATL) In the case for 68Ga3+ cation, there are two features (besides biodistribution) that give 68Ga­DOTA-Peptide entities their importance in nuclear medicine imaging. Firstly (1), 68Ga is of great interest from an imaging standpoint, due to (1) its high positron emission fraction ­89% (Emax at 1899 KeV, Emin at 890 KeV), providing enough radioactivity levels for high-quality images, and (2) the peptide pharmacophore for its giving direction to biodistribution.

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From the standpoint of chelation, Ga3+ is not “just another metal cation.” There are special nuances (3) that render the 68Ga3+ cation unique in its role in strengthening the entity that are fundamental in the development of a 68Ga-radiopharmaceutical from a metal-ligand coordination entity, reference to the concept of “stability by design”.

Characterization of 68Ga-DOTA0-Phe1-Tyr3-Octreotide (68Ga­DOTATOC) Structure determination of 68Ga-DOTATOC follows the well-established methodology for radiopharmaceuticals - by comparison of chromatographic retention time of the RAD peak for 68Ga-DOTATOC with that of a suitable, authentic reference standard (natGa-DOTATOC). These details are described in the Drug Substance / Drug Product review (John Amartey, Ph.D.).

♦ DOTATOC Peptide Moiety The structure of DOTATOC is that structure shown

(b) (4)

(b) (4)

♦ Reference Standard, NatGa-DOTA0-Phe1-Tyr3-Octreotide Pivotal to the methodology for establishing the identity of the drug substance molecule following radiolabeling is the Reference Standard. Because of the indirect nature of this identity determination, authenticity of this standard is paramount, and is in Section 3.2.P.6. (Reference Standards). No issues were identified for the reference standard sourced fromthe primary reviews. There is an MS spectrum in the COA that provides evidence for a 1:1 stoichiometry for Ga-DOTATOC. There is also an FT-IR spectrum in the COA fromno interpretation is provided in either the COA or NDA (as previously mentioned). But, the FT­IR says something about the coordination details and begs some attention here.

Firstly, most of the signal pattern in the IR of the reference standard is expected to be similar to that of DOTATOC peptide, and that is borne out by comparing the spectrum of Ga-DOTATOC with DOTATOC (from Lit). What is different is the relatively narrow region (1000-1250 cm-) that corresponds to the C-N stretching vibration of tertiary amines (Lit), belonging to the DOTA ring. This is seen as a strong absorption at 1102 - 1107 cm- in the spectrum DOTATOC, but markedly depressed in the spectrum of Ga-DOTATOC. This would be consistent with IR theory. On coordination of Ga3+ with DOTATOC, electrons are drawn away from the N-atoms toward the metal cation (Fajans polarization of the ligand atoms by Ga3+). It makes sense that that will affect the frequency of a stretching vibration for a C-N bond of DOTA, and its intensity of IR absorption is expected to decrease accordingly. With so great depression of the strong absorption at 1102 -1107 cm-, the inference is that coordination is to all 4 tertiary N-atoms of DOTA. That would be consistent with Kubicek’s octahedral structure for Ga-DOTA.

♦ 68Ga3+ Binding to DOTA chelate in 68Ga-DOTATOC (by ATL) Ga3+ can have coordination numbers of 2, 4 and 6 (maximum). Representing coordination number of 6, Ga3+ forms octahedral entities with some anions, e.g., (GaCl6)3-, neutral ligands [Ga(H2O)6]3+ (an aquo ion, as it exists in aqueous solution), and organic ligands (lit). As mentioned previously, a multidentate entity (Ga-DOTA) also exists for which its structure and stability is the subject of a 2010 paper [Vojtech Kubicek, et.al., Inorg. Chem., 2010, 49, (23), pp.

based on

but

(b) (4)

(b) (4)

7

10960-10969]. Fortuitously, the multidentate entity (Ga-DOTA) becomes a well-positioned model for insights on the structure of 68Ga-DOTATOC, since it appears in the latter as the “68Ga-DOTA moiety.” Ga-DOTA is an octahedral entity formed from multidentate DOTA, and is supported by single crystal X-Ray Crystallography of [Ga(H2dota)](ClO4)0.5HClO4•5H2O with defined geometric parameters (Kubicek). The Ga3+ ion is coordinated in a distorted cis-O2N4

octahedron, as the result of steric effects of the carboxylic acid groups of the Ga-DOTA entity. The following is the molecular structure of the [Ga(H2dota)]+cation, determined from the geometric parameters acquired in the X-Ray Crystallography of the above crystal [from the Inorg. Chem. Paper], showing the distortion in the DOTA ring.

APPEARS THIS WAY ON ORIGINAL

the other two carboxylic acid O-atoms unbonded.

It is a 3-dimensional structure (top view, perpendicular to the plane of the paper and looking through the Ga), as determined by X-Ray Crystallography, showing how Ga3+ binds to DOTA, but not equidistant from the 4 ring-N atoms (i.e., the 4 Ga-N bonds are not the same length). So, Ga3+ lies above the plane of the N-atoms in DOTA and shifted some to one side. You can see the 2 free carboxylic acid groups (upper righthand side, lower left-hand side and behind), and the other two carboxylic acid O-atoms bound to Ga3+, satisfying the maximum 6 coordination sites of Ga3+. The following version (also taken from the Inorg. Chem paper) without the distortion in the DOTA ring. Nevertheless, it provides a simpler version from which you can clearly see the orientation of the DOTA ring N-atom bonds (4 bonds), the 2 carboxylic acid O-atom bonds, and

This should be taken strictly as a stick model to show simplified geometry, with no implication as to the nature of the “connecting bonds” as drawn between Ga3+ and the ligand atoms. Rotating the above pictorial 900 counterclockwise gives the disposition of the free carboxylic acid groups in the structure by X-Ray Crystallography.

♦ Conclusions on the structure of 68Ga-DOTATOC (68Ga-DOTA + Phe1-Tyr3­octreotide) – by ATL Using the above structure as a model, the peptide in Ga-DOTATOC would be connected at the carboxylic acid site on either side of the entity. As a derivative of Ga-DOTA, in 68Ga­DOTATOC, 68Ga3+ binds to all 4 N-atoms in the DOTA ring and two of the carboxylic acid groups, satisfying the maximum coordination number of 6 for Ga3+. Having met the maximum coordination number, there are no remaining coordination sites left in Ga3+for taking up the remaining carboxylic acid group in the ligand (refer to the above structure in relation to 68Ga-DOTATOC), and thus the third carboxylic acid group remains unbound.

Radiochemistry (68Ga-DOTATOC) The radiochemistry is essentially that of 68Ga, except for the effect of its ionizing radiation on the peptide portion of the radiolabeled molecule. That will be dealt with later in this IQA (under

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STABILITY). Since 68Ga-DOTATOC is into the final drug product, its method of manufacture from DOTATOC peptide will be discussed under the DRUG PRODUCT section of this IQA.

The radiochemistry of 68Ga is defined by the plethora of isotopes of Ga, and by the chemistry of its most common oxidation

(b) (4)

(b) (4)

(b) (4)

state, Ga(III). In number, there are 14 isotopes of Ga, 12 of which are radioactive (including 68Ga), and 2 which are stable (69Ga, 60.2% natural abundance; 71Ga, 39.8% natural abundance). 68Ga derives primarily from one of its immediate period neighbors in the Periodic Table, namely from either 68Ge or 67,68Zn.

(b) (4)

(b) (4)

Imaging following administration of 68Ga-labeled DOTATOC depends on the following nuclear 31Ga → (30+38)reaction describing the decay of 68Ga: [(31+37)

30Zn + β+ + ν]. β+ particles (e+) collide with electrons (e-), annihilate and produce two 511 KeV gamma rays approximately 1800 apart. The latter are picked up by a PET camera. The full complement of radiations from 68Ga include 1.90 MeV (max) β+, Zn X-rays, 511 KeV (176%, γ±), 0.80 KeV γ (0.4%), 1.078 MeV (3.5%), 1.24 MeV (0.14%) and 1.87 MeV (0.15%). It has a physical half-life of 68.3 min. (b) (4)

(b) (4)

An upfront, concise summary of the issues and assessments have been presented in the foregoing tables. What follows is a more complete discussion of the issues.

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(b) (4)

QUALITY SUMMARY – Two

issues pertaining the (74-day letter-#1, #4), comment #1 regards the and comment #4 . In the manufacturing

procedures , a clear description for is needed, as well as . In the second of these, an explanation is needed for a discrepancy noted in

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

These issues were satisfactorily addressed in the responses from UIHC (September 25, 2018) ­Resolved.

B. Drug Product [Established Name] Quality Summary 68Ga-DOTATOC is provided in a sterile aqueous solution of Sodium Chloride Injection (0.9%)

(b) (4)

(b) (4) (b) (4)and 10% (v/v) Ethanol in a multi-dose vial. It contains 18.5 - 148 MBq (0.5 – 4 mCi) of 68Ga radioactivity per mL at EOS. Per (14 mL), the amount of radioactivity is – 2072 MBq (7 – 56 mCi). The target dose for adults is 111-185 MBq (3-5 mCi), and for pediatrics it

(b) (4)is 11.1-111 MBq (0.3-3 mCi). (b) (4)

The container closure is a 30 mL capacity USP glass vial with gray rubber stopper and aluminum crimp seal.

QUALITY SUMMARY – DRUG PRODUCT: ♦ Production The Drug Product is manufactured at the University of Iowa Health Center (UIHC)–PET Imaging Center (200 Hawkins Drive, Iowa City, IA 52242). It is packaged, labeled, tested and released at UIHC.

(b) (4)

(b) (4)

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each (74-day letter #12). This was resolved by submission of COA’s.

. To establish real-world production performance capability for radiopharmaceuticals, relative to the shelf-life of the product at the

(b) (4)

expected strength to be used in the clinical doses, it is customary that the typical scale be done at the highest radioactivity expected for production batches. Yet, in the 6 validation

(b) (4)batches produced with the radioactivity scale is seen to be suboptimal (74 day letter-#5). All issues (74 day letter-#1, #2, #3, #5 and #6, #12, #13) were satisfactorily resolved in the September 25, 2018 responses.

Subsequent to these initial comments identified in the 74-day letter, there were additional comments conveyed to the sponsor (IR, 10/01/2018 #1, #2, #3, #4)

For these issues, the comments were to address certain information that was discovered to be absent during continued review (primary) following that

(b) (4)

identified and conveyed in the 74-day letter.

(b) (4)

With regards to this protocol, the Action Letter should include the following statement: “(b) (4)

We acknowledge your proposed comparability protocol

11

which will be submitted in a prior approval supplement (PAS) , post-approval. Include in the PAS comparative batch data

.”

(b) (4)

(b) (4)

(b) (4)

(b) (4)

12

(b) (4)

♦ Quality Controls: (b) (4)

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(b) (4)

A number of other issues of lesser importance for quality controls were identified in the primary review (John Amartey, Ph.D.), and these are captured in the 74-day letter (#8, #9 and #11). All these issues (74-day letter #7, #8, #9, #10 and #11) were satisfactorily resolved in the September 25, 2018 response.

♦ Stability and Structure Any instability of 68Ga-DOTATOC is expected to be comprised of two contributions, (1) loss of 68Ga3+ from the “68Ga-DOTA moiety,” and (2) insult to the peptide itself. From the standpoint of the ability of 68Ga to stay bound to DOTA and remain in the DOTA cavity (1) is expected to mirror that of NatGa-DOTA [log K, 26.05; Vojtech Kubicek, et.al., Inorg. Chem., 2010, 49, (23), pp. 10960-10969], within the limitations defined by any steric effect of the pendent peptide and the effect of ionizing radiation from 68Ga. Any radiolytic sensitivity of the peptide is expected to mediate the overall stability of the radiolabeled entity.

The shelf-life was determined to be 3 hours at room temperature. But, also note that in 3 hours from initial manufacture, there will be a loss in radioactivity of ~84 %, due to the half-life of 68Ga. After 3 hours there will be little radioactivity left and would appear to adversely impact any subsequent usefulness. Looking at the RCP, after decay-correction there was no evidence in its wavering over the 3-hour period (99%), suggesting that the shelf-life is more reflective of the decay of 68Ga rather than any actual “molecular instability” over the given test period.

Interaction with container closure It is well-known that container closure systems affect stability. No less for radiopharmaceuticals. In fact, some of the most interesting nuances in stability with radioactive substances arise as a result of reactions with various container materials, including glass, metals, as well (of course) closure materials (an extension of experience drawn from conventional drugs). These interactions are of various kinds and may be either physicochemical or chemical in nature. Although there was nothing unusual in these regards noted in the stability data for 68Ga­DOTATOC product (primary review) for the upright vials, there were 6 registration batches in the stability study section that were inverted at room temperature, but for which there was no data collected as to whether product was retained as a result of interaction with the closure (IR-1, 10/01/2018, #5). In the response, they showed that the product is not retained to any significant extent by the container closure system, thus resolving this issue.

DRUG PRODUCT LABLING A missing (1) drug preparation description in package insert was flagged –

But, on this issue there is concurrence (b) (4)

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with the applicant – a description not needed, because the drug is provided to users as a “ready­to-use” product Secondly (2), the structure for 68Ga-DOTATOC in Figure 1 of package insert is

However, in contrast to the structures of 68Ga-DOTATOC shown in other places in the NDA, the applicant presents a structure in the labeling (Figure 1) that is not only incorrect as noted above, but also with bonding of 68Ga3+ only to the 4 N-atoms. The applicant is not incorrect showing it with N2N2-bonding, but it is only part of the way to full-bonding that would two of the carboxylic acid groups in a 6-coordinate structure. As mentioned previously, Ga3+ can be 2, 4 or maximally 6 coordinate. Generally, in metal-ligand coordination entities of this type, the more coordination sites, the larger will be the number of incipient chelate rings on complexation. That leads to greater stability [see Cotton and Wilkinson, and authorities on this subject].

6-Coordinate, N2N2O2-bonding is, of course, a prediction, based on sound principles of which I have discussed previously. Nevertheless, it should be considered in that context, awaiting confirmation by whatever experimental techniques can be utilized. Based on this perspective, and some historical precedence, it is just as reasonable to leave the structure without any speciation on binding until proven (with the understanding that I have unfolded in the introduction). I would prefer this in light of it being less misleading. Showing it as 4-coordinate when it is likely 6-coordinate is not in keeping with sound theory from the knowledge base that is historically well-founded within the class of metal-ligand coordination entities.

MICROBIOLOGY PRODUCT QUALITY Microbiology had completed a review of the applicant’s IR response on 11/09/2018. But, there is a follow-up IR to the applicant ((12/20/2018). There are requests to provide information

incorrect. The structure in the package insert was revised. Both issues for labeling are resolved.

(b) (4)

addressing the (b) (4)

FACILITY INSPECTION STATUS The applicant facility (UIHC-PET Imaging Center) was found compliant, based on a PAI inspection conducted from 6/27-28/2018 and 7/2/2018. There was a one item FDA 483 for inadequate quality procedures related to final product release, supplier’s qualification and audit trail review of HPLC analysis by the QC lab. The firm’s response to the FDA 483 was found acceptable on review. The recommendation by OPF/DAI B3 is adequate (2/20/2019).

C. Summary of Drug Product Intended Use: sterile diagnostic radiopharmaceutical for imaging somatostatin receptor positive neuroendrocrine tumors (NETs).

D. Biopharmaceutics Considerations: N/A E. Novel Approaches: N/A F. Any Special Product Quality Labeling Recommendations: N/A G. Life Cycle Knowledge Information (see Attachment A): N/A

15

Risk Identification1 Review Assessment4,5,6

Attribute/ CQA

Factors that can impact the CQA

Initial Risk Ranking2

Risk Mitigation Approach3

Final Risk Evaluation3

Lifecycle Considerations/

Comments**

Radiochemical Identity

Radiochemical Purity

Chemical Purity

Strength (mCi/mL)

Stability

•Analytical method & validation characteristics

•RAD/VIS congruence Methodology

•Reference standard •Acceptance criteria

•Analytical method & validation characteristics

•Degree of resolution of radiochemical impurity peaks from drug substance peak

•DL/QL •

•Source / impurity profile of peptide (precursor)

•Radiochemical yield •Method of production of drug product; formulation

•Strength (mCi/mL) •Sensitivity of molecular structure to ionizing radiation

•Analytical methods

RPN<25

25<RPN<60

25<RPN<60

RPN < 25

25<RPN<60

RPN<25

RPN<25

RPN<25

RPN<25

RPN<25

N/A

N/A

N/A

N/A

N/A

(b) (4)

(b) (4)

(b) (4)

(b) (4)

1. Based on FMECA (Failure Modes, Effects and Criticality Analysis) developed by Risk Ranking Team

2. RPN < 25 (Low Risk), 25 < RPN < 60 (Medium Risk), RPN > 60 (High Risk) 3. Based on CMC drug product quality 4. Labeling – all issues for CMC resolved 5. Facilities inspections – The applicant facility (UIHC-PET Imaging Center) was found compliant,

based on a PAI inspection conducted from 6/27-28/2018 and 7/2/2018. There was a one item FDA 483 for inadequate quality procedures related to final product release, supplier’s qualification and audit trail review of HPLC analysis by the QC lab. The firm’s response to the FDA 483 was found acceptable on review. The recommendation by OPF/DAI B3 is adequate (2/20/2019).

6. Microbiology - all issues resolved, but with a non-hold comment regarding the comparability protocol that needs to be conveyed to the applicant. In essence, this

16

comment directs the applicant that in support of the proposed post-approval change they should refer to FDA

(b) (4)

guidance PET drugs (CGMP) and USP <823> Positron Emission Tomography Drugs.

Application Technical Lead: Eldon E. Leutzinger, Ph.D., CMC Lead

17

48 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately following this page

QUALITY ASSESSMENT

MICROBIOLOGY

Product Background:

NDA: 210828

Drug Product Name / Strength: Ga-68-DOTATOC injection, 18.5-148 MBq (0.5-4.0 mCi/mL)

Route of Administration: Intravenous

Applicant Name: UIHC PET Imaging Center

Manufacturing Site: UIHC PET Imaging Center

200 Hawkins Drive, Iowa City, IA 52242

Method of Sterilization: (b) (4)

Review Recommendation: The submission is recommended for approval on the basis of sterility

assurance.

Review Summary: The subject PET drug product is

container closure system.

(b) (4)

List Submissions Being Reviewed: Submission Received Assigned to Reviewer

Original 05/23/2018 05/31/2018

Amendments*

(IR responses)

09/25/2018, 11/09/2018, 01/08/2019, 02/06/2019,

02/15/2019, 03/06/2019, 03/08/2019 N/A

* Submissions on 08/22/2018, 10/12/2018 and 03/19/2019 are noted but not reviewed as there are no relevant updates

Highlight Key Outstanding Issues from Last Cycle: N/A – this is a first cycle review.

Concise Description Outstanding Issues Remaining:

There are no deficiencies identified based on the information submitted. A non-hold comment regarding the comparability protocol needs to be conveyed to the Applicant.

Supporting/Related Documents:

Type V DMF

and the associated microbiology review D M01R01.docx dated 12/20/2018

(adequate) is referenced .

Type II DMF and the associated

Microbiology review D M01R01.docx dated 04/12/2019 (adequate) is referenced for

information on excipient

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Microbiology review A209342mr01.docx dated 05/11/2018 (adequate) is referenced for (b) (4)

Microbiology review i125673-20171011-mr01.pdf is referenced for pre-NDA meeting responses.

List Number of Comparability Protocols: 1

QUALITY ASSESSMENT

S Drug Substance Since the drug product is , the drug substance (b) (4)

will not be reviewed.

Note to reviewer: The drug substance precursor DOTATOC ,

is . Certificate of

analysis was not provided. Microbiology specification of TAMC ≤ 2 cfu/mg, TYMC ≤ 1 cfu/mg

and bacterial endotoxins ≤ IU/mg was met by the 3 exhibit lots.

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

P.1 Description of the Composition of the Drug Product

Description of drug product – The subject drug product is a PET pharmaceutical provided as a 14 mL sterile solution for injection

in a multiple-dose 30mL (b) (4) glass vial with gray (b) (4) rubber stopper. The volume of dose

administered will vary depending on the radioactive concentration at the time of administration.

Drug product composition – Component Quantity per mL* Quantity per 14 mL Function

Ga-68 DOTATOC, in-house 0.5–4 mCi

(18.5–148 MBq)

7–56 mCi

(259–2072 MBq)

Active

NaCl injection (0.9%), USP QS to 1 mL** QS to 14 mL

Ethanol, USP 10% (v/v) 10% (v/v)

* At end-of-synthesis (EOS)

(b) (4)

(b) (4) (b) (4)

* Equivalent to 9 mg NaCl

Description of container closure system – Configuration Component Description Manufacturer

18.5-148 MBq

(0.5-4.0 mCi/mL)

Container 30mL USP glass vial,

20mm neck diameter

Closure 20mm gray rubber stopper

Seal Aluminum crimp seal

Note to reviewer: The final drug product container closure is obtained

.

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

Reviewer’s Assessment: Adequate

The Applicant has provided an adequate description of the drug product composition and the container

closure system.

P.2 Pharmaceutical Development

P.2.5 Microbiological Attributes

Container-Closure and Package Integrity Testing – The subject PET drug product has a short expiry (3 hours post end-of-synthesis). Container closure

integrity testing is not required.

Reviewer’s Assessment: Not applicable

QUALITY ASSESSMENT

Antimicrobial Effectiveness Testing – Although the subject PET drug product is multi-dose and does not contain any preservatives, it has

a short expiry (3 hours post end-of-synthesis). Antimicrobial effectiveness testing is not required.

Reviewer’s Assessment: Not applicable

P.3 Manufacture

P.3.1 Manufacturers

(Drug Product manufacturing, packaging and labeling, release and stability testing) UIHC PET Imaging Center 200 Hawkins Drive, Iowa City, IA 52242 FEIN 3009718180

Note to reviewer: Bacterial endotoxins and sterility testing is performed in-house.

Reviewer’s Assessment: Adequate

P. 3.3 Description of the Manufacturing Process and Process Controls

(b) (4)

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(b) (4)

REVIEW MEMORANDUM

NDA 210828: ENVIRONMENTAL ASSESSMENT

R Regional Information

Environmental Analysis: ADEQUATE

UIHC PET Imaging Center claims categorical exclusion for environmental assessment under 21 CFR 25.31(b). The estimated concentration of the product at the point of entry into aquatic environment is calculated to be below 1 ppb. The applicant arrived at this conclusion based on the following assumptions.

1. 1GBq of Ga-68 DOTATOC = (b) (4) ng 2. The largest batch size made = (b) (4) GBq at EOS = (b) (4) ng Ga-68 DOTATOC. 3. Suppose peak production is (b) (4)

(b) (4)

1. Similarly, if the maximum allowed (b) (4) (non-radioactive) = (b) (4) µg/mL and the batch volume = (b)

(4)mL, maximum non-radioactive material/ batch = (b) (4)µg.

2. Therefore, the amount of non-radioactive material = (b) (4)kg/yr.

The results are reproduced in the table below, and the equation for the calculation. (We note a typographical error in the table (b) (4) should read (b) (4)).

1

(b) (4)

(b) (4)

2

Danae Digitally signed by Danae Christodoulou Date: 5/03/2019 10:22:23AMChristodoulou GUID: 5050dd27000012a4c69bfc70b47660b7

Eldon Digitally signed by Eldon Leutzinger Date: 5/14/2019 03:42:29PMLeutzinger GUID: 508da7210002a0781943eff6cc724d1f