Chemical Engineering

CENTER FOR DRUG EVALUATION AND
RESEARCH
APPLICATION NUMBER:
206316Orig1Orig2s000
CHEMISTRY REVIEW(S)
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration

Silver Spring, MD 20993
CMC Memo to File

To:
Date
Sponsor:
Drug:
Subject
Reviewer
NDA 206316
15 December 2014
Daiichi-Sankyo
Edoxaban Tablets, 15 mg, 30 mg and 60 mg
OC recommendation
Dr. Akm Khairuzzaman
Pursuant the overall acceptable recommendation given on 14-Nov-2014 for the

manufacturing facilities by the Office of Compliance, the CMC recommendation is no changed
to Recommended for Approval from CMC perspective.
HFD-/Division File
HFD-120
Akm Khairuzzaman, Ph.D.
Chemistry Reviewer
Olen Stephens, Ph.D.
Acting Branch Chief, ONDQA
Reference ID: 3672974
NDA 206-316
Page 2
Attachment
(b) (4)
--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed

electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------AKM KHAIRUZZAMAN
12/15/2014
Recommended for Approval from CMC point of view
OLEN M STEPHENS
12/15/2014
Savaysa (edoxaban) tablets

NDA 206316
Summary Basis for Recommended Action
from Chemistry, Manufacturing, and Controls
Applicant:
Daichii Sankyo.
US Agent: Doreen V. Morgan
399 Thornall Street, 10th Floor
Edison
NJ 08837
Indication:
To reduce the risk of stroke and systemic embolism in

patients with nonvalvular atrial fibrillation (DCRP)
Treatment of deep vein thrombosis and pulmonary
embolism (DHP)
(b) (4)
Presentation: The product will be available in 15 mg, 30 mg, and 60 mg strength,

immediate release, film coated tablets. The tablets are orange, roundshaped, debossed with DSC L15 (15 mg tablets), pink, round shaped,
debossed with DSC L30 (30 mg), and yellow, round shaped, debossed
with DSC L60 (60 mg tablets). The tablets are packaged in HDPE
bottles with 7, 30, 90 and 500 counts. The tablets are also available in
(b) (4)
aluminum foil blister unit dose packages of 7 and 10
counts.
EER Status: Overall recommendation is pending as of 2-Oct-2014.
Consults:
ONDQA Biopharmaceutics - Acceptable with PMC (Sandra Suarez, 9Sep-2014).

Microbiology - Acceptable (Steven Donald, 3-Apr-2014)
Methods Validation - Acceptable (Jason Rodriguez, 5-Sep-14)
EA Categorical exclusion granted.
1
Post-Approval Agreements: The biopharmaceutics reviewer recommends PostMarketing Commitment from the company to develop an improved discriminating and
canonical method and set the final dissolution acceptance criteria for the product using
the new method.
Drug Substance:
The drug substance, edoxaban tosylate, a new molecular entity, is a white to pale
yellowish crystalline powder. Edoxaban tosylate can exist in
(b) (4)
The drug substance, edoxaban tosylate, is synthesized using a

(b) (4)
The drug substance quality is ensured through quality control of all starting materials, inprocess controls throughout the manufacturing process, appropriate quality control of the
isolated intermediates and the appropriate final drug substance specification. The drug
substance acceptance specification includes tests and acceptance criteria for drug
substance critical quality attributes, e.g., appearance, identification, assay, organic
(b) (4)
impurities,
heavy metals, residue on ignition, water content, residual
solvents and particle size distribution. The analytical procedures have been adequately
described and validated to control the quality of the drug substance. The stability of the
drug substance (b)
has
been demonstrated through appropriate stability studies to support a
(4)
(b) (4)
retest period of
months when stored
Drug product:
Savaysa (edoxaban) tablets are an immediate release product to be marketed in 15 mg, 30
mg and 60 mg strengths. The three strengths are dose proportional that use standard
compendial excipients, e.g., mannitol, pregelatinized starch, crospovidone,
(b) (4)
hydroxypropyl cellulose, and magnesium stearate. The manufacturing process is a
The manufacturing process has appropriate inprocess controls to ensure the quality of the drug product. The product release testing is
(b) (4)
done through
for most of the attributes. The product specification
includes testing for appearance, identification, assay, uniformity of dosage units, related
substances, and dissolution. All analytical procedures for the drug product are adequately
described and validated. The provided stability data support the proposed 36-month
expiration period for this product.
The drug product is stored at 25C with excursions permitted 15-30C (59-86F).
Conclusion: Adequate from CMC perspective.
Additional Items:
2
All associated Drug Master Files are acceptable or the pertinent information has been
adequately provided in the application.
Overall Conclusion: The application is recommended for Approval from CMC
perspective pending a final overall Acceptable recommendation from the Office of
Compliance about the manufacturing facilities.
Ramesh K. Sood, Ph.D.
Acting Director, DPA I/ONDQA
3

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------RAMESH K SOOD
10/07/2014
Memorandum
DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
Date:
21-Aug-2014
From:
Janice Brown, M.S.

CMC Lead
DNDQA I/ONDQA
Through:
Ali Al-Hakim, Ph.D.

Chief, Branch II
New Drug Quality Assessment Division I1
ONDQA
To:
NDA 206316
Edoxaban Tablets
Subject:
Risk Assessment
As per a new policy, each NDA with GRMP dates on or after August 1, 2014 will include
a risk assessment in the Executive summary. This will be based on an initial risk
assessment that would be captured in all IQAs written for NDAs received on or after June
1, 2014. It was decided that the CMC Lead would perform a retrospective risk
assessment for those NDAs received prior to June 1, 2014 that had GRMP dates after
August 1, 2014.
The following IQA template was provided:
In an email dated 30-May-2014, Dr. Ramesh Sood provided follow-up guidance on how
to fill out the required IQA template that is used to populate the NDA template. The
guidance provided templates for the most common dosage forms.
1
This memo captures both the table that would normally be in the IQA and populates the
first three columns of the NDA template that will be filled in by the primary CMC
reviewer.
IQA RISK ASSESSMENT
Product
attribute/CQA
Factors that can

impact the CQA
Assay, stability
Formulation
Container closure
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Exclude major
reformulations
Process parameters
Scale/equipment
Site
Physical stability
(solid state)
Content
Uniformity
Microbial limits
Dissolution
Probability
(O)
Severity
of Effect
(S)
2
Detectability
(D)
3
(Crystalline)
3
(BCS
IV)
36
12
10
OPS Micro will assess
32
ONDQA BioPharm will

assess
(b) (4)
Release (1)
Stability (3)
FMECA
RPN
Number
Release (6)
stability
(18)
Comment
Moderately Stable Drug:
Single impurity > (b) (4)
Total impurities <
Risk
L
The evaluation from the IQA table was transferred to the following NDA table that can
be used by the primary reviewer as a part of the NDA review.
2
NDA RISK ASSESSMENT TABLE

From Initial Quality Assessment
Product
Factors that can
Risk
attribute/
impact the CQA
Ranking
CQA
Assay, stability
Physical stability
(solid state)
Content Uniformity
Microbial limits
Dissolution
Formulation
Container closure
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Formulation
Raw materials
Exclude major reformulations
Process parameters
Scale/equipment
Site
Review Assessment
Risk
Mitigation
approach
Risk
Evaluation
Lifecycle
Considerations
/ Comments
3

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------JANICE T BROWN
08/22/2014
ALI H AL HAKIM
08/22/2014
CHEMISTRY REVIEW
Submission Type: Standard; Type 1 submission
Recommendation: Pending
NDA 206316
Review 1
Review Date Sept 8, 2014
Drug Name/Dosage Form
Strength
Route of Administration
Rx/OTC Dispensed
Applicant
US agent, if applicable
Endoxaban / Immediate Release Tablets

15, 30 and 60 mg
oral
Rx
Daichii Sankyo
Doreen V. Morgan, Pharm D. Exe. Director, Regulatory Affairs

Phone #: (732) 590-5198; Fax #: (732) 906-6652
Add: 399 Thornall Street, 10th floor, Edison, NJ 08837
Submission Reviewed
Original NDA Submission
Quality/Response To Information Request
Received Date
08-Jan-2014
22-Jan-14
14-Feb-2014
03-Apr-2014
18-Apr-2014
23-Apr-2014
29-Apr-2014
30-Apr-2014
05-May-2014
09-May-2014
16-Jun-2014
07-Jul-2014
10-Jul-2014
24-Jul-2014
01-Aug-2014
18-Aug-2014
Quality Review Team

DISCIPLINE
Drug Substance
Drug Product
NIR Procedures
Microbiology
Facility
Biopharmaceutics
CMC Lead
Project Manager
REVIEWER
Debasis Ghosh
Akm Khairuzzaman
Yubing Tang
Steve Donald
Vibhakar Shah, Vipul Dholakia
Sandra Suarez
Kasturi Srinivasachar (DCRP),
Janice Brown (DHP)
Yvonne Knight
BRANCH/DIVISION
Branch II/ Division I
Branch I/ Division I
Branch VI/ Division II
CHEMISTRY REVIEW
Technical Lead
Laboratory (OTR)
ORA Lead
Environmental Assessment (EA)
Sharmista Chatterjee
John Kauffman, Jason Rodriguez
Quality Review Data Sheet

1. LEGAL BASIS FOR SUBMISSION: 505 (b) (1)
2. RELATED/SUPPORTING DOCUMENTS:
A. DMFs:
OTR/DPA
CHEMISTRY REVIEW
DMF #
CODE1
STATUS2
DATE REVIEW
COMPLETED
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
III
N/A
TYPE
ITEM
REFERENCED
(b) (4)
(b) (4)
HOLDER
Action codes for DMF Table:

1 DMF Reviewed.
Other codes indicate why the DMF was not reviewed, as follows:
CHEMISTRY REVIEW
2 Type 1 DMF
3 Reviewed previously and no revision since last review
4 Sufficient information in application
5 Authority to reference not granted
6 DMF not available
7 Other (explain under "Comments")
2
Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not
need to be reviewed)
B. Other Documents: IND, RLD, or sister applications

DOCUMENT
EOP2 CMC Only

Pre-NDA Meeting
APPLICATION NUMBER
IND 63266
IND 63266
DATE
01-Jul-2010
24-Sep-2013
3. CONSULTS:
DISCIPLINE
Division of
Pharmaceutical
Analysis/OTR
STATUS
Completed
RECOMMENDATION
Methods are suitable for their
intended use
DATE
5-Sep-2014
REVIEWER
Dr. Jason
Rodriguez
CHEMISTRY REVIEW
Executive Summary
I.
Recommendations
A. Recommendation and Conclusion on Approvability
a. Summary of Complete Response issues
Recommendation pending EES recommendation and response from the firm
(b) (4)
regarding concerns with dissolution method and
proposal.
Additionally, the applicant has committed to several changes in the drug
substance specifications and change management of the drug product design
spaces, but has not formally updated the NDA. These amendments will be
captured in following reviews.
b. Action letter language, related to critical issues such as expiration date
These will be communicated with the final recommendation
B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
Risk Management Steps, if Approvable
The biopharmaceutics reviewer is in negotiations regarding a post-marketing
commitment to develop a more discriminating dissolution method and associated
acceptance criteria within one year of approval. This commitment has not yet been
finalized.
II.
Summary of Quality Assessments
Drug Substance [USAN Name] Quality Summary

a. Chemical Name or IUPAC Name/Structure
Endoxaban tosylate monohydrate
b. Properties/CQAs Relevant to Drug Product Quality

Solubility (acid soluble, base or water insoluble), hygroscopicity (non(b) (4)
hygroscopic), particle size and
Chiral compound (no inversion of
(b) (4)
configuration). Based on NDA, edoxaban tosylate
possibly
(b) (4)
(b) (4)
CHEMISTRY REVIEW
(b) (4)
c. List of starting materials & Suppliers of starting materials (site)

Chemical Name of Starting Material Supplier
(b) (4)
Custom manufacturer
Non pharmaceutical market and
commercially available
The proposed starting materials are consistent with ICH Q11.
d. Summary of Synthesis
The drug substance, edoxaban tosylate monohydrate, is synthesized using a
(b) (4)
(b) (4)
e. Process
f. Drug Substance Specification
(b) (4)
CHEMISTRY REVIEW
Release and stability specification included tests for: appearance, identification,
(b) (4)
organic impurities,
heavy metals, residue on ignition, water
content, residual solvent, assay, particle size distribution. Though
(b) (4)
is important to drug product quality, supporting batch data was
(b) (4)
presented to show consistent generation of
The justification for the
(b) (4)
exclusion of
in the release and stability
specifications is provided. It is acceptable.
g. Container Closure System
The drug substance is packaged in double low density polyethylene (LDPE)
bags with twist ties and placed in a high density polyethylene (HDPE) drum.
h. Retest Period &(b)Storage Conditions
The proposed (4) months of retest period, when stored at long-term storage
(b) (4)
conditions
in the proposed container closure system, is acceptable
Drug Product [Edoxaban tosylate, tablets] Quality Summary

a. Strength
Available in three strengths, 15, 30 and 60mg
b. Description/Commercial Image
c. Summary of Product Design

Dose proportional formulation, manufactured using a
(b) (4)
d. List of Excipients:
Mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose,
(b) (4)
magnesium stearate, and film coating materials
orange, pink and
yellow). All ingredients are of USP grade and IIG limits of all excipients are
well within limits used for commercial product manufacture.
e. Process Selection (Unit Operations Summary)
The drug product is manufacturing process by
(b) (4)
CHEMISTRY REVIEW
(b) (4)
f. Drug product specifications

was proposed for almost all attributes with the
exception of description that are included in the specification This included: (b) (4)
(b) (4)
proposed for dissolution as a function of some

.
However, as detailed in the biopharmaceutics review this
approach was found to be unacceptable. The biopharmaceutics
has a verbal agreement with the applicant to remove the model
(b) (4)
supporting
of dissolution, implementing release testing with
the current dissolution method with associated acceptance
criteria, and to commit to a post-marketing commitment to
develop a more discriminating method.
(b) (4)
- No microbial testing for routine release. This is supported by
activity results that show finished product doesnt support
microbial growth.
(b) (4)
(b) (4)
is used as a backup method for
(b) (4)
(b) (4)
It is also the regulatory analytical method.

(b)
The method was validated using the (4) mg strength, since other
strengths are dose proportional. Validation data provided
followed the requierments as outlined in ICH Q2(R1) and was
found to be adequate
g. Container Closure
SAVAYSA Tablets will be packaged in all aluminum blisters as well as in
HDPE bottles.
CHEMISTRY REVIEW
h. Expiration Date & Storage Conditions
Proposed shelf life is 36 months at long term storage conditions of
25C/60%RH. This is supported by 24 months of registration stability batch
data and 48 months of clinical (phase 3) batch stability data. Batches used in the
registration stability program were manufactured by the final commercial
process at pilot-scale.
i. List of co-packaged components
NA
CHEMISTRY REVIEW
Summary of Drug Product Intended Use
Proprietary Name of the Drug Product

Non Proprietary Name of the Drug Product
Proposed Indication(s) including Intended
Patient Population
Savaysa TM
Edoxaban Tosylate
Reduce the risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation (DCRP)
Treatment of deep vein thrombosis and pulmonary
embolism (DHP)
(b) (4)
Duration of Treatment
Maximum Daily Dose
Alternative Methods of Administration
60 mg
NA
Biopharmaceutics Considerations
(For additional details regarding biopharmaceutics considerations refer to the review by
Sandra Suarez)
a. BCS Classification: (b)lass IV
b. Specification: NLT (4)% in 30 min
c. Biowaivers/Biostudies
Biowaiver Requests : NA
PK studies
IVIVC : None
Novel Approaches
Applicant has proposed for
(b) (4)
for all quality attributes except for

(b) (4)
Following
(b) (4)
CHEMISTRY REVIEW
(b) (4)
However, this approach was found to be inadequate upon review. Also, change control protocols
(b) (4)
were included for managing post approval changes to
. Upon review, the
applicant was asked to modify and resubmit the reporting categories for some potential changes
as a protocol. The applicant agreed to the information request, and a comparability protocol was
submitted in Amendment 08/01/2014 in Section 3.2.R. This only includes changes and
(b) (4)
maintenance of the
the applicant has not yet sent a similar protocol for the drug
product design spaces. No comparability protocol for design space is submitted in Section 3.2.R.
Any Special Product Quality Labeling Recommendations NA
CHEMISTRY REVIEW
Lifecycle Knowledge Management
a) Drug Substance
From Initial Risk Identification
Attribute/
CQA
Initial Risk
Ranking*
Justification
Risk Mitigation Approach

(b) (4)
Organic
impurities
including
genotoxic
impurities
Review Assessment
Lifecycle
Final Risk
Considerations/
Evaluation
Comments**
Acceptable
Elemental
impurities/residual
solvents
Acceptable
Particle size
distribution
Acceptable
Assay
Acceptable
Water content
Acceptable
Stability
Acceptable
Note: Since initial risk ranking was not done for the drug substance, these cells are greyed out
Limits for genotoxic impurities

to be revisited if there is a
change in drug substance
processing conditions
Limits for residual solvents to be
revisited if there is a change in
drug substance synthesis or any
of the starting materials
Limits for elemental impurities
to be revisited if there is a
change in drug substance
processing conditions
Evaluate adequacy of existing
PSD specifications if there is a
change in drug product
manufacturing conditions or
change in bulk excipient PSD
(due to a change in supplier or
grade)
None
Evaluate adequacy of existing
water content specifications if
there is a change in drug product
manufacturing, e.g. change in
type and amount of excipients
Stability data to be evaluated if
there is a change in drug
substance synthesis. A post
approval stability protocol and
stability commitment included in
the application and are consistent
with ICH Q1A
CHEMISTRY REVIEW
a) Drug Product
From Initial Risk Identification
Initial
Factors that
Attribute/
Risk
can impact the
CQA
Ranking
CQA
*
Assay, stability
Formulation
Container closure
Raw materials
Process parameters
Scale/equipment
Site
Physical stability
(solid state)
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Content
Uniformity
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Microbial limits
Formulation
Raw materials
Process parameters
Scale/equipment
Site
Dissolution
API particle size,

Granule characteristics,
Moisture,
Tab hardness and
density, Disintegration,
formulation components
Review Assessment
Risk Mitigation
Approach
Final Risk
Evaluation
Lifecycle Considerations/ Comments**

(b) (4)
*Risk ranking applies to product attribute/CQA

**For example, critical controls, underlying control strategies assumptions, post marketing commitment, knowledge management post
approval, etc.
226 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------AKM KHAIRUZZAMAN
09/08/2014
DEBASIS GHOSH
09/08/2014
Responsible for Drug Substance Review only
YUBING TANG
09/08/2014
SHARMISTA CHATTERJEE
09/08/2014
OLEN M STEPHENS
09/08/2014

Date:
September 5, 2014
From:
Jason D. Rodriguez, Ph.D., Chemist, OPS/OTR/ DPA
To:
Yubing Tang, OPS/ONDQA/DNDQAII/BRVI

Yvonne Knight, OPS/ONDQA
Through:
John Kauffman, Ph.D., Deputy Director, OPS/OTR/ DPA
Subject:
DPA Consult for NDA206316 Edoxaban Tablets
Center for Drug Evaluation and Research

Division of Pharmaceutical Analysis
1114 Market Street, Room 1002
St. Louis, Missouri 63101
Telephone (314) 539-3855
FAX (314) 539-2113
Background
(b) (4)
The Division of Pharmaceutical Analysis reviewed the
methods for
NDA206316 with emphasis on the questions raised in the consult request from Yvonne Knight
(b) (4)
dated January 18, 2014 The methods described in the application employ both
Conclusion
(b) (4)
In general the
are well-described and seem to be appropriate for their application
and use and we find the methods adequate as amended. The applicant has placed emphasis on
several different hazards that are important in determining the performance of the methods. In
(b) (4)
general, the hazards cited are commonly known for
and have been documented in literature
(b) (4)
for several decades. The models developed are based on well-known
and references are provided throughout the document when necessary. Specific areas
where more information would be helpful are identified in Attachment 1 in red and summarized
below.
Areas Needing Clarification
(b) (4)
should be documented for all the models developed. All models

follow the same general procedure and are claimed to be suitable for their intended
(b) (4)
purpose based primarily on the linear trend between the
method and the reference
methods.
(b) (4)
The section dealing the determination of the effective
has few details to fully evaluate the conclusions reached
in the application.
DPATR-FY14-060
Overall Evaluation and Review Outcome:

The following Information Request was sent to the applicant on June 17, 2014:
1. Provide technical details to show how mean areas were calculated by using
2. For figures 1.136 through 1.138 in section 3.2.P.2.3, provide the measured
(b) (4)
(b) (4)
3. Clarify whether batch samples used in method validations were representative of the
expected process and material variability, and these samples were different from those
used in the calibration set.
On July 7, 2014 the applicant submitted an amendment addressing these areas as follows:
(b) (4)
1.
(b) (4)
2. The
for the figures 1.136 through 1.138 are not given due to limitations of
(b) (4)
the software used for these identification tests. The Applicant provides a
3. The information from the Applicant clearly shows that the batch samples used in the
validation are both different from the calibration samples and representative of
expected material variability.
Evaluation:
Adequate as Amended
The Division of Pharmaceutical Analysis has found the responses by the Applicant to the
information request to be adequate.
3 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately

following this page
DPATR-FY14-060

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------MICHAEL L TREHY
09/05/2014

METHODS VALIDATION REPORT SUMMARY

TO:
Akm Khairazzuman and Debasis Ghosh, CMC Reviewer

Office of New Drug Quality Assessment (ONDQA)
E-mail Address: [email protected]
Phone: (301)-796-3886 (Akm); (301) 796-4093 (Debasis)
Fax:
(301)-796-9747
FROM: FDA
Michael Trehy, MVP Coordinator
645 S Newstead Avenue
St. Louis, MO 63110
Phone: (314) 539-3815
Through: John Kauffman, Deputy Director
Phone: (314) 539-2168
SUBJECT: Methods Validation Report Summary
Application Number: 206316
Name of Product: Savaysa (edoxaban), Tablets 15, 30 amd 60 mg
Applicant: Daiichi Sankyo, Inc.
Applicants Contact Person: Doreen V. Morgan, Pharm.D.; Executive Director, Regulatory Affairs
th
Address: 399 Thornall Street, 10 floor, Edison, NJ 08837

Telephone: (732) 590-5198
Fax: (732) 906-5562
Date Methods Validation Consult Request Form Received by DPA: Feb-28-2014

Date Methods Validation Package Received by DPA: Feb-28-2014
Date Samples Received by DPA: Apr-15-2014
Date Analytical Completed by DPA: June-24-2014
Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes.
2. Methods are acceptable with modifications (as stated in accompanying report).
3. Methods are unacceptable for regulatory purposes.
Comments: See attached memo for analysts comments and data summary.
DPATR-FY14-055
Page 1 of 5
Version: 2/6/2013

St. Louis, MO 63101
Tel. (314) 539-3852
Date:
June 23, 2014
From:
Changning Guo, Chemist (DPA)
To:
Akm Khairazzuman and Debasis Ghosh, CMC Reviewers,

Kasturi Srinivasachar, CMC Lead
Through:
John Kauffman, Deputy Director, Division of Pharmaceutical Analysis (DPA)
Subject:
Method Validation for NDA 206316

Edoxaban Tablets, 15 mg, 30 mg, and 60 mg
Daiichi Sankyo, Inc
The following methods were evaluated and are acceptable for quality control and regulatory purposes:
1.
(b) (4)
(Daiichi Sankyo, Inc, 3.2.S.4.2)

2.
(b) (4)

3.
(b) (4)

4.
(b) (4)
(Daiichi Sankyo, Inc, 3.2.P.5.2)

5.
(b) (4)

6.
Dissolution, Apparatus 2, 50 rpm, UV-VIS

The following method was not evaluated due to lack of the required sampling unit at DPA:
(b) (4)
Link to analysts work sheets and data:

http://ecmsweb.fda.gov:8080/webtop/drl/objectId/090026f88073196b
DPATR-FY14-055
Page 2 of 5
Version: 2/6/2013
DPA has the following comments pertaining to the following methods.

(b) (4)

(b) (4)
2 Page(s) has been Withheld in Full as B4 (CCI/TS) immediately following this page
DPATR-FY14-055
Page 3 of 5
Version: 2/6/2013

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------MICHAEL L TREHY
06/24/2014
JOHN F KAUFFMAN
06/25/2014
EDOXABAN TOSYLATE / N 206-316
INSPECTIONAL ASSIGNMENT
(EMAIL TRANSMITTAL)
Date:
May 23, 2014
To:
International
Division of Medical Products and Tobacco Inspections
Office of Regulatory Affairs
Facility(ies):
Daiichi Sankyo Propharma Co., Ltd. (DSPP)

Akita Plant, 1-10-1, Mukaihama, Akita-shi
Akita, 010-1601, Japan
FEI No: 3002806777
and
Daiichi Sankyo Chemical Pharma Co., Ltd. (DSCP)
Odawara Plant, 477, Takata, Odawara-shi,
Kanagawa 250-0216, Japan
FEI No.: 3003279188
Drug Name
(dosage form,
strength/concentration):
Profile Class:
Edoxaban Tosylate Drug Substance
(b) (4)
A/NDA No.:
NDA 206-316
Chemistry Reviewer
Debasis Ghosh, Ph.D.

CDER/OPS/ONDQA/DNDQAI/BRII
[email protected] Tel: 310-796-4093
Microbiology Reviewer (if

applicable)
N/A
OC Compliance Officer
Vipul Dholakia, Ph.D,

CDER/OC/OMPQ HFD-320
[email protected] Tel. 301-796-5065
CDER has identified specific area(s) for inspectional focus for drug substance
manufacturing in connection with the NDA 206-316. In accordance with the API Process
Inspection Compliance Program 7356.002F, PAIs provide for continuity in our premarket review of drug product by focusing on areas in which data is questionable; drug
characteristics or sensitivities 1 indicate special scrutiny, the overall manufacturing and

control strategy appears lacking; and potential manufacturing weaknesses may exist.
Summary of Drug Substance and Manufacturing Process
Edoxaban, an antithrombotic agent, is a member of the anti-factor Xa class of
compounds. Edoxaban Tosylate is a white to pale yellowish-white powder and is a pure,
(b) (4)
stable crystalline solid which exhibits
(b) (4)
Edoxaban tosylate exists i
Edoxaban is a new molecular entity indicated to reduce the risk of stroke and systemic
embolic events in patients with nonvalvular atrial fibrillation, and the treatment of venous
thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary
(b) (4)
embolism (PE),
Manufacturing Process:
(b) (4)
The manufacturing process for Edoxaban Tosylate
(b) (4)
The manufacturing process for
The
tosylate are summarized below:
(b) (4)
for manufacturing edoxaban

(b) (4)
(b) (4)
9 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this

page
The following is a brief explanation of product or process specific issues that should
receive follow-up during the inspection.
I. Chemistry Review
The chemistry reviewer, Debasis Ghosh did not have any major issue for inspectional
coverage.
II. Microbiology Review

The microbiology reviewer, Steven Donald did not have any major issue for inspectional
coverage.
III. Manufacturing
Edoxaban Tosylate (Daiichi Sankyo Propharma Co. Ltd.)
(b) (4)
a.
(b) (4)
b.
(b) (4)
c.
1 Page has been Withheld in Full as b4 (CCI/TS) immediately

following this page

(b) (4)
IV. Quality Control / Quality Assurance
a. Quality System:
i.
Determine if all laboratory test instruments are adequate for their

intended use (qualified). Review the HPLC analytical method used
(b) (4)
and determine if the HPLC

method is validated.
ii.
Determine if any OOS results or deviations or rejections have

occurred during development or scale up, and report on adequacy of
investigations.
b. Validation:
i. Review the process performance qualification protocol (if available),
which specifies the procedures (and tests) to be conducted and the data to
be collected. Determine if the validation protocol includes equipment
qualification, an evaluation of the suitability of materials and evaluation of
consistent adherence to pre-established process parameters and quality
attributes. If process validation batches have been manufactured, review
the data generated from these batches.
ii. Determine if the firm has integrated this drug into its
(b) (4)
approach for
equipment and evaluate the
(b) (4)
(b) (4)
program.
c. Stability
i. Review the stability data generated by the firm for this product to
determine if the testing was conducted in accordance with the submitted
stability protocol, whether stability samples were stored under appropriate
storage conditions, whether the testing was conducted appropriately, and
whether the stability test results meet all specifications. Include a review
of pertinent raw test data.
d. Raw Materials:
i. Determine if there were any OOS results for any incoming raw materials
used in the formulation. If so, verify the adequacy of investigations, and
determine what corrective/preventive actions are implemented to address
these OOS results.
(b) (4)
ii.
e. Distribution Supply Chain:

(b) (4)
i.
A pre-inspection briefing may be scheduled if additional clarification or background is

needed. Should you have questions prior to or post inspection or for significant
deficiencies observed during inspection, please contact the CDER officials identified
above.
Please report your findings regarding these issues in the Establishment Inspection Report
(EIR) under the heading, ADDITIONAL INFORMATION with the subheading,
Follow-up to CDER Questions.
THIS ASSIGNMENT IS CONFIDENTIAL FDA CORRESONDENCE

cc:
HFD-320 (Division Chron File)
HFD-323 (New Drug Manufacturing Assessment Branch)
OC Doc. No.: KTM-2014-012
APPENDIX I
In-Process Controls for the Manufacturing of Edoxaban Tosylate
(b) (4)
In-Process Controls for the Manufacturing of
(b) (4)
(b) (4)
APPENDIX II
Specifications for
(b) (4)
(b) (4)
(b) (4)
APPENDIX III
Release and Shelf-Life Specifications for Edoxaban Tosylate Drug Substance
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b)
(4)

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------VIPULCHANDRA N DHOLAKIA
05/23/2014
MAHESH R RAMANADHAM
05/23/2014
NEW DRUG APPLICATION OMPQ REVIEW
Initial Manufacturing (CGMP/Facilities)

Assessment (IMA) and Filing Review for PreMarketing Applications (Original)
I.
II.
III.
IV.
V.
Review Cover Sheet

Application Detail
Filing Checklist
Manufacturing Summary
Overall Conclusions and Recommendations
I. Review Cover Sheet

1. OMPQ Reviewer:
Vipul Dholakia, Ph.D. (Drug Substance)

Vibhakar Shah, Ph.D. (Drug Product)
2. NDA/BLA Number:
Submission Date:
21st C. Review Goal Date:
PDUFA Goal Date:
206316
01/08/2014
09/09/2014
01/08/2015
3. PRODUCT PROPERTIES:
Trade or Proprietary Name:
Savaysa (Proposed)
Established or Non-Proprietary
Name (USAN) and strength:
Edoxaban Tosylate Tablet (15 mg, 30 mg, and 60 mg)
Dosage Form:
Tablet
4. SUBMISSION PROPERTIES:
Review Priority :
STANDARD
Applicant Name:
Daiichi Sankyo, Inc.
Responsible Organization
(OND Divisions):
DCRP and DHP
Page 1 of 11
OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review

For Pre-Marking Applications
II. Application Detail

1. INDICATION:
Reduce the risk of stroke and systemic

embolism in patients with nonvalvular atrial
fibrillation; treatment of venous
thromboembolism including DVT and PE,
(b) (4)
2. ROUTE OF ADMINISTRATION:
Oral
3. STRENGTH/POTENCY:
15 mg, 30 mg and 60 mg
4. Rx/OTC DISPENSED:
Rx
OTC
5. ELECTRONIC SUBMISSION (yes/no)?
Yes
No
6. PRIORITY CONSIDERATIONS:
Parameter
1. NME / PDUFA V
2.
3.
4.
5.
6.
7.
8.
Yes
X
Breakthrough Therapy
Designation
Orphan Drug
Designation
Unapproved New Drug
Medically Necessary
Determination
Potential Shortage
Issues [either alleviating
or non-approval may
cause a shortage]
Rolling Submission
Drug/device
combination product
with consult
No
Unk
Comment
X
X
X
X
X
X
X
QbD and
approaches are indicated for the
manufacture, control and release of the DP
(b) (4)
9. Complex manufacturing
10.
Other (e.g., expedited

for an unlisted reason)
VDholakia & VShah/OMPQ/OC/CDER
X
X
Page 2 of 11
NDA206316IMA.Doc

III. FILING CHECKLIST

The following parameters are necessary in order to initiate a full review (i.e., the application is complete
enough to start review but may have deficiencies). On initial review of the NDA application:
A. COMPLETENESS OF FACILITY INFORMATION
Parameter
Yes No
Comment
Is a single comprehensive list

of all involved facilities
11.
X
available in one location in the
application?
Is all site information complete
12. (e.g., contact information,
X
responsibilities, address)?
For testing labs, is complete
information provided
13. regarding which specific test is
X
performed at each facility and
what stage of manufacturing?
Do all sites indicate they are
All sites involved in the manufacture of drug
14. ready to be inspected (on
X
substance and product are stated to be ready on
the FDA form 356h.
356h)?
Additional notes (non-filing
issue)
1. Are all sites registered
X
or have FEI #?
2. Do comments in EES
CMC reviewer is interested in participating on the
15.
PAI of the DP mfg facility.
indicate a request to
X
participate on
inspection(s)?
3. Is this first application
X
by the applicant?
*If any information regarding the facilities is missing/omitted, communicate to OPS/ONDQA
regarding missing information and copy EESQ. Notify OMPQ management if problems are
not resolved within 3 days and it can be a potential filing issue.
Page 3 of 11
NDA206316IMA.Doc

16.
B. DRUG SUBSTANCE (DS) / DRUG PRODUCT (DP)

Parameter
Yes No
Comment
Have any Comparability
X
Protocols been requested?
Parameter
Does this application fit one of the
17.
EES Product Specific Categories?
Have EERs been cross referenced
against the 356h and product
specific profile for accuracy and
18.
completion?
Have all EERs been updated with
final PAI recommendation?
From a CGMP/facilities
perspective, is the application
fileable?
19.
IMA CONCLUSION
Yes No
X
Comment
NME
If the NDA is not fileable from a

product quality perspective, state the
reasons and provide filing comments
to be sent to the Applicant.
Page 4 of 11
NDA206316IMA.Doc

IV. Manufacturing Summary:

Critical Issues and Complexities
Does the submission contain any of the following elements?
(b) (4)
Nanotechnology
PAT
PET
Design Space
Other (explain):
Drug/Device Combo
Continuous Mfg
Naturally derived API
Quality by Design approach to drug product manufacture
Manufacturing Highlights
1. Drug Substance
Parameter
Yes
Is manufacturing process
considered complex (e.g.,
unusual unit operations,
innovative manufacturing
technology, unusual control
strategy)?
No
Comment
(b) (4)
is manufactured at
Daiichi Sankyo chemical pharma site.
The final drug product, Edoxaban Tosylate

tablet is manufactured at Daiichi Sankyo
Propharma site.
2. Drug Product
Parameter
Is manufacturing process
considered complex (e.g.,
unusual unit operations,
innovative manufacturing
technology, unusual control
strategy)?
Yes
No
Comment
Applicant has proposed implementation of
(b) (4)
3. Facility-Related Risks or Complexities (e.g., number of foreign sites, large number of

sites involved, etc.)
Drug substance, edoxaban tosylate is manufactured by Daiichi Sankyo Propharma Co. Ltd
(b) (4)
(DSPP), Akita, Japan and the
used in the manufacture of drug
substance is manufactured by Daiichi Sankyo Chemical Pharma Co. Ltd., Odawara, Japan.
Release and stability testing are also performed at the respective sites.
Additional information on Manufacturing issues or Complexities
Page 5 of 11
NDA206316IMA.Doc

Drug Substance Manufacturing Process (see eCTD Section 3.2.S.2.2)

Manufacturing Stages and Reaction Steps for Edoxaban Tosylate
(b) (4)
Manufacturing Stages
(b) (4)
(b) (4)
Page 6 of 11
NDA206316IMA.Doc

Drug Product:
Daiichi Sankyo Propharma Co., Ltd. (FEI # 3010164826 ), located in Hiratsuka, Kaganawa,
Japan is identified as the manufacturer of the drug product. The applicant has indicated to
employ an enhanced QbD approach in developing the manufacturing process, controls and
quality assurance for Edoxaban tablets.
As part of the controls strategy, applicant has proposed to
(b) (4)
Applicant has proposed to implement
(b) (4)
Refer to the process flow chart for in-process controls and critical in-process controls relating to
(b) (4)
.
Additional information on Manufacturing issues or Complexities:
Drug Product Manufacturing Process (see eCTD Section 3.2.P.3.2.3)
(b) (4)
Page 7 of 11
NDA206316IMA.Doc

Edoxaban Tablet Manufacturing Process Flow Chart
(b) (4)
Page 8 of 11
NDA206316IMA.Doc

Edoxaban Tablet Manufacturing Process Flow Chart

(b) (4)
(b) (4)
Page 9 of 11
NDA206316IMA.Doc

4. Establishment Evaluation Status

Drug substance and Drug product Manufacturing Facilities
GMP Compliance Status Chart
(as of March 5, 2014)
Establishment
Name
FEI
Num
District
Short
Country
Code
Responsibilities
Profile
Code
Inspection
History, Dates,
Classifications
Facts
Assignment
ID
Inspection
Start -End
Date
Most
Recent
Milestone
Most
Recent EER
Compliance
Status
Comment
CSN
CSN
[AC, 07/30/2009]
9168316
6/2-6/2014
INSPECTION
Scheduled
PN
DS is NME
(b) (4)
Daiichi
Pharmaceutical
Co., Ltd.
Daiichi Sankyo
Chemical Pharma
Co., Ltd.
Daiichi Sankyo
3002806777
ROW
JPN
(b) (4)
3003279188
3003673570
ROW
PHI
JPN
USA
CSN
TCM
No prior GMP
history
TCM, (b)
(4)
[AC, 04/20/2012]
(b) (4)
9216817
6/1620/2014
INSPECTION
Scheduled
OC
Recommendation
PN
AC
[AC, 04/14/2009]
Daiichi Sankyo
Propharma Co.,
Ltd. (DSPP)
Hiratsuka Plant
(b) (4)
3010164826
ROW
JPN
TCM
No prior GMP
history
9168315
6/9-13/2014
INSPECTION
Scheduled
PN
DS: Drug Substance, DP: Drug Product; AC: Acceptable; NA: Not Applicable; TBD: To be determined; PN; Pending; NME: New Molecular Entity
Based on
Profile
23-Jan-2014
EER-ReEval by:
20-APR-2016
Page 10 of 11
NDA206316IMA.Doc

V. Overall Conclusions and Recommendations

Is the application fileable?
At this time, is a KTM warranted for any PAI?
Yes
Yes
To facilitate the pre-approval inspections of both the drug substance and the drug product
manufacturing facilities, Knowledge Transfer Memoranda are recommended.
Are there comments/issues to be included in the 74 day letter, including appropriate
identification of facilities?
No
Comments for 74 Day Letter
None
1.
2.
3.
REVIEW AND APPROVAL

(DARRTS)
Page 11 of 11
NDA206316IMA.Doc

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------VIBHAKAR J SHAH
03/05/2014
VIPULCHANDRA N DHOLAKIA
03/05/2014
MAHESH R RAMANADHAM
03/05/2014

METHODS VALIDATION CONSULT REQUEST FORM

TO:
FDA
Attn: Michael Trehy
Suite 1002
1114 Market Street
St. Louis, MO 63101
FROM: Akm Khairazzuman and Debasis Ghosh, CMC Reviewers

Kasturi Srinivasachar, CMC Lead
E-mail Address: [email protected]; [email protected]
Phone: (301)-796 3886 (Akm); (301)-796 4093 (Debasis)
Fax.: (301)-796 9747
Through: Olen Stephens, Acting Branch Chief
Phone: (301)-796 3901
and
Youbang Liu, ONDQA Methods Validation Project Manager
Phone: (301)-796 1926
SUBJECT: Methods Validation Request
Application Number: NDA 206316
Name of Product: Savaysa (edoxaban), Tablets, 15, 30 and 60 mg
Applicant: Daiichi Sankyo, Inc.
Applicants Contact Person: Doreen V. Morgan, Pharm.D., Executive Director, Regulatory Affairs
th
Address: 399 Thornall Street, 10 floor, Edison, NJ 08837

Telephone: 732-590-5198
Fax: 732-906-5562
Date NDA Received by CDER: 1-8-14
Submission Classification/Chemical Class: NME
Date of Amendment(s) containing the MVP: 1-8-14
Special Handling Required: No
DATE of Request: 2-28-14
DEA Class: N/A
Requested Completion Date: 5-28-14
Format of Methods Validation Package (MVP)
PDUFA User Fee Goal Date: 1-8-15
Paper
X Electronic
Mixed
We request suitability evaluation of the proposed manufacturing controls/analytical methods as descr bed in the subject application. Please submit a
letter to the applicant requesting the samples identified in the attached Methods Validation Request. Upon receipt of the samples, perform the tests
indicated in Item 3 of the attached Methods Validation Request as described in the NDA. We request your report to be submitted in DARRTS promptly
upon completion, but no later than 45 days from date of receipt of the required samples, laboratory safety information, equipment, components, etc.
We request that you notify the ONDQA Methods Validation Requestor and the ONDQA Methods Validation Project Manager of the date that the
validation process begins. If the requested completion date cannot be met, please promptly notify the ONDQA Methods Validation Requestor and the
ONDQA Methods Validation Project Manager.
Upon completion of the requested evaluation, please assemble the necessary documentation (i.e., original work sheets, spectra, graphs, curves,
calculations, conclusions, and accompanying Methods Validation Report Summary). The Methods Validation Report Summary should include a
statement of your conclusions as to the suitability of the proposed methodology for control and regulatory purposes and be electronically signed by the
laboratory director or by someone designated by the director via DARRTS. The ONDQA CMC Reviewer, ONDQA Methods Validation Project Manager,
and ONDQA CMC Lead/Branch Chief should be included as cc: recipients for this document.
All information relative to this application is to be held confidential as required by 21 CFR 314.430.
Page 1 of 4
Version: 02/06/2013
ATTACHMENT(S): Methods Validation Request Sheet, NDA Methods Validation Package (if not available in the EDR).
MVP Reference #
METHODS VALIDATION REQUEST
NDA #
206316
ITEM 1: SAMPLES AND ANY SPECIAL EQUIPMENT/REAGENTS BEING FORWARDED BY APPLICANT
ITEM
QUANTITY
CONTROL NO. OR OTHER IDENTIFICATION
Upon FDA request, four

representative samples of the drug
substance and drug product
will be provided to perform each test
described in the application three
times by the Agency. Reference
standards will also be provided upon
request to complete the testing.
Volume/Page Number(s)
ITEM 2: Contents of Attached Methods Validation Package
Statement of Composition of Finished Dosage Form(s)
3.2.P.1.
Specifications/Methods for New Drug Substance(s)
3.2.S.4.1 / 3.2.S.4.2
Specifications/Methods for Finished Dosage Form(s)
3.2.P.5.1 / 3.2.P.5.2
3.2.S.4.3 / 3.2.P.5.3
Supporting Data for Accuracy, Specificity, etc.

Applicant's Test Results on NDS and Dosage Forms
3.2.S.4.4 / 3.2.P.5.4
Other: MVP
3.2.R.
ITEM 3: REQUESTED DETERMINATIONS

Perform following tests as directed in applicant's methods. Conduct ASSAY in duplicate.
Method ID
Drug Substance
EDX_QB06
MV Request
Category
Volume/Page
(see
attached)
Method Title
(b) (4)
3.2.S.4.2
Drug Substance
EDX_QB12
3.2.S.4.2
Drug Substance
EDX_QB12
3.2.S.4.2
Drug Substance
EDX_QB11
3.2.S.4.2
0,4
Drug Product
400081-5 (15 mg
400082-5 (30 mg)
400083-5 (60 mg)
Drug Product
400081-6 (15 mg)
400082-6 (30 mg)
400083-6 (60 mg)
3.2.P.5.2
3.2.P.5.2
Page 2 of 4
Comments
(b) (4)
Version: 02/06/2013
Dissolution, Apparatus 2, 50 rpm,

Drug Product
400081-3 (15 mg) UV-VIS
400082-3 (30 mg)
400083-3 (60 mg)
3.2.P.5.2
Additional Comments: The Applicant has proposed

(b) (4)
(b) (4)
It is also proposed to omit the

However, the conventional methods will be used for stability
testing of the product.
Methods Validation Request Criteria
MV
Request
Category
Description
New Molecular Entity (NME) application, New Dosage Form

or New Delivery System
Methods using new analytical technologies for

pharmaceuticals which are not fully developed and/or
accepted or in which the FDA laboratories lack adequate
validation experience (e.g., NIR, Raman, imaging methods)
Critical analytical methods for certain drug delivery systems

(e.g., liposomal and microemulsion parenteral drug products,
transdermal and implanted drug products, aerosol, nasal, and
dry powder inhalation systems, modified release oral dosage
formulations with novel release mechanisms)
Methods for biological and biochemical attributes (e.g.,

peptide mapping, enzyme-based assay, bioassay)
Certain methods for physical attributes critical to the

performance of a drug (e.g., particle size distribution for drug
substance and/or drug product)
Page 3 of 4
Version: 02/06/2013
Novel or complex chromatographic methods (e.g., specialized

columns/stationary phases, new detectors/instrument set-up,
fingerprinting method(s) for a complex drug substance,
uncommon chromatographic method
Methods for which there are concerns with their adequacy

(e.g., capability of resolving closely eluting peaks, limits of
detection and/or quantitation)
Methods that are subject to a for cause reason
Page 4 of 4
Version: 02/06/2013

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------KASTURI SRINIVASACHAR
02/28/2014
OLEN M STEPHENS
02/28/2014
YOUBANG LIU
02/28/2014
ONDQA Initial Quality Assessment (IQA) and Filing Review

IQA and Filing Review Cover Sheet

1. NEW DRUG APPLICATION NUMBER: 206316
2. DATES AND GOALS:
Letter Date:
Jan. 8, 2014
PDUFA Goal Date:
Submission Received Date :

Jan. 8, 2014
Jan. 8, 2015
3. PRODUCT PROPERTIES:
Trade or Proprietary Name:
Established or Non-Proprietary
Name (USAN):
Dosage Form:
Route of Administration
Strength/Potency
Rx/OTC Dispensed:
Savaysa (proposed)
Edoxaban
Tablets, immediate release
Oral
15, 30 and 60 mg
Rx
4. INDICATION: 1) To reduce the risk of stroke and systemic embolism in

patients with nonvalvular atrial fibrillation; 2) for the treatment of venous
thromboembolism including DVT and PE;
(b) (4)
5. DRUG SUBSTANCE STRUCTURAL FORMULA:
6. NAME OF APPLICANT (as indicated on Form 356h):

Daiichi Sankyo, Inc.
Page 1 of 22

7. SUBMISSION PROPERTIES:
Review Priority:
Standard
Submission Classification
(Chemical Classification
Code):
Type 1, NME
Application Type:
505(b)(1)
Breakthrough Therapy
No
Responsible Organization
(Clinical Division):
Division of Cardiovascular and Renal Products and Division of

Hematology Products
8. CONSULTS:
CONSULT
Biometrics
Clinical Pharmacology
Establishment Evaluation
Request (EER)
Pharmacology/Toxicology
Methods Validation
Environmental Assessment
CDRH
Other
YES
NO
X
X
COMMENTS: (list date of request if already sent)
X
X
X
If needed by reviewer for genotoxic impurities

X
X
Microbiology
Page 2 of 22

Overall Filing Conclusions and Recommendations

CMC:
Is the Product Quality Section of the application fileable from a CMC perspective?
Yes
Are there potential CMC review issues to be forwarded to the Applicant with the 74-Day
letter?
No
CMC Comments for 74-Day Letter:
1.
Biopharmaceutics:
Is the Product Quality Section of the application fileable from a Biopharmaceutics
perspective?
Yes
Biopharmaceutics Filing Issues:
1.
Are there potential Biopharmaceutics review issues to be forwarded to the Applicant with
the 74-Day letter?
Yes
Biopharmaceutics Comments for 74-Day Letter:
Refer to page 12.
Microbiology:
Is the Product Quality Section of the application fileable from a Microbiology perspective?
Yes
Steven Donald: Micro Reviewer
1. Based on the information provided, the application is fillable from a microbiology
point of concern. However, issues remain that must be addressed by the applicant.
2. The applicant proposes to perform

for microbial limits testing
(bioburden) for product release. The applicant proposes to perform

of drug product at release.
(b) (4)
3.

tests must be performed for every lot.
(b) (4)
(b) (4)
All release
4. However, Microbial Limits Testing may be omitted from the product release
specifications if process control is demonstrated, from a microbiological
standpoint. The reviewer has determined that adequate information is most likely
available to qualify the application for reduced microbial limits testing, if the
applicant so chooses.
Page 3 of 22

5. The post-approval and annual stability protocols and their acceptance criteria are
acceptable, from a microbiological standpoint.
Page 4 of 22

Summary of Initial Quality Assessment

Does the submission contain any of the following elements?
Nanotechnology
QbD Elements
PET
No
Yes
No
Other, please explain

(b) (4)
Is a team review recommended? Yes

Suggested expertise for team: This is a fairly complicated QbD submission with
proposed
A team with a
(b) (4)
drug substance reviewer trained in
and a drug product reviewer with a
(b) (4)
thorough understanding of QbD concepts is recommended. In addition, since the
someone with expertise in this area should also be included in the team.
(b) (4)
(b) (4)
Summary of Critical Issues and Complexities

Drug Substance:
(b) (4)
Has adequate justification been provided for the designation of
(b) (4)
as starting materials? Are the specifications for these materials, particularly
acceptable?
(b) (4)
Since the only potential genotoxins controlled in the drug substance are
have other possible genotoxic impurities from the synthesis been adequately controlled
(b) (4)
Pharm/Tox consult may be needed for some aspects of genotoxic impurity

controls.
(b) (4)
(b) (4)
A
procedure is proposed for both the
(b) (4)
if specifications are not met. Has the Applicant shown that
did not have to undergo this
procedure? Have any constraints been placed on how large the deviation from the
(b) (4)
specifications have to be
?
(b) (4)
Has it been conclusively established that
The
and their applicability
to commercial scale should be evaluated.
Regarding the specification
(b) (4)
o There is no separate ID or assay for the
Is this acceptable?
(b) (4)
o The Applicant was recommended to propose a
particle size distribution in
(b) (4)
the pre-NDA meeting but chose to
Have they
provided an adequate justification for this?
Since only 6 months data have been provided for the site-specific batches, is (b)
there
any
(4)
need to request additional data from the on-going studies in order to grant the
month
retest period proposed?
Is there a discussion of possible degradation pathways for edoxaban tosylate
(b) (4)
Page 5 of 22

Drug Product
Since it is claimed that an enhanced QbD approach was used for the drug product, all
aspects of formulation and manufacturing process development need to be critically
evaluated:
(b) (4)
o Are design spaces for
acceptable? This is not in
accordance with ICH Q8 as discussed with the Applicant at meetings
during drug development. It is claimed that using this approach the
(b) (4)
Does this imply that the firm can make

changes to these factors without submitting post-approval supplements?
(b) (4)
o Has equivalence of the results calculated using
and those obtained using conventional testing
been established for batches manufactured at commercial scale?
(b) (4)
o Are the analytical methods for
been adequately validated?
(b) (4)
(b) (4)
o The specification table for
lists
(b) (4)
methods for
tests. Has it
(b) (4)
been clearly delineated under what circumstances
(b) (4)
methods would be employed? How will failure of a
method be
handled?
o Table 1.13 in Section 3.2.P.3.4 lists the proposed regulatory filing
(b) (4)
categories for post-approval changes to
are these
acceptable?
Are the master batch records sufficiently detailed and do they include the proposed
design spaces?
(b) (4)
Is the justification for not performing the
adequate?
An equivalency protocol for post-approval changes to container closure materials of
construction has been submitted and should be evaluated, with input from the PostMarketing Division, if needed.
(b) (4)
Is the
in the registration stability batches
acceptable?
The post-approval stability commitment protocol for the first 3 commercial batches
(b) (4)
(b) (4)
includes a
proposal for the
. This is contrary to ICH Q1A which states that the protocol for the
full-scale commitment batches should be the same as the pilot scale registration batches.
Is the proposed matrix for testing the marketed presentations in the annual stability
program acceptable?
Page 6 of 22

Initial Quality Assessment

This is a 505(b)(1) application for Savaysa (edoxaban) tablets, 15, 30 and 60 mg. A single NDA
has been submitted for the following indications in two clinical divisions:
To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial
fibrillation (Division of Cardiovascular and Renal Products [DCRP]).
For the treatment of venous thromboembolism including deep vein thrombosis and
(b) (4)
pulmonary embolism,
(Division of
Hematology Products [DHP]).
Edoxaban tosylate, an antithrombotic agent, is an NME which belongs to the anti-factor Xa class
of compounds. It was developed under INDs 63266 (DHP) and 77254 (DCRP). Three major
CMC related meetings were held with the Applicant during the development of this drug an
EOP2 on Nov. 6, 2008, a Type C Guidance meeting on June 2, 2010 to discuss Daiichis QbD
strategy and a pre-NDA meeting on May 17, 2013. The main focus of the EOP2 meeting was
the designation of starting materials for the synthesis of edoxaban tosylate, the adequacy of the
drug substance and drug product specifications, the general outline of Daiichis QbD strategy,
(b) (4)
and the acceptability of the
stability designs for the registration drug product batches.
The Agency response to questions in these area was that, in general, Daiichis approach seemed
reasonable but that more information/data were needed for review either later in development or
in the NDA to make a final determination. The Guidance meeting in 2010 provided details of
(b) (4)
(b) (4)
the Applicants QbD strategy, including their
proposal.
The Pre-NDA meeting in 2013 included a comprehensive discussion of drug substance, drug
product and dissolution issues. Regarding the drug substance, the most controversial issue was
(b) (4)
the designation of
as a starting material in the synthesis of edoxaban tosylate.
Daiichi had misinterpreted the Agency advice at the EOP2 meeting as agreement with this
(b) (4)
designation and were surprised that the Agencys current response was an unequivocal no
Post-meeting, Daiichi filed an official protest to re-iterate
(b) (4)
that the Agency was not consistent in its response regarding
The Applicant was
(b) (4)
(b) (4)
overruled and
was deemed by the Agency
Daiichi
(b) (4)
proposed that they could designate
The Agency agreed to this
(b) (4)
proposal but Daiichi decided not to avail of this offer and has designated
as a starting
material in the original NDA.
Other drug substance issues related to the completeness and acceptability of the specification.
(b) (4)
The Agency recommended the inclusion of an
or
justification for their exclusion. The pharm./tox reviewer provided input on the control strategy
for potential genotoxic impurities.
(b) (4)
Concerning drug product stability, the Option 2
proposal was deemed
reasonable and also recommended for the annual stability batches. Acceptance of the proposal
(b) (4)
was considered a review
Page 7 of 22

issue since insufficient information was submitted in the briefing package. The Applicant was
(b) (4)
recommended to consolidate
Since an
extensive QbD program is proposed, the Agency indicated that definitive answers to many of the
questions posed could only be give after in-depth review of all supporting data in the NDA.
(b) (4)
However, some general guidelines and concerns were provided to Daiichi
Drug Substance: Edoxaban tosylate is a white to pale yellowish-white crystalline powder, mp ~

(b) (4)
249 C with decomposition. It has 3 asymmetric centers and is synthesized as a
The exact stereochemistry at the 3 stereogenic centers has been established by
(b) (4)
It is obtained as a monohydrate. The solubility of
edoxaban tosylate is pH dependentslightly soluble in water, pH 3,4, and 5 buffers, very
(b) (4)
slightly soluble at pH 6 and 7 and practically insoluble at pH 8 and 9.
(b) (4)
It exists in
The drug substance is synthesized at
(b) (4)
Page 8 of 22

Specifications for the drug substance are proposed based on release data from 24 lots, ranging
(b) (4)
from pilot to commercial scale
Kg), used in toxicology, clinical and registration stability
(b) (4)
(b) (4)
studies. Test attributes are appearance, identification,
impurities
impurities, assay, heavy metals, residue on
(b) (4)
ignition, water content,
and particle size distribution. Batch analysis data to
support the proposed acceptance criteria have been submitted.
Stability studies have been conducted on 3 primary, pilot scale registration batches manufactured
at Hiratsuka and 3 site-specific
commercial scale batches manufactured at Akita. The pilot scale
(b)
(b) (4)
(4)
batches were approx. % of the commercial scale of
Kg. 36 months long term registration
batch stability data and 6 months of data at accelerated conditions have been submitted and show
no change from the initial time point for any of the test attributes. Similarly, studies at ICH
elevated temperature and humidity conditions showed no change in any stability indicating or
quality parameters after 6 months. The site-specific stability data on commercial scale batches
confirm these results although only 6 months data are currently available. Photostability testing
under ICH conditions on one lot again showed
no change from the initial time point. Based on
(b)
(4)
these results the Applicant has proposed a
month retest period for the drug substance stored in
(b) (4)
Drug Product: Edoxaban tosylate drug product is an immediate release, roundshaped , film
coated, unscored debossed tablet in 3 strengths, 15, 30 and 60 mg. The tablet strengths are based
on edoxaban free base and are differentiated by size, weight, color and debossed information.
Standard compendial excipients are used in the manufacture of the tablets mannitol,
pregelatinized starch, crospovidone, hydroxypropyl cellulose, and magnesium stearate. The film
(b) (4)
coating agents,
orange, pink and yellow are non-compendial but comprised of
compendial ingredients. The proposed commercial formulations of edoxaban 15 and 30 mg
tablets are identical to the Phase 3 clinical formulation with the exception of colors. It is claimed
that bioequivalence has been demonstrated between the 60 mg tablet and two 30 mg tablets. All
(b) (4)
3 strengths are manufactured from
and are dose proportional.
(b) (4)
(b) (4)
The commercial manufacture of the
requires the manufacture o
. This commercial batch size yields
tablets for the 15 mg strength,
(b) (4)
tablets of the 30 mg strength and
60 mg tablets. The manufacturing process consists of
(b) (4)
(b) (4)
(b) (4)
The Applicant claims to have developed edoxaban tablets using an enhanced QbD approach
based on the principles of experimental design, quality risk management, prior knowledge and
(b) (4)
manufacturing experience. This was implemented by
Page 9 of 22

(b) (4)
(b) (4)
(b) (4)
is proposed for microbial limits. Batch analysis data for 9

registration stability batches, 19 Phase 3 clinical batches and 15 Phase1/2 clinical batches have
been provided. Primary stability data have been submitted for the registration batches,
manufactured by the commercial process at pilot scale and packaged in the proposed commercial
(b) (4)
configurations, HDPE bottles and
/Aluminum blisters. 24 months long term and 6 months
accelerated data are available. A 36 month expiration dating period is proposed based on these
data for all 3 strengths of edoxaban tablets.
Additional Comments:
Categorical exclusion from Environmental Assessment has been requested based on 21CFR
25.31 (b). Facilities for inspection have been entered in the EES database. Since this is an NME,
Method Validation will be requested shortly from FDA laboratories in St. Louis.
Page 10 of 22

Biopharmaceutics Assessment
Biopharmaceutics Critical Issues or Complexities
Submission: Edoxaban tosylate drug product is an immediate release, round-shaped, filmcoated, unscored, debossed tablet. The tablets are available in three strengths, 15mg, 30mg, and
(b) (4)
60mg. The three strengths of edoxaban tablets are manufactured from
and
are dose proportional to one another.
The pivotal Phase 3 clinical trials in atrial fibrillation (AF) and venous thromboembolism (VTE)
indications used 15 and 30 mg strength tablets. The proposed commercial strengths include 15,
30 and 60 mg tablets to provide maximum flexibility for dose adjustment. A BE Study (A-U142)
was conducted to bridge between the 30 mg and 60 mg tablets.
Product Manufacturing: According to the Applicant, the manufacturing process development of
(b) (4)
edoxaban tablets was conducted according to a QbD approach
Review: The Biopharmaceutics review will focus on the evaluation and acceptability of the
following:
- The conventional dissolution method
- The proposed dissolution acceptance criterion
(b) (4)
- The proposed
- The BE study A-U-142 conducted to bridge the 30 mg and 60 mg tablets
Page 11 of 22

Some biopharmaceutics information/data needed for the review of this NDA was not provided.
The following comments and requests for information should be conveyed to the Applicant in
the 74-Day letter or before.
Comments to be conveyed to the Applicant:
1. Provide dissolution profile comparisons in the proposed QC dissolution method for the batches
tested in BE studies A-U140, A-U142 (e.g. one 30 mg tablet vs. one 60 mg tablet for all the
batches tested).
2. Provide dissolution profile comparisons including statistical testing (e.g. f2 similarity testing)
between the 15 mg, 30 mg and 60 mg commercial batches using the QC dissolution method. The
dissolution testing for each strength should be done using only one tablet per vessel (n=12).
(b) (4)
3. Provide explanation as to why the coated tablets from BA study DU176b-PRT012
from BA study DU176-E-PRT001) (refer to Figure 1.1 section 3.2.P.5.6).
4. As per ICH Q6A guidance, it is recommended that you use dissolution testing to monitor for the
(b) (4)
amount/type of
at release and on stability. For this purpose, provide
information/data showing that your proposed dissolution testing methodology and proposed
(b) (4)
acceptance criterion are able to reject batches with inadequate amount/type of
(b) (4)
(b) (4)
Submit dissolution profiles as a function of
(e.g
.
(b) (4)
In addition, the setting of an acceptable specification limit of
allowed by the
dissolution acceptance criterion should be supported by clinical information (i.e., bioavailability,
exposure-response, etc.).
(b) (4)
(b) (4)
5. Alternatively, monitor the
content at release and on stability using a
In addition, the
(b) (4)
(b) (4)
setting of an acceptable limit of the
allowed by
specification should be
supported by clinical information (i.e., bioavailability, exposure-response, etc.).
6. Submit the following data for verification of the dissolution model:
7. Step by step model development procedure, including the statistics for all the models tested (the pvalues, estimated coefficients and their standard errors of the final model).
8. Raw data including both model inputs and outputs used for model development and validation
9. Provide available data showing that the model can predict failed batches (i.e. batches that failed
(b) (4))
the dissolution acceptance criterion). This data are needed since dissolution was
)%
for all the batches used for model validation. In addition, dissolution data used in the construction
(b) (4)
of the model (e.g. (b) (4) are
% and there were values for which dissolution was
(b) (4)
%. Also, evaluate the predictive power of the model by using batches that failed in
vivo BE, if available.
10. In order to verify the proposed design space (e.g. same in vitro and in vivo performance) provide
dissolution profiles comparisons (with statistical data) and/or in vivo data (e.g. PK data) among
the batches manufactured at the extremes of the design space using the target (clinical batches) as
the reference.
Page 12 of 22

FILING REVIEW CHECKLIST

The following parameters are necessary in order to initiate a full review, i.e., complete enough to
review but may have deficiencies. On initial overview of the NDA application for filing:
1.
2.
3.
4.
Parameter
Is the CMC section organized
adequately?
Is the CMC section indexed and
paginated (including all PDF
files) adequately?
Are all the pages in the CMC
section legible?
Has all information requested
during the IND phase, and at the
pre-NDA meetings been
included?
A. GENERAL
Yes No
Comment
X
X
X
X
B. FACILITIES*
If any information regarding the facilities is omitted, this should be addressed ASAP with the
applicant and can be a potential filing issue or a potential review issue.
Parameter
Yes No
Comment
Is a single, comprehensive list of
5. all involved facilities available in
X
one location in the application?
For a naturally-derived API only,
NA
are the facilities responsible for
critical intermediate or crude API
manufacturing, or performing
upstream steps, specified in the
6.
application? If not, has a
justification been provided for
this omission? This question is
not applicable for synthesized
API.
*
Page 13 of 22

Parameter
Are drug substance manufacturing
sites identified on FDA Form 356h or
associated continuation sheet? For
each site, does the application list:
7.
Name of facility,
Full address of facility including
street, city, state, country
FEI number for facility (if previously
registered with FDA)
Full name and title, telephone, fax
number and email for on-site contact
person.
Is the manufacturing responsibility
and function identified for each
facility?, and
DMF number (if applicable)
Yes
No
Comment
Are drug product manufacturing sites

identified on FDA Form 356h or
associated continuation sheet. For
each site, does the application list:
8.
Name of facility,
FEI number for facility (if previously
registered with FDA)
number and email for on-site contact
person.
Is the manufacturing responsibility
and function identified for each
facility?, and
Page 14 of 22

Parameter
Are additional manufacturing,
packaging and control/testing
laboratory sites identified on FDA
Form 356h or associated
continuation sheet. For each site,
does the application list:
9.
Name of facility,
FEI number for facility (if
previously registered with FDA)
number and email for on-site
contact person.
Is the manufacturing
responsibility and function
identified for each facility?, and
Is a statement provided that all

facilities are ready for GMP
10.
inspection at the time of
submission?
Yes
No
Comment
C. ENVIRONMENTAL ASSESMENT
Parameter
Yes No
Comment
Has an environmental assessment
Categorical exclusion
11. or claim of categorical exclusion
X
been provided?
Page 15 of 22

12.
13.
14.
15.
16.
17.
18.
D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API)

Parameter
Yes No
Comment
Does the section contain a
description of the DS
X
manufacturing process?
Does the section contain
identification and controls of
X
critical steps and intermediates of
the DS?
information regarding the
X
characterization of the DS?
Does the section contain controls
X
for the DS?
Has stability data and analysis
been provided for the drug
X
substance?
Does the application contain
(b) (4)
Quality by Design (QbD)
X
information regarding the DS?
Process Analytical Technology
X
(PAT) information regarding the
DS?
Page 16 of 22

19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
E. DRUG PRODUCT (DP)

Parameter
Yes No
Comment
Is there a description of
manufacturing process and
methods for DP production
X
Master Batch Record submitted
through finishing, including
formulation, filling, labeling and
packaging?
identification and controls of
critical steps and intermediates of
the DP, including analytical
X
procedures and method
validation reports for assay and
related substances if applicable?
Is there a batch production record
and a proposed master batch
X
Executed batch records provided
record?
Has an investigational
formulations section been
provided? Is there adequate
X
linkage between the
investigational product and the
proposed marketed product?
Have any biowaivers been
X
requested?
description of to-be-marketed
X
container/closure system and
presentations?
Does the section contain controls
X
of the final drug product?
Has stability data and analysis
X
been provided to support the
requested expiration date?
Quality by Design (QbD)
X
information regarding the DP?
Process Analytical Technology
(b) (4)
X
(PAT) information regarding the
DP?
(b) (4)
F. METHODS VALIDATION (MV)

Parameter
Yes No
Comment
Is there a methods validation
X
package?
Page 17 of 22

30.
31.
Parameter
If appropriate, is a separate
microbiological section included
assuring sterility of the drug
product
G. MICROBIOLOGY
Yes No
Comment
NA
H. MASTER FILES (DMF/MAF)

Parameter
Yes No
Is information for critical DMF
See table below
references (i.e., for drug
substance and important
X
packaging components for nonsolid-oral drug products)
complete?
DMF #
(b) (4)
TYPE
IV
HOLDER
ITEM REFERENCED
(b) (4)
Comment
LOA DATE
COMMENTS
2-23-2011
IV
4-9-2013
III
3-20-2012
III
5-7-2013
III
5-8-2013
III
2-12-2013
III
6-4-2013
III
5-3-2013
III
2-7-2013
III
5-2-2013
III
4-20-2012
III
3-30-2012
Page 18 of 22

(b) (4)
32.
33.
(b) (4)
III
5-3-2013
III
3-20-2012
III
4-9-2012
Parameter
Has the draft package insert been
provided?
Have the immediate container
and carton labels been provided?
I. LABELING
Yes No
Comment
X
X
J. BIOPHARMACEUTICS
Yes No Comment
The following dissolution method was found
acceptable during the IND stage:
USP 11, 50 rpm, citrate/phosphate buffer pH
6. (refer to
dissolution data?
\\cdsesub1\evsprod\NDA206316\0000\m2\27clin-sum under summary-biopharm, section
1.4
Parameter
34.
(b)
The proposed acceptance criterion is: Q (4)%

at 30 min
(\\cdsesub1\evsprod\NDA206316\0000\m3\32
-body-data\32p-drug-prod\edoxabantablets\32p5-contr-drug-prod\32p56-justifspec).
35.
36.
37.
38.
Is the dissolution test part of the

DP specifications?
Does the application contain the

dissolution method development
report?
Is there a validation package for
the analytical method and
dissolution methodology?
Does the application include a
biowaiver request?
Note that although a conventional dissolution

method was developed, the Applicant is
(b) (4)
proposing a
The
manufacturing controls for edoxaban tablets
(b) (4)
will be conducted
to assure the target
dissolution rate at 30 minute.
\\cdsesub1\evsprod\NDA206316\0000\m3\32body-data\32p-drug-prod\edoxabantablets\32p2-pharm-dev
The CMC review team will evaluate the
validation data.
Page 19 of 22

39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Does the application include data

supporting the biowaiver?
Does the application include an
IVIVC model?
Is information such as BCS
classification mentioned, and
supportive data provided?
Is information on mixing the
product with foods or liquids
included?
Is there any in vivo BA or BE
information in the submission?
Is the to-be-marketed
formulation the same as that
used in pivotal clinical trials?
Is In vitro Release identified as a

CQA and as a measured
response for DOE in defining
Design Space and control
strategy?
Has the risk assessment been
performed for the criticality of
the in vitro release?
BE study A-U-142 was conducted to bridge

the 30 mg and 60 mg tablet. This Study will be
reviewed by ONDQA (refer to
\\cdsesub1\evsprod\NDA206316\0000\m5\53clin-stud-rep\531-rep-biopharm-stud\5312compar-ba-be-stud-rep\du176b-a-u142
The proposed commercial formulations of
15 mg and 30 mg tablets are identical to
the Phase 3 tablets.
The 60 mg tablet was developed for
commercial use and confirmed as BE to
the 30 mg Phase 3 tablets.
There were some major changes implemented
to the Phase 1 and Phase 2 formulation.
Additional data may be needed to bridge
across these phases depending on the impact
the results of these studies in the product
labeling. This issue will be discussed with the
OCP reviewer.
\\cdsesub1\evsprod\NDA206316\0000\m3\
32-body-data\32p-drug-prod\edoxabantablets\32p2-pharm-dev under
pharmaceutical-developmentmanufprocdev.pdf
32-body-data\32p-drug-prod\edoxabantablets\32p2-pharm-dev under productdevelopment-drugproduct.pdf
Does the QbD approach contain

RTRT elements? Is a
32-body-data\32p-drug-prod\edoxabandissolution model for RTRT
tablets\32p2-pharm-dev Section 1.7.1.4.1
purposes being proposed?
FILING CONCLUSION
Parameter
Yes No
Comment
IS THE
BIOPHARMACEUTIC
SECTIONS OF THE
APPLICATION FILEABLE?
Page 20 of 22

49.
50.
If the NDA is not fileable from

the product quality perspective,
state the reasons and provide
filing comments to be sent to the
Applicant.
If the NDA is not fileable from
the biopharmaceutics
perspective, state the reasons
and provide filing comments to
be sent to the Applicant.
N/A (fileable)
N/A (fileable)
The dissolution acceptance criterion
is not supported by the data
(requesting additional information)
The discriminating ability of the
dissolution method is uncertain
(requesting additional information)
(b) (4)
The
steps for
the dissolution model did not include
data to demonstrate the ability of the
(b) (4)
model to
(requesting additional data).
Need additional data to support the
approval of the 15 mg strength
51.
Are there any potential review

issues identified?
52.
Are there any filing comments

to be conveyed to the
Applicant?
See Biopharmaceutics comments in

page12.
Are there any comments to be

conveyed to other review
disciplines?
Comments Conveyed to the OCP Review

Team on 02/20/14: There were major
changes implemented to the drug product
tested in Phase 1 and Phase 2 studies that
may require additional data to support the
bridging. The need for these data will be
determined by the impact/relevance of the
PK studies conducted in early phases of the
development to the product labeling.
53.
Page 21 of 22

This document will be sequentially signed in DARRTS by all of the following who authored or
reviewed this assessment:
See appended electronic signature page}
Kasturi Srinivasachar, Ph.D

CMC-Lead or
Division I, Branch 1
Office of New Drug Quality Assessment
{See appended electronic signature page}
Sandra Suarez, Ph.D.

Biopharmaceutics Reviewer
Angelica Dorantes, Ph.D.

Biopharmaceutics Team Leader
Olen Stephens, Ph.D.

Acting Branch Chief
Division I, Branch 1
Page 22 of 22

signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------KASTURI SRINIVASACHAR
02/24/2014
SANDRA SUAREZ
02/24/2014
ANGELICA DORANTES
02/24/2014
OLEN M STEPHENS
02/24/2014

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CENTER FOR DRUG EVALUATION AND

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration

CMC Memo to File

Pursuant the overall acceptable recommendation given on 14-Nov-2014 for the

Reference ID: 3672974

Reference ID: 3672974

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed

Reference ID: 3672974

Savaysa (edoxaban) tablets

To reduce the risk of stroke and systemic embolism in

Presentation: The product will be available in 15 mg, 30 mg, and 60 mg strength,

ONDQA Biopharmaceutics - Acceptable with PMC (Sandra Suarez, 9Sep-2014).

The drug substance, edoxaban tosylate, is synthesized using a

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed

Reference ID: 3640230

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Janice Brown, M.S.

Ali Al-Hakim, Ph.D.

Factors that can

OPS Micro will assess

ONDQA BioPharm will

NDA RISK ASSESSMENT TABLE

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed

Reference ID: 3614785

Endoxaban / Immediate Release Tablets

Doreen V. Morgan, Pharm D. Exe. Director, Regulatory Affairs

Quality Review Team

Reference ID: 3623807

Quality Review Data Sheet

Reference ID: 3623807

Action codes for DMF Table:

Reference ID: 3623807

B. Other Documents: IND, RLD, or sister applications

EOP2 CMC Only

Reference ID: 3623807

Summary of Quality Assessments

Drug Substance [USAN Name] Quality Summary

b. Properties/CQAs Relevant to Drug Product Quality

Reference ID: 3623807

c. List of starting materials & Suppliers of starting materials (site)

f. Drug Substance Specification

Reference ID: 3623807

Drug Product [Edoxaban tosylate, tablets] Quality Summary

c. Summary of Product Design

Reference ID: 3623807

f. Drug product specifications

proposed for dissolution as a function of some

It is also the regulatory analytical method.

Reference ID: 3623807

Reference ID: 3623807

Summary of Drug Product Intended Use

Proprietary Name of the Drug Product

Applicant has proposed for

for all quality attributes except for

Reference ID: 3623807

Reference ID: 3623807

Risk Mitigation Approach