center for drug evaluation and researchper 21 cfr 25.31(b), categorical exclusion can be granted for...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761139Orig1s000

PRODUCT QUALITY REVIEW(S)

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BLA 761139 Quality Review

Recommendation: Approval

BLA Number: 761139 Review Number:1

Review Date: December 19, 2019

Drug Name/Dosage Form ENHERTU® [fam-trastuzumab deruxtecan-nxki] for Injection Strength/Potency 100 mg lyophilized powder in a single-dose vial Route of Administration Intravenous infusion Rx/OTC dispensed Rx

Daiichi Sankyo Co., Ltd

Indication

Applicant/Sponsor

Product Overview

Enhertu (fam-trastuzumab deruxtecan-nxki, DS-8201a) is an antibody-drug conjugate (ADC) comprised of a recombinant, humanized anti-human epidermal growth factor receptor 2 (HER2) antibody conjugated to a topoisomerase I inhibitor. The anti-HER2 component, MAAL-9001, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (MAb) that has the same amino acid sequence as trastuzumab. It is produced in CHO cells. The drug, MAAA-1181a1, is a topoisomerase I inhibitor derivative of exatecan. The MAb and the drug are bound together by a cleavable maleimide tetrapeptide drug-linker designed to be stable in plasma to reduce systemic exposure to the released drug. The drug-linker, MAAA-l 162a (or deruxtecan), is bound to the antibody component through thioester bonds formed with free cysteine residues resulting from the reduction of four interchain disulfide bonds. The target number of drug-linker coupled to one antibody molecule is 8, resulting in a drug-to-antibody ratio (DAR) of 8.

Enhertu binds to the HER2 extracellular domain and induces apoptosis of the target tumor cells via inhibition of topoisomerase I by the released drug. In addition, Enhertu has HER2-mediated Akt phosphorylation inhibition and ADCC activity through the monoclonal antibody. Enhertu is indicated for

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Quality Review Team

Discipline Reviewer Branch/Division Drug Substance Jun Liu/Frances Namuswe DBRRIII/OBP Drug Product Zhenzhen Liu Di/Frances Namuswe DBRRIII/OBP Microbiology Drug Substance Viviana Matta/ Jessica Hankins/Patricia Hughes DIA and DMA/OPMA Microbiology Drug Product Steven Fong/ Jessica Hankins/Patricia Hughes DIA and DMA/OPMA

1 Late in the review cycle, the Sponsor updated the USPI to change the name of the topoisomerase inhibitor from the company’s internal code “MAAA-1181a” to the public code “DXd”. This change was accepted because there is publicly available information that relates DXd and MAAA-1181a. However, due to this change being made late in the review cycle, MAAA-1181a was retained in the reviews.

1

Reference ID: 4537420


Small Molecule Ben Zhang/Suong Tran NDB1/DNDAPI/ONDP Facility Viviana Matta/Steve Fong/Thuy Nguyen/Zhihao

(Peter) Qiu DIAOPMA

Labeling Vicky Borders-Hemphill OBP Immunogenicity Zhenzhen Liu/Frances Namuswe/Maria Teresa

Gutierrez-Lugo DBRRIII/OBP

Application Team Lead Frances Namuswe DBRRIII/OBP Application Tertiary reviewer Maria Teresa Gutierrez-Lugo DBRRIII/OBP OPQ RBPM Marquita Burnett RBPMB1/DRBPM1/OPRO

Multidisciplinary Review Team

Discipline Reviewer Office/Division OND RPM Sherry Hou OHRAB1/DOHRA/OHOP Cross-disciplinary Team Lead Harpreet Singh/Christy Osgood DOPIII/OHOP Medical Officer Preeti Narayan DOP1/OHOP Pharm/Tox Haw-Jyh(Brian) Chiu/Tiffany Ricks DHOT/OHOP Clinical Pharmacology Edwin Chow/Pengfei Song OCP Statistics Wei Zhang/Shenghui Tang OB/DBV

1. Names: a. Proprietary Name: ENHERTU b. Trade Name: ENHERTU c. Non-Proprietary/USAN: fam-trastuzumab deruxtecan/trastuzumab deruxtecan d. CAS name and number: 1826843-81-5 e. Common name: DS-8201a f. INN Name: trastuzumab deruxtecan h. OBP systematic name: CONJ: MAB HUMANIZED (IGG1) ANTI P04626

(ERBB2_HUMAN); DERUXTECAN [DS8201A] i. Other names: DS-8201a

2. Pharmacological class: HER2-targeted antibody and topoisomerase inhibitor conjugate

Submissions Reviewed

Submission #: Date Received: Submission Type STN 761139/0002 August 29, 2019 Original Submission STN 761139/0004 September 6, 2019 Response to Product Quality IR STN 761139/0010 September 26, 2019 Response to Product Quality IR STN 761139/0014 September 30, 2019 Response to Product Quality IR STN 761139/0016 October 03, 2019 Response to Product Quality IR STN 761139/0017 October 04, 2019 Response to Product Quality IR STN 761139/0019 October 08, 2019 Product Quality Information STN 761139/0024 October 16, 2019 Response to Product Quality IR STN 761139/0026 October 18, 2019 Response to Immunogenicity IR STN 761139/0028 October 21, 2019 Response to Product quality IR STN 761139/0033 October 24, 2019 Response to Product Quality IR STN 761139 / 0035 October 25, 2019 Response to Product quality IR

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STN 761139 /0039 October 28, 2019 Response to Product Quality IR STN 761139 /0040 October 30, 2019 Response to Product Quality IR STN 761139 /0042 November 01, 2019 Response to Product Quality IR STN 761139 /0045 November 05, 2019 Response to Product Quality IR STN 761139 /0047 November 08, 2019 Response to Product Quality IR STN 761139 /0048 November 12, 2019 Response to Product Quality IR STN 761139 /0051 November 14, 2019 Response to Product Quality IR STN 761139 /0053 November 15, 2019 Response to Product Quality IR STN 761139 /0054 November 18, 2019 Response to Product Quality IR STN 761139 /0055 November 19, 2019 Response to Product Quality IR STN 761139 /0059 November 22, 2019 Response to Product Quality IR STN 761139 /0060 November 22, 2019 Response to Product Quality IR STN 761139 /0062 November 25, 2019 Response to Product Quality IR STN 761139 /0063 November 25, 2019 Response to Product Quality IR STN 761139 /0064 November 26, 2019 Response to Product Quality IR STN 761139 /0065 November 27, 2019 Response to Product Quality IR STN 761139 /0066 November 29, 2019 Response to Product Quality and

Immunogenicity IRs STN 761139 /0067 November 29, 2019 Response to Product Quality IR STN 761139 /0068 November 29, 2019 Response to Product Quality IR STN 761139 /0070 December 02, 2019 Response to Product Quality IR STN 761139 /0072 December 04, 2019 Response to Product Quality IR STN 761139 /0075 December 04, 2019 Response to Product Quality IR STN 761139 /0076 December 06, 2019 Response to Product Quality IR STN 761139 /0077 December 09, 2019 Response to Product Quality IR STN 761139 /0080 December 09, 2019 Response to Product Quality IR STN 761139 /0081 December 10, 2019 Quality Information STN 761139 /0083 December 11, 2019 Response to Product Quality IR STN 761139 /0084 December 11, 2019 Response to Product Quality IR STN 761139 /0085 December 12, 2019 Response to Product Quality IR STN 761139 /0087 December 13, 2019 Response to Product Quality IR STN 761139 /0089 December 16, 2019 Response to Product Quality IR STN 761139 /0092 December 18, 2019 Response to Product Quality IR STN 761139 /0093 December 18, 2019 Response to Product Quality IR STN 761139 /0094 December 18, 2019 Response to Product Quality IR STN 761139 /0095 December 19, 2019 Response to Product Quality IR

Quality Review Data Sheet

1. Legal Basis for Submission: 351(a)

2. Related/Supporting Documents

A. DMFs

DMF# DMF Holder Item Referenced Letter of Cross-

Reference

Comments (status)

3


4


DMF Type II

Yes DMF reviewed and determined to be adequate to support the BLA

DMF Type III

Yes Review not needed as all relevant information related to compatibility with the product is in the BLA.

DMF Type III


DMF Type III


DMF Type V

Yes DMF previously reviewed and found adequate

B. Other documents: IND, Referenced Listed Drug (RLD), or sister application.

Application Number DescriptionIND 127553 DS-8201a

3. Consults

None issued.


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Executive Summary

I. Recommendations

A. Recommendation and Conclusion on Approvability

a. Recommendation

The Office of Pharmaceutical Quality (OPQ), CDER recommends approval of STN 761139 for Enhertu manufactured by Daiichi Sankyo, Inc. The data and information submitted in this application are sufficient to support the conclusion that the manufacture of Enhertu is well controlled and leads to a product that is pure and potent for the duration of the product shelf life. OPQ recommends that this product be approved for human use under the conditions specified in the package insert.

b. Summary of Complete Response issues: None

c. Approval Action Letter Language

Manufacturing location:o Drug Substance: Daiichi Sankyo Chemical Pharma Co, Ltd., (Onahama Plant), 389-

4, Izumimachi Shimokawa Aza, Otsurugi, Iwaki, Fukushima, 971-8183, Japano Drug Product:

o MAAL-9001 Drug Substance Intermediate: Daiichi Sankyo Chemical Pharma Co.,

Ltd. (Tatebayashi Plant), 2716-1 Aza Kurakake, Oaza Akaiwa, Chiyodamachi, Oura-gun, Gunma, 370-0503, Japan

Fill size and dosage form: 100 mg lyophilized powder in a single-dose vial

Dating period:

o Drug Product: 24 months at 2-8°Co Drug Substance: months at °Co MAAL-9001 Drug Substance Intermediate: months at °Co Drug-linker intermediate: See DMFo For packaged Products: Not Packagedo Stability option:

We have approved the stability protocol(s) in your license application for the purpose of extending the expiration dating period of your MAAL-9001 drug substance intermediate, drug substance, and drug product under 21 CFR 601.12.

Exempt from lot releaseo Enhertu is exempted from lot release per Docket No 95-29960 because it is a well

characterized recombinant monoclonal antibody.


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d. Benefit/Risk Considerations

Enhertu received breakthrough designation

There is currently no clear standard of care after 2 lines of treatment in a metastatic setting. Therefore, Enhertu represents a novel therapy for patients heavily pretreated with metastatic HER2+ breast cancer. The available efficacy data from a multicenter, single-arm trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies show an objective response rate (ORR) of 60.3% (95% CI: 52.9, 67.4), with a 4.3% complete response rate and a 56% partial response rate, and a median response duration of 14.8 months (95% CI: 13.8, 16.9). These results are significantly better than other available therapies.

The data submitted in this application are sufficient to demonstrate that the manufacture of Enhertu is well-controlled and leads to a product that is safe, pure and potent. Therefore, from a product quality perspective, this product is approvable for human use as described in the product labeling. The Sponsor agreed to several post-marketing commitments (PMCs) to improve the robustness of the DSI, DS, and DP manufacturing processes and overall product control strategy as outline in Section B below.

e. Environmental Assessment or Claim Of Categorical Exclusion

Daiichi Sankyo requests a categorical exclusion for Enhertu under 21 CFR 25.15, 21 CFR 25.31(b), and 21 CFR 25.31(c). Enhertu is comprised of MAAL-9001 (the MAb) and the drug-linker (MAAA-1162a), from which the released drug is MAAA-1181a. Per 21 CFR 25.31(c), categorical exclusion can be granted for MAAL-9001 because its metabolites (amino acids) are considered naturally occurring in the environment. Use of Enhertu is not expected to significantly alter the concentration of amino acids in the environment. MAAA-1181a is excreted into the environment. Daiichi’s calculations show that the expected introduction concentration for MAAA-1181a will be ppb. Per 21 CFR 25.31(b), categorical exclusion can be granted for MAAA-1181a because the estimated concentration at the point of entry into the aquatic environment will be below 1 part per billion. In addition, Daiichi states that to their knowledge, no extraordinary circumstances exist (21 CFR 25.15(d)).

Therefore, the claim of categorical exemption for Enhertu is accepted.

B. Recommendation on Phase 4 (Post-Marketing) Commitments, Requirements, Agreements, and/or Risk Management Steps, if approvable:

The following post marketing commitments have been proposed and accepted by the Sponsor:


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Microbiology

3762-3: Provide the bioburden test method qualification report for two additional batches of and DS-8201a drug substance in-process and release samples by May 2020.

Final Report Submission: May 2020.

3762-4: Perform the microbial ingress container closure integrity test to validate the maximum and minimum crimping pressures and include a positive control with a breach size of ≤ 20 microns. In addition, monitor the viability of the challenge microorganism at the end of testing.

Final Report Submission: January 2020.

3762-5: Provide data from a media fill run to support the use of the drug product specific container closure system.

Final Report Submission: January 2020.

3762-6: Provide endotoxin method qualification using two (2) additional drug product batches manufactured at Final Report Submission: January 2020

3762-7: Provide bioburden method qualification using 100 mL sample volumes from three (3) batches of DP manufactured at

Final Report Submission: March 2020

3762-8: Perform the dye ingress method validation for container closure integrity testing of the drug product stability samples using positive controls with a ≤ 20 micro breach size.

Final Report Submission: June 2020.

Product Quality

3762-9: Improve the requalification procedures for the current primary reference standard (PRS) and secondary reference standard (SRS) by revising the requalification protocols to include numerical acceptance criteria for HER2 binding of the PRS and stability trending of additional quantitative quality attributes with pre-defined trending rules and criteria, to allow timely detection of changes in the quality attributes of the PRS and SRS and to inform when the current RSs should be replaced. The acceptance criteria for HER2 binding of the PRS, the selected quality attributes for trending, the trending rules and criteria, and the criteria for assessment of when the RSs should be replaced will be scientifically justified. The revised qualification protocol will be submitted to the Agency per 21 CFR 601.12.

Final report submission date: March 20, 2020


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3762-10: Improve the requalification procedures for the current DS-8201a primary reference standard (PRS) and secondary reference standard (SRS) by revising the requalification protocols to include numerical acceptance criteria for cell growth inhibition and HER2 binding activity and stability trending of additional quantitative quality attributes with pre-defined trending rules and criteria, to allow timely detection of changes in the quality attributes of the PRS and SRS and to inform when the current RSs should be replaced. The numerical acceptance criteria for cell growth inhibition and HER2 binding activity, the selected quality attributes for trending, the trending rules and criteria, and the criteria for assessment of when the RSs should be replaced will be scientifically justified. The revised qualification protocols will be submitted to the Agency per 21 CFR 601.12.

Final report submission date: March 20, 2020

3762-11: Confirm that the potency of the current DS-8201a primary reference standard and secondary reference standard is precise and accurate by conducting additional qualification of potency for primary reference standard using a sufficient number of independent assays and replicates. The number of independent assays and replicates will be scientifically justified. The qualification data will be reported as per 21 CFR 601.12.

Final report submission date: February 20, 2020.

3762-12: Confirm that the potency of primary reference standard is precise and accurate by conducting additional qualification of potency of primary reference standard using a sufficient number of independent assays and replicates. The number of independent assays and replicates will be scientifically justified. The qualification data will be reported as per 21 CFR 601.12.


3762-13: Strengthen the qualification of the current primary and secondary reference standards by conducting additional characterization studies including full glycan profile analysis and FcRIIIA binding activity of primary reference standard and secondary reference standard to support the use of these reference standards in comparability assessments. The qualification data will be reported as per 21 CFR 601.12


3762-14: Strengthen the qualification of the DS-8201a primary and secondary reference standards by conducting characterization of FcRIIIA binding activity for primary reference standard to support the use of these reference standards in comparability assessments. The qualification data will be reported as per 21 CFR 601.12. Final report submission date: February 20, 2020.

3762-15: Re-evaluate precision for the protein concentration and glycan analysis methods at Daiichi Sankyo Tatebayashi Plant, and for protein concentration, non-proteinaceous impurities (NPI) and purity of payload (PoP) methods for DS-8201a drug substance at Daiichi Sankyo Onahama Plant and . The final report will be reported as per 21 CFR 601.12. Final report submission date: March 20, 2020


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II. Summary of Quality Assessments

Table 1 summarizes the critical quality attributes (CQA) that are intrinsic to fam-trastuzumab deruxtecan drug substance. Although Daiichi did not categorize primary structure, high order structure, HER2 - mediated Akt phosphorylation inhibition, ADCC activity, and Fc binding of fam-trastuzumab deruxtecan as CQAs, they are considered CQAs of the drug substance and are included in the Table below. The secondary and tertiary structure are largely intrinsic to the mAb DSI, but may be slightly influenced by conjugation with MAAA-1162a. HER2 - mediated Akt phosphorylation inhibition, ADCC activity, and Fc binding have some (minor) contribution to the mechanism of action.

Table 2 summarizes the CQAs that are derived from the drug substance manufacturing process and general drug substance attributes.

The CQAs and control strategy for the MAb and drug-linker drug substance intermediates are included in Section C, Tables 3 and 4, respectively.

A. CQA Identification, Risk and Lifecycle Knowledge Management

Table 1: Active Pharmaceutical Ingredient CQA Identification, Risk and Lifecycle Knowledge Management

CQA (type) Risk Origin Control StrategyIdentity(General)

Safety and Efficacy Intrinsic to the molecule

Primary Structure Efficacy

Higher Order Structure

Efficacy

Cell growth inhibition (Potency)

Efficacy and safety

-Intrinsic to the molecule -Impacted by the DS manufacturing process,

HER2 binding (potency)

Efficacy Intrinsic to the molecule

HER2- mediated Akt phosphorylation inhibition,

Efficacy(Minor contribution to MOA)

Intrinsic to the molecule

ADCC Activity(potency)

Efficacy -Intrinsic to the molecule


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(Minor contribution to MOA)

FcγRIIIa Binding Activity(potency)

Efficacy(impacts ADCC activity)


FcRn binding (potency)

Efficacy (reported to impact half-life of IgG1 antibodies in serum)


Glycan Profile(afucosylation)

Efficacy(impacts ADCC activity)

-Intrinsic to the molecule

manufacturing processGlycan Profile(high mannose)

Efficacy(impacts ADCC activity and PK)

-Intrinsic to the molecule

manufacturing process Heavy and Light Chain(Purity)

Efficacy and Safety

processesDrug-linker distribution

Efficacy and Safety

processes

B. Enhertu (fam-trastuzumab deruxtecan) Drug Substance Quality Summary

Table 2: Drug Substance CQA Process Risk Identification and Lifecycle Knowledge Management.

CQA (type) Risk Origin Control StrategyAppearance(general)

Safety Manufacturing process, formulation

Identity(general)

Efficacy and Safety


pH(general)

Safetyand stability

determined at the

Osmolality(general)

Safety (since there’s no further dilution to generate DP)

Formulation

Protein concentration (general)

Efficacy DS manufacture

Purity of Payload Efficacy manufacturing process-degradation


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Bioburden(Contaminant)

Safety, purity, and efficacy (degradation of modification of the product by contaminating microorganisms)

Bioburden can be introduced from raw materials and throughout the manufacturing process.

Endotoxin (Contaminant)

Safety and purity

Endotoxin can be introduced from raw materials and throughout the manufacturing process.

Mab Product VariantsHigh molecular weight species (product impurities)

Efficacy and safety

Introduced by the manufacturing process May increase during storage.

Low molecular weight species and fragments (product impurities)

Efficacy -Introduced by the manufacturing process --May increase during storage

Charge heterogeneity

(product variants)

Efficacy

-Increase during DS manufacture

Non-conjugated MAb Efficacy DS manufacture

Non-Proteinaceous Impurities- (Impurity)

Safety

- (Impurity)

Safety degradation

-(Impurity)

Potentially safety

--(Impurities)

Safety DS manufacturing process by products

- Safety degradation


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- Form

-Reagents

Safety -DS manufacturing process

Residual Solvents Safety -DS manufacturing process

process

Leachables(impurities)

Safety, product stability

-Manufacturing equipment -Container closure systems

a. Description Enhertu (fam-trastuzumab deruxtecan) is an ADC comprised of a recombinant, humanized anti-human epidermal growth factor receptor 2 (HER2) antibody conjugated to a topoisomerase I inhibitor. The anti-HER2 component is a humanized IgG1 monoclonal antibody (MAb) produced in CHO cells with the same amino acid sequence as trastuzumab. The drug is a topoisomerase I inhibitor conjugated to the MAb through a cleavable maleimide tetrapeptide drug-linker. The drug-linker, MAAA-l 162a (or deruxtecan), is bound to the antibody through thioester bonds formed with free cysteine residues resulting from the reduction of four interchain disulfide bonds. The target number of drug-linker coupled to one antibody molecule is 8, resulting in a drug-to-antibody ratio (DAR) of 8.

b. Mechanism of Action (MoA)Enhertu is indicated

Enhertu binds to the HER2 extracellular domain and induces apoptosis of the target tumor cells via the inhibition of topoisomerase I by the released drug. In addition, Enhertu has HER2-mediated Akt phosphorylation inhibition and antibody dependent cellular cytotoxic (ADCC) activity through the monoclonal antibody.

c. Potency AssayThe potency of Enhertu is determined using a cell growth inhibition assay, which measures cell viability. SK-BR-3 is a human breast cancer cell line that overexpresses Her2. Enhertu and a standard are incubated with SK-BR-3 cells followed by addition of a luminescent viability reagent. The luminescence intensity is plotted against the concentration of Enhertu and fit to an appropriate 4-PL fit. Potency of Enhertu is reported relative to the reference standard.


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d. Reference Materials

Qualification of these reference

standards is sufficient to support their current use and approval. The Sponsor established an adequate link between these reference standards and reference standards and used to release clinical material.

However, the Sponsor agreed to three PMCs to strengthen the qualification of the current reference standards for their intended use and to improve their requalification/stability testing protocols. See PMCs 3762-10, 3762-11, 3762-14 above. No protocols for qualification or requalification of future reference standards are approved as part of the original BLA approval. Qualification of future reference standards should be reported in prior approval supplements.

e. Critical starting materials or intermediatesThe antibody (MAAL-9001) and drug-linker (MAAL-1162a) DSIs are described in Section C.

f. Manufacturing process summary

g. Container closure

h. Dating period and storage conditionsEnhertu drug substance is stored at °C. The data support a shelf life of months under these storage conditions.


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D. Drug Product [Enhertu] Quality Summary:

Table 3 provides a summary of the CQAs that derive from the drug product manufacturing process and general drug product attributes, their origin and associated risk and control strategy.

Table 3: Drug Product CQA Identification, Risk, and Lifecycle Management

CQA (Type) Risk Origin Control StrategyAppearance(before and after reconstitution)(General)

Safety, Efficacy, product stability

Formulation, contamination, lyophilization, or degradation

Identity Safety and Efficacy Intrinsic to the molecule

Sterility (Contaminant)

Safety risk to patients (infection), efficacy (degradation or modification of the product by microorganisms or

Contamination could be introduced throughout the DP manufacturing process


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their byproducts)

Endotoxin (Contaminant)

Safety, purity and immunogenicity

Contamination could be introduced throughout the manufacturing process.

Container Closure Integrity (Sterility Assurance)

Safety (loss of sterility due to breaches in CCI)

Storage conditions

Particulate Matter (Visible and Sub-Visible Particulates)(General)

Safety and Immunogenicity

Particulates can be introduced by the manufacturing process, container closure system, or during reconstitution

pH (as reconstituted product)(General)

Stability -DS manufacture

Leachables(Impurities)

Safety and product stability

Manufacturing product contact equipment and container closure system

Extractable volume (after reconstitution)(General)

Dosing Manufacturing process

Osmolality(General)

Patient Discomfort DS Formulation

Protein Quantity(General)

Efficacy Manufacturing process/Formulation

Water content(General)

Safety and stability (high levels may

DP manufacturing process (lyophilization)


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a. Potency and StrengthEnhertu is supplied as a 100 mg single-dose sterile lyophilized powder in a glass vial. The potency of Enhertu is determined using the same cell growth inhibition assay as the one used for drug substance. Refer to the drug substance section for description of the potency assay.

b. Summary of Product DesignEnhertu (DS-8201a drug product) is supplied as a 100 mg single-dose sterile lyophilized powder in a glass vial. Prior to use, the drug product is reconstituted with 5 mL of water for injection to provide a solution with a DS-8201a concentration of 20 mg/mL in histidine buffer that contains 90 mg/mL sucrose and polysorbate 80 at pH of 5.5. The reconstituted solution is a sterile solution for intravenous infusion that is diluted in 100 mL 5% dextrose prior to use.

c. List of ExcipientsExcipients in Enhertu drug product include L-histidine (4.45 mg), L-histidine hydrochloride monohydrate (20.2 mg) , Sucrose (450 mg), Polysorbate 80 (1.5 mg), and sterile water for injection USP (used for reconstitution).

d. Reference MaterialsThe same primary and secondary reference standards are used for drug substance and drug product testing. Refer to the drug substance Section above.

e. Manufacturing process summary

increase rate of degradation)

and storage

Reconstitution time(General)

product quality DP manufacturing process (lyophilization process)

Content Uniformity(General)

Efficacy DP manufacture


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f. Container closureThe drug product container closure system includes a 10 mL glass vial sealed with a rubber stopper and a /aluminum yellow flip-off crimp cap.

g. Dating period and storage conditionsThe dating period for drug product is 24 months at 2-8°C protected from light.

h. List of co-package components, if applicable: None

E. Novel Approaches/Precedents: None

F. Any Special Product Quality Labeling Recommendations:

Enhertu is a cytotoxic drug. Follow applicable special handling and disposal procedures. Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until reconstitution to protect from light. Prior to use, reconstitute each 100 mg vial with 5 mL sterile WFI and then dilute Enhertu in 100 mL of 5% Dextrose Injection. Do not use sodium chloride. The reconstituted product may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) protected from light. Do not freeze and do not shake diluted or reconstituted drug. The drug is compatible with the infusion bags, infusion sets and infusion filters specified in the label. Data to support chemical and microbial stability of the reconstituted and diluted drug under these conditions of use were provided.

G. Establishment Information

OVERALL RECOMMENDATION: ApproveDrug Substance and MAb Drug Substance Intermediate

Function Site Information FEI Number Final Recommendation-DS-8201a DS manufacture and bulk packaging

-DS-8201a DS in process and release testing

-WCB storage

Daiichi SankyoChemical Pharma Co., Ltd.(Onahama Plant)

389-4, Izumimachi Shimokawa Aza Otsurugi, Iwaki, Fukushima971-8183, Japan

3002808054 Acceptable

-DS-8201a DS stability testing Acceptable


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- MAAL-9001 DSI manufacture and bulk packaging

- MAAL-9001 DSI release and stability testing

-MCB and WCB storage

Daiichi Sankyo Chemical Pharma Co., Ltd.(Tatebayashi Plant)

2716-1 Aza Kurakake, Oaza Akaiwa,Chiyodamachi, Oura-gun, Gunma,370-0503, Japan


MAAL-9001 DSI testing

Acceptable

Drug-Linker IntermediateManufacturing: MAAA-1162a

Packaging: MAAA-1162a

Daiichi SankyoChemical Pharma Co., Ltd.

1-12-1, Shinomiya,Hiratsuka,Kanagawa 254-0014,Japan


Testing: MAAA-1162a Daiichi SankyoChemicalPharma Co., Ltd.

477, Takada,Odawara,Kanagawa 250-0216,Japan


Manufacturing and testing: MAAA-1162a

Packaging: MAAA-1162a

Acceptable

Manufacturing and testing: Acceptable

Drug ProductFunction Site Information FEI Number Final Recommendation

DS-8201a DP manufacture, release and stability testing (except testing for cell growth inhibition) Acceptable

- DS-8201a DP testing for cell growth inhibition at release and on stability

Acceptable


(b) (4)

(b) (4)

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

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

24


DS-8201a DP storage and release Daiichi Sankyo Europe GmbH

Luitpoldstrasse 1,85276 PfaffenhofenGermany


DS-8201a DP Packaging and labelling Acceptable

ID testing Acceptable

H. Facilities

Daiichi Sankyo Chemical Pharma Co., Ltd. Tatebayashi Plant (FEI 3012477651). A Pre-license Inspection of the Daiichi Sankyo Chemical Pharma Co., Ltd. Tatebayashi Plant was conducted from 10/28/2019 – 11/01/2019 in support of MAAL-9001 DSI manufacture and testing for BLA 761139. The inspection covered Quality Procedures, Facilities and Equipment, Materials Management, Production Processes and Contamination Prevention, and Laboratory Controls. A 5-item FDA-483 was issued. Inspection was classified as VAI and approval was recommended.

MAAA-1162A manufacturers: -A Pre-license Inspection of the Daiichi Sankyo Chemical Pharma facility (FEI 3014592242) in support of BLA 761139 was performed from 11/11 – 15/2019. The inspection was classified as NAI with an approval recommendation.

-The compliance status of the is acceptable. Approval decision based is on previous history.

Daiichi Sankyo Chemical Pharma Co., Ltd. Onahama Plant (FEI 3002808054): A Pre-license Inspection of the Daiichi Sankyo Chemical Pharma Co., Ltd. Onahama Plant was conducted from 11/5 – 11/08/2019 in support of MAAL-9001 DSI manufacture and testing for BLA 761139. The inspection covered Quality Procedures, Facilities and Equipment, Materials Management, Production Processes and Contamination Prevention, and Laboratory Controls. A 5-item FDA-483 was issued. The inspection was classified as VAI and approval was recommended.

: A Pre-license Inspection (PLI) of was completed from in support of Enhertu

drug product manufacture for BLA 761139. The inspection covered Quality, Production, Materials, Facilities/Equipment, and Laboratory Controls. A 9-item FDA-483 was issued. The firm’s response received on 11/26/2019 was reviewed and found to be acceptable. The inspection was reclassified as VAI from an initial withhold recommendation. is recommended for approval for manufacturing and testing of Enhertu drug product under BLA 761139


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

25


Other facilities: The compliance status of the additional testing, release, storage, packaging and labeling sites is acceptable (see Table above).

Consequently, the GMP facilities associated with the manufacture of MAAL-9001 DSI, MAAL-1162a drug linker, and Enhertu drug substance and drug product are acceptable from a facilities assessment standpoint.

I. Lifecycle Knowledge Management

a. Drug Substance:

i. Protocols approved: 1. Annual post-approval stability protocol for MAAL-9001 DSI and drug

substance2. Stability protocols for extension of MAAL-9001 DSI and drug substance

shelf-life 3. Protocols for requalification/stability testing of the current primary and

secondary reference standards used for MAAL-9001 DSI, DS, and DP testing

4. Protocols for qualification of new working cell banks5. Protocols for concurrent

ii. Outstanding review issues/residual risk: See Post Marketing Commitments in Section 1B III

iii. Future inspection points to consider: None

b. Drug Product

i. Protocols approved: 1. Annual post-approval stability protocol 2. Stability protocol for extension of drug product expiry

ii. Outstanding review issues/residual risk: See Post Marketing Commitments in Section 1B III

iii. Future inspection points to consider: None


(b) (4)

(b) (4)

--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

FRANCES NAMUSWE12/19/2019 10:30:23 PM

MARIA T GUTIERREZ LUGO12/19/2019 10:35:19 PM

Signature Page 1 of 1


Center for Drug Evaluation and Research Office of Pharmaceutical Quality Office of Biotechnology Products

Page 1 of 9

LABELS AND LABELING ASSESSMENT

Date of Assessment: December 9, 2019

Assessor: Vicky Borders-Hemphill, PharmD Labeling Assessor Office of Biotechnology Products (OBP)

Through: Zhenzhen Liu, PhD, Product Quality Assessor OBP/Division of Biotechnology Review and Research III

Application: BLA 761139

Applicant: Daiichi Sankyo, Inc

Submission Date: July 10, 2019

Product: Enhertu (fam-trastuzumab deruxtecan-nxki)

Dosage form(s): For injection

Strength and Container-Closure:

100 mg lyophilized powder in a single-dose vial

Purpose of assessment:

The Applicant submitted a biologics license application for Agency assessment

Recommendations: The prescribing information, container labels, carton labeling and the medication guide (submitted on December 9, 2019) were assessed and found to be acceptable from an OBP labeling perspective

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Materials Considered for this Label and Labeling Assessment

Materials Assessed Appendix Section

Proposed Labels and Labeling A

Evaluation Tables B

Acceptable Labels and Labeling C

n/a = not applicable for this assessment DISCUSSION We assessed the proposed labels and labeling for compliance with applicable requirements in the Code of Federal Regulations. Also, we assessed the proposed labels and labeling for consistency with recommended labeling practices. (see Appendix B) CONCLUSION The prescribing information, container labels, carton labeling and the medication guide (submitted on December 9, 2019) were assessed and found to be acceptable (see Appendix C) from an OBP labeling perspective. APPENDICES Appendix A: Proposed Labeling Prescribing Information (submitted on August 29, 2019 \\cdsesub1\evsprod\bla761139\0002\m1\us\114-labeling\draft\labeling\us-pi-clean.docx) Medication Guide (submitted on August 29, 2019 \\cdsesub1\evsprod\bla761139\0002\m1\us\114-labeling\draft\labeling\us-medguide-clean.doc) Container Labels (submitted on August 29, 2019)

1 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS) immediately following this page

(b) (4)

of 23

Appendix B: Evaluation Tables Evaluation Tables: Label1,2 and Labeling3 Standards

Container4 Label Evaluation

Proper Name (container label) Acceptable

Regulations: 21 CFR 610.60(a)(1), 21 CFR 201.10(g)(2), 21 CFR 610.62(a), 21 CFR 610.62(b), 21 CFR 610.62(c), 21 CFR 610.60(c), 21 CFR 201.50(b), 21 CFR 201.10(a), 21 CFR 201.10(h)(2)(i)(1)(i)

Yes

☐ No

☐ N/A

Recommended labeling practices (placement of dosage form below the proper name)

Yes

☐ No

☐ N/A

Manufacturer name, address, and license number (container label) Acceptable

Regulations: 21 CFR 610.60(a)(2), 21 CFR 201.1(a), 21 CFR 610.60(c), 21 CFR 201.10(h)(2)(i)(1)(iv), 21 CFR 201.100(e)

Yes

☐ No

☐ N/A

Recommended labeling practices (using the qualifying phrase “Manufactured by:”)

Yes

☐ No

☐ N/A

Recommended labeling practices (U.S license number for container bearing a partial label)

Yes

☐ No

☐ N/A

Comment/Recommendation: FDA’s biological product regulations (21 CFR 600.3(t)) define “manufacturer” as “any legal person or entity engaged in the manufacture of a product subject to license under the PHS Act,” including “any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards”. A manufacturer thus includes a license applicant, who may or may not own the facilities engaged in significant manufacturing steps, when such an applicant assumes responsibility for compliance with the applicable product and establishment standards, including, but not limited to, 21 CFR Parts 210, 211, 600 through 680, and 820. Therefore, the applicant written on Form FDA 356h is considered the following terms: license applicant, license manufacturer, or manufacturer. Revise the manufacturer information to appear as the applicant on FDA form 356h as follows: Manufactured by: Daiichi Sankyo, Inc. Basking Ridge NJ 07920

1 Per 21 CFR 1.3(b) Label means any display of written, printed, or graphic matter on the immediate container of any article, or any such matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity. 2 Per CFR 600.3(dd) Label means any written, printed, or graphic matter on the container or package or any such matter clearly visible through the immediate carton, receptacle, or wrapper. 3 Per 21 CFR 1.3(a) Labeling includes all written, printed, or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after shipment or delivery in interstate commerce. 4 Per 21 CFR 600.3(bb) Container (referred to also as “final container”) is the immediate unit, bottle, vial, ampule, tube, or other receptacle containing the product as distributed for sale, barter, or exchange.

of 23

U.S. License No. xxxx The Applicant revised as requested

Lot number or other lot identification (container label) Acceptable

Regulations: 21 CFR 610.60(a)(3), 21 CFR 610.60(c), 21 CFR 201.18, 21 CFR 201.100(b)(6), 21 CFR 201.10(h)(2)(i)(1)(iii)

Yes

☐ No

☐ N/A

Expiration date (container label) Acceptable

Regulations: 21 CFR 610.60(a)(4), 21 CFR 201.17 Yes

☐ No

☐ N/A

Recommended labeling practices references: USP General Chapters <7> Labeling, Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 lines 178-184, which, when finalized, will represent FDA’s current thinking on topic

Yes

☐ No

☐ N/A

Beyond Use Date (Multiple-dose containers) (container label) Acceptable

Recommended labeling practices: USP General Chapters: <659> Packaging and Storage Requirements and <7> Labeling

☐ Yes

☐ No

☒ N/A

Product Strength (container label) Acceptable

Regulations: 21 CFR 201.10(d)(1), 21 CFR 201.100(b)(4)

Yes

☐ No

☐ N/A

Recommended labeling practices (expression of strength for injectable drugs) references: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 176, which, when finalized, will represent FDA’s current thinking on topic USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Multiple-dose containers (container label) Acceptable

Regulations: 21 CFR 610.60(a)(5), 21 CFR 201.55 (recommended individual dose)

☐ Yes

☐ No

☒ N/A

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Statement: “Rx only” (container label) Acceptable

Regulations: 21 CFR 610.60(a)(6), 21 CFR 201.100(b)(1) Yes

☐ No

☐ N/A

Recommended labeling practices (prominence of Rx Only statement) reference: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 147, which, when finalized, will represent FDA’s current thinking on topic

Yes

☐ No

☐ N/A

Medication Guide (container label) Acceptable

Regulations: 21 CFR 610.60(a)(7), 21 CFR 208.24(d)

☐ Yes

☐ No

☒ N/A

Comment/Recommendation: partial label

No Package for container (container label) Acceptable

Regulation: 21 CFR 610.60(b) ☐ Yes

☐ No

☒ N/A

No container label (container label) Acceptable

Regulation: 21 CFR 610.60(d) ☐ Yes

☐ No

☒ N/A

Ferrule and cap overseal (for vials only) Acceptable

Recommended labeling practices references: United States Pharmacopeia (USP) General Chapters: <7> Labeling (Ferrules and Cap Overseals)

Yes

☐ No

☐ N/A

Comment/Recommendation: Confirm there is no text on the ferrule and cap overseal of the vials. Applicant’s response: The Sponsor confirms there is no text on the ferrule and cap overseal of the vials. The cap and vial comply with the revised USP General Chapters <7> Labeling (Ferrules and Cap Overseal).

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Visual inspection Acceptable

Regulation: 21 CFR 610.60(e) Yes

☐ No

☐ N/A

Comment/Recommendation: Confirm that sufficient area of the container remains uncovered for its full length or circumference to allow for visual inspection when the label is affixed to the container and indicate where the visual area of inspection is located Applicant’s response: The Sponsor confirms that when affixed, the vial label partially wraps around the vial leaving a 4 mm gap for full length view through which the product may be visually inspected. This complies with 21 CFR 610.60(e). Applicant’s response is acceptable

Route of administration (container label) Acceptable

Regulations: 21 CFR 201.5(f), 21 CFR 201.100(b)(3), 21 CFR 201.100(d)(1)

Yes

☐ No

☐ N/A

Recommended labeling practices (route of administration statement to appear after the strength statement on the principal display panel)

Yes

☐ No

☐ N/A

NDC numbers (container label) Acceptable

Regulations: 21 CFR 201.2, 21 CFR 207.35 Yes

☐ No

☐ N/A

Preparation instructions (container label) Acceptable

Regulation: 21 CFR 201.5(g) Yes

☐ No

☐ N/A

Recommended labeling practices: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 426-430), which, when finalized, will represent FDA’s current thinking on topic

☐ Yes

☐ No

☒ N/A

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Package type term (container label) Acceptable

Recommended labeling practices: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP chapter <659> Packaging and Storage Requirements

Yes

☐ No

☐ N/A

Misleading statements (container label) Acceptable

Regulation: 21 CFR 201.6 ☐ Yes

☐ No

☒ N/A

Prominence of required label statements (container label) Acceptable

Regulation: 21 CFR 201.15 Yes

☐ No

☐ N/A

Spanish-language (Drugs) (container label) Acceptable


☐ No

☒ N/A

FD&C Yellow No. 5 and/or FD&C Yellow No. 6 (container label) Acceptable


☐ No

☒ N/A

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Bar code label requirements (container label) Acceptable


☐ No

☐ N/A

Recommended labeling practices references: Guidance for Industry: Bar Code Label Requirements Questions and Answers, August 2011 Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 511-512), lines 780-786), which, when finalized, will represent FDA’s current thinking on topic

Yes

☐ No

☐ N/A

Comment/Recommendation: Ensure that a linear bar code appears on the container label The Applicant added a linear barcode as requested

Strategic National Stockpile (exceptions or alternatives to labeling requirements for human drug products) (container label)

Acceptable

Regulations: 21 CFR 610.68, 21 CFR 201.26 ☐ Yes

☐ No

☒ N/A

Net quantity (container label) Acceptable


☐ No

☒ N/A

Recommended labeling practices references: Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (line 461- 463) which, when finalized, will represent FDA’s current thinking on topic Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products Guidance for Industry, June 2015 (line 68, 93-99) USP General Chapters <1151> Pharmaceutical Dosage Forms (Excess volume in injections).

Yes

☐ No

☐ N/A

Statement of Dosage (container label) Acceptable

Regulations: 21 CFR 610.60(a)(5), 21 CFR 610.60(c), 21 CFR 201.55, 21 CFR 201.100(b)(2)

Yes

☐ No

☐ N/A

Comment/Recommendation: Consider revising the statement of dosage from .” to read as follows “Dosage: See

Prescribing Information” The Applicant revised as requested

(b) (4)

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Inactive ingredients (container label) Acceptable


☐ No

☒ N/A

Recommended labeling practices reference: USP General Chapters <1091> Labeling of Inactive Ingredients and USP General Chapters <7> Labeling

☐ Yes

☐ No

☒ N/A

Comment/Recommendation: partial label

Storage requirements (container label) Acceptable

Recommended labeling practices references: USP General Chapters <7> Labeling, USP General Chapters <659> Packaging and Storage Requirements

Yes

☐ No

☐ N/A

Dispensing container (container label) Acceptable

Regulation: 21 CFR 201.100(b)(7)

☐ Yes

☐ No

☒ N/A

Package5 Labeling Evaluation

Proper name (package labeling) Acceptable

Regulations: 21 CFR 610.61(a), 21 CFR 201.50(b), 21 CFR 201.10(g)(2) Yes

☐ No

☐ N/A

Manufacturer name, address, and license number (package labeling) Acceptable

Regulations: 21 CFR 610.61(b), 21 CFR 201.1(a), 21 CFR 201.1(i), 21 CFR 201.100(e)

Yes

☐ No

☐ N/A

Recommended labeling practices (using the qualifying phrase “Manufactured by:”)

Yes

☐ No

☐ N/A

5 Per 21 CFR 600.3(cc) Package means the immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the preceding sentence, is used, the container shall be deemed to be the package. Thus, this includes the carton, prescribing information, and patient labeling.

of 23

Comment/Recommendation: FDA’s biological product regulations (21 CFR 600.3(t)) define “manufacturer” as “any legal person or entity engaged in the manufacture of a product subject to license under the PHS Act,” including “any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards”. A manufacturer thus includes a license applicant, who may or may not own the facilities engaged in significant manufacturing steps, when such an applicant assumes responsibility for compliance with the applicable product and establishment standards, including, but not limited to, 21 CFR Parts 210, 211, 600 through 680, and 820. Therefore, the applicant written on Form FDA 356h is considered the following terms: license applicant, license manufacturer, or manufacturer. Revise the manufacturer information to appear as the applicant on FDA form 356h as follows: Manufactured by: Daiichi Sankyo, Inc. Basking Ridge NJ 07920 U.S. License No XXXX The Applicant revised as requested

Lot number or other lot identification (package labeling) Acceptable

Regulation: 21 CFR 610.61(c), 21 CFR 201.18

Yes

☐ No

☐ N/A

Expiration date (package labeling) Acceptable

Regulations: 21 CFR 610.61(d), 21 CFR 201.17

Yes

☐ No

☐ N/A

Beyond Use Date (Multiple-dose containers) (package labeling) Acceptable

Recommended labeling practices: USP General Chapters: <659> Packaging and Storage Requirements and <7> Labeling

☐ Yes

☐ No

☒ N/A

Preservative (package labeling) Acceptable

Regulation: 21 CFR 610.61(e) Yes

☐ No

☐ N/A

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Number of containers (package labeling) Acceptable

Regulation: 21 CFR 610.61(f) Yes

☐ No

☐ N/A

Product Strength (package labeling) Acceptable

Regulations: 21 CFR 610.61(g), 21 CFR 201.10(d)(1), 21 CFR 201.100(b)(4) Yes

☐ No

☐ N/A

Recommended labeling practices references: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (line 176), which, when finalized, will represent FDA’s current thinking on topic USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Storage temperature/requirements (package labeling) Acceptable

Regulation: 21 CFR 610.61(h) Yes

☐ No

☐ N/A

Recommended labeling practices reference: USP General Chapters: <7> Labeling, USP General Chapters <659> Packaging and Storage Requirements

Yes

☐ No

☐ N/A

Comment/Recommendation: Consider revising the storage statement from

to read “Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light until time of reconstitution. DO NOT FREEZE. DO NOT SHAKE.” Applicant’s response: The Sponsor accepts the Agency’s storage statement revision. With this submission, the Sponsor proposes the additional following changes: “Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light until time of reconstitution. DO NOT FREEZE. Do not freeze. DO NOT SHAKE.”. “DO NOT FREEZE” was changed from all caps to sentence case for ease of reading and “DO NOT SHAKE” was removed to be consistent with the USPI. The Applicant’s response is acceptable Consider adding storage information for the reconstituted product as follows: “Reconstituted solution may be stored in the original vial refrigerated at 2°C to 8°C (36°F - 46°F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze. Do not shake.”

(b) (4)

of 23

Applicant’s response: The Sponsor accepts the addition of storage information for the reconstituted product. With this submission, the Sponsor proposes to consolidate the reconstitution statement from the back panel with the instructions on the side panel: “If not used immediately, store the reconstituted solution in the original vial refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze. Do not shake.” The Applicant’s response is acceptable

Handling: “Do Not Shake”, “Do not Freeze” or equivalent (package labeling)

Acceptable

Regulation: 21 CFR 610.61(i) Yes

☐ No

☐ N/A

Multiple dose containers (recommended individual dose) (package labeling)

Acceptable

Regulation: 21 CFR 610.61(j) ☐ Yes

☐ No

☒ N/A

Route of administration (package labeling) Acceptable

Regulations: 21 CFR 610.61(k), 21 CFR 201.5(f), 21 CFR 201.100(d)(1)

Yes

☐ No

☐ N/A

Recommended labeling practices (route of administration statement to appear after the strength statement on the principal display panel)

Yes

☐ No

☐ N/A

Known sensitizing substances (package labeling) Acceptable

Regulations: 21 CFR 610.61(l), 21 CFR 801.437 (User labeling for devices that contain natural rubber)

☐ Yes

☐ No

☒ N/A

(b) (4)

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Inactive ingredients (package labeling) Acceptable


☐ No

☐ N/A

Recommended labeling practices references: USP General Chapters <1091> Labeling of Inactive Ingredients, USP General Chapters <7> Labeling

Yes

☐ No

☐ N/A

Comment/Recommendation: Revise ingredient statement as follows: “Each single-dose vial delivers 100 mg of fam-trastuzumab deruxtecan-xxxx, L-histidine (4.45 mg), L-histidine hydrochloride monohydrate (20.2 mg), polysorbate 80 (1.5 mg), and sucrose (450 mg). Following reconstitution with 5 mL Sterile Water for Injection USP, the resulting concentration of fam-trastuzumab deruxtecan-xxxx is 20 mg/mL. Applicant’s response: The Sponsor has revised the ingredient statement with this submission. In order to create space for additional ingredient information, the Sponsor proposes to remove “Discard Unused Portion” as this information appears on the principal display panel. The Applicant’s response is acceptable

Source of the product (package labeling) Acceptable

Regulation: 21 CFR 610.61(p) ☐ Yes

☐ No

☒ N/A

Minimum potency of product (package labeling) Acceptable

Regulation: 21 CFR 610.61(r) Yes

☐ No

☐ N/A

Rx only (package labeling) Acceptable

Regulations: 21 CFR 610.61(s), 21 CFR 201.100(b)(1) Yes

☐ No

☐ N/A

Recommended labeling practices references: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (line 147-149), which, when finalized, will represent FDA’s current thinking on topic

Yes

☐ No

☐ N/A

Divided manufacturing (package labeling) Acceptable

Regulation: 21 CFR 610.63 (Divided manufacturing responsibility to be shown) ☐ Yes

☐ No

☒ N/A

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Distributor (package labeling) Acceptable

Regulation: 21 CFR 610.64, 21 CFR 201.1(h)(5) Yes

☐ No

☐ N/A

Comment/Recommendation: Confirm the distributor information since the manufacturer information on applicant on FDA form 356h appears as Daiichi Sankyo, Inc. Basking Ridge NJ 07920. Applicant’s response: The Sponsor confirms that Daiichi Sankyo, Inc. Basking Ridge, NJ 07920 is the distributor. The Applicant’s response is acceptable

Bar code (package labeling) Acceptable


☐ No

☐ N/A

Recommended labeling practices references: Guidance for Industry: Bar Code Label Requirements Questions and Answers, August 2011 Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 511-512), lines 780-786)

Yes

☐ No

☐ N/A

Strategic National Stockpile (exceptions or alternatives to labeling requirements for human drug products) (package labeling)

Acceptable

Regulations: 21 CFR 610.68, 21 CFR 201.26 ☐ Yes

☐ No

☒ N/A

NDC numbers (package labeling) Acceptable


☐ No

☐ N/A

Preparation instructions (package labeling) Acceptable

Regulation: 21 CFR 201.5(g) Yes

☐ No

☐ N/A

Recommended labeling practices references: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize

Yes

☐ No

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Medication Errors, April 2013 (lines 426-430), which, when finalized, will represent FDA’s current thinking on topic USP General Chapters <7> Labeling

☐ N/A

Comment/Recommendation: see inactive ingredient comment above

Package type term (package labeling) Acceptable

Recommended labeling practices: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP chapter <659> Packaging and Storage Requirements

Yes

☐ No

☐ N/A

Misleading statements (package labeling) Acceptable


☐ No

☒ N/A

Prominence of required label statements (package labeling) Acceptable


☐ No

☐ N/A

Spanish-language (Drugs) (package labeling) Acceptable


☐ No

☒ N/A

FD&C Yellow No. 5 and/or FD&C Yellow No. 6 (package labeling) Acceptable


☐ No

☒ N/A

Phenylalanine as a component of aspartame (package labeling) Acceptable

Regulation: 21 CFR 201.21(c) ☐ Yes

☐ No

☒ N/A

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Sulfites; required warning statements (package labeling) Acceptable

Regulation: 21 CFR 201.22(b) ☐ Yes

☐ No

☒ N/A

Net quantity (package labeling) Acceptable


☐ No

☐ N/A

Recommended labeling practices references: Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (line 461- 463) which, when finalized, will represent FDA’s current thinking on topic Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products Guidance for Industry, June 2015 (line 68, 93-99) USP General Chapters <1151> Pharmaceutical Dosage Forms (Excess volume in injections).

Yes

☐ No

☐ N/A

Statement of Dosage (package labeling) Acceptable

Regulations: 21 CFR 201.55, 21 CFR 201.100(b)(2) Yes

☐ No

☐ N/A

Comment/Recommendation: Revise the statement of dosage from

to read as follows: “Dosage: See Prescribing Information.” You may delete the route of administration from this side panel since the statement “For intravenous infusion only” appear on the principal display panel top create space for other important information such as the reconstitution instructions. The Applicant revised as requested

Dispensing container (package labeling) Acceptable

Regulation: 21 CFR 201.100(b)(7) ☐ Yes

☐ No

☒ N/A

(b) (4)

(b) (4)

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Medication Guide (package labeling) Acceptable

Regulations: 21 CFR 610.60(a)(7), 21 CFR 208.24(d) Yes

☐ No

☐ N/A

Prescribing Information Evaluation PRESCRIBING INFORMATION

Highlights of Prescribing Information

PRODUCT TITLE Acceptable

Regulation: 21 CFR 201.57(a)(2)

Yes

☐ No

☐ N/A

Recommended labeling practices reference: Draft Guidance for Industry on Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products - Content and Format (January 2018), which, when finalized, will represent FDA’s current thinking on topic

Yes

☐ No

☐ N/A


DOSAGE AND ADMINISTRATION Acceptable

Recommended labeling practices reference: USP nomenclature for diluents and

intravenous solutions Yes

☐ No

☐ N/A

Comment/Recommendation: This was revised to USP nomenclature “Sodium Chloride Injection, USP” The Applicant revised as requested


DOSAGE FORMS AND STRENGTHS Acceptable

Regulations: 21 CFR 201.57(a)(8), 21 CFR 201.10, 21 CFR 201.100

Yes

☐ No

☐ N/A

Recommended labeling practices references: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP chapter <659> Packaging and Storage Requirements USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

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Full Prescribing Information

2 DOSAGE AND ADMINISTRATION Acceptable

Regulation: 21 CFR 201.57(c)(3)(iv) Yes

☐ No

☐ N/A

Recommended labeling practices reference: USP nomenclature for diluents and intravenous solutions and storage instructions for reconstituted and diluted products

Yes

☐ No

☐ N/A

Comment/Recommendation: Adding the verbatim statement per 21 CFR 201.57(c)(3)(iv) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The Applicant revised as requested Revised the special handling statement to read: “ENHERTU (fam-trastuzumab deruxtecan-xxxx) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1” The Applicant revised as requested


3 DOSAGE FORMS AND STRENGTHS Acceptable

Regulation: 21 CFR 201.57(c)(4)

Yes

☐ No

☐ N/A

Recommended labeling practices references: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP chapter <659> Packaging and Storage Requirements USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Comment/Recommendation: Adding identifying characteristics of the dosage form per 21 CFR 201.57(c)(4) The Applicant revised as requested

of 23


11 DESCRIPTION Acceptable

Regulations: 21 CFR 201.57(c)(12), 21 CFR 610.61 (m), 21 CFR 610.61(o), 21 CFR 610.61 (p), 21 CFR 610.61 (q)

Yes

☐ No

☐ N/A

Recommended labeling practices references: USP General Chapters <1091>, USP General Chapters <7>

Yes

☐ No

☐ N/A

Comment/Recommendation: The was deleted since this paragraph discusses the drug substance The Applicant revised as requested Adding the pharmacological or therapeutic class of the drug (per 21 CFR 201.57(c)(12) The Applicant revised as requested Relocating the strength to help differentiate the inactive ingredients from the active ingredient We revised the inactive ingredients to appear in alphabetical order (see USP General Chapters <1091>: Labeling of inactive ingredients in alphabetical order) The Applicant revised as requested


15 Cytotoxic Drug reference Acceptable

Regulation: 21 CFR 201.57(c)(17)(iv)

xxxx is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 1.OSHA Hazardous Drugs. OSHA. [Accessed on June 9, 2017, from http://www.osha.gov/SLTC/hazardousdrugs/index.html

Yes

☐ No

☐ N/A


16 HOW SUPPLIED/ STORAGE AND HANDLING Acceptable

Regulation: 21 CFR 201.57(c)(17) Yes

☐ No

☐ N/A

Recommended labeling practices: to ensure placement of detailed storage conditions for reconstituted and diluted products

Yes

☐ No

☐ N/A

Comment/Recommendation: Adding the dosage form and the identifying characteristics of the dosage form per 21 CFR 201.57(c)(17). The Applicant revised as requested

(b) (4)

of 23

Revised to add “in the original carton to protect from light” and “do not shake” handling instructions for consistency with the proposed carton labeling The Applicant revised as requested Revised the special handling statement to read: “ENHERTU (fam-trastuzumab deruxtecan-xxxx) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1” The Applicant revised as requested


MANUFACTURER INFORMATION Acceptable

Regulations: 21 CFR 201.100(e), 21 CFR 201.1

Yes

☐ No

☐ N/A

Recommended labeling practices references: 21 CFR 610.61(b) (add the US license number for consistency with the carton labeling), and 21 CFR 610.64 (Name and address of distributor may appear and use a qualifying phrase for consistency with the carton labeling, when applicable)

Yes

☐ No

☐ N/A

Comment/Recommendation: Revise the manufacturer information to appear as the applicant on FDA form 356h. The Applicant revised as requested Confirm the distributor information since the manufacturer information on applicant on FDA form 356h appears as Daiichi Sankyo, Inc. Basking Ridge NJ 07920. The Applicant confirmed as requested

Medication Guide Evaluation

MEDICATION GUIDE

TITLE (NAMES AND DOSAGE FORM) Acceptable

Regulation for Medication Guide: 21 CFR 208.20(a)(7) Yes

☐ No

☐ N/A

MEDICATION GUIDE

STORAGE AND HANDLING Acceptable

Regulation for Medication Guide: 21 CFR 208.20(a)(2) ☐ Yes

☐ No

☒ N/A

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MEDICATION GUIDE

INGREDIENTS Acceptable

Recommended labeling practice: To ensure labeling of inactive ingredients are in alphabetical order (see USP General Chapters <1091>)

Yes

☐ No

☐ N/A

Comment/Recommendation: We revised the inactive ingredients to appear in alphabetical order (see USP General Chapters <1091>: Labeling of inactive ingredients in alphabetical order) The Applicant revised as requested

MEDICATION GUIDE

MANUFACTURER INFORMATION Acceptable

21 CFR 208.20(b)(8)(iii)

Yes

☐ No

☐ N/A 21 CFR 610.61 (add the US license number for consistency with the carton labeling), 21 CFR 610.64 (Name and address of distributor may appear and use a qualifying phrase for consistency with the carton labeling, when applicable)

Yes

☐ No

☐ N/A

Comment/Recommendation: Revise the manufacturer information to appear as the applicant on FDA form 356h as follows: Manufactured by: Daiichi Sankyo, Inc. Basking Ridge NJ 07920 U.S. License No XXXX The Applicant revised as requested Confirm the distributor information since the manufacturer information for applicant on FDA form 356h appears as Daiichi Sankyo, Inc. Basking Ridge NJ 07920. The Applicant confirmed as requested

Patient Information Labeling Evaluation (N/A) Instructions for Use Evaluation (N/A) APPENDIX C. Acceptable Labels and Labeling Prescribing Information (submitted on December 9, 2019 \\cdsesub1\evsprod\bla761139\0078\m1\us\114-labeling\draft\labeling\us-pi-clean.docx) Medication Guide (submitted on December 9, 2019 \\cdsesub1\evsprod\bla761139\0078\m1\us\114-labeling\draft\labeling\us-medguide-clean.docx)

1 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS) immediately following this page

VickyBorders-Hemphill

Digitally signed by Vicky Borders-HemphillDate: 12/09/2019 10:51:29AMGUID: 50814c7000007a3d59329f660d8ddf02

ZhenzhenLiu

Digitally signed by Zhenzhen LiuDate: 12/09/2019 11:16:21AMGUID: 555108d8007bb3724ef2a6d3413e2758