CENTER FOR DRUG EVALUATION AND RESEARCH
APPLICATION NUMBER:
208447Orig1s000
CHEMISTRY REVIEW(S)
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XiaoChen
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FDA/CDER/OPQ/OTR
Division of Pharmaceutical Analysis 645 S. Newstead Ave.
St. Louis MO 63110 P: 314.539.2135
Page 1 of 2 DPA-TR17-058
METHOD VERIFICATION REPORT SUMMARY
Date: February 10, 2017 To: Sharon Kelly, Drug Substance Reviewer William Adams, Drug Product Reviewer Anamitro Banerjee, Branch Chief ONDP Through: Michael Trehy, Ph.D., Acting Lab Chief, Branch II, CDER/OPQ/OTR/DPA From: Daniel J. Mans, Ph.D., Chemist, CDER/OPQ/OTR/DPA Jeffrey Woodruff, Chemist, CDER/OPQ/OTR/DPA Brandon Thomas, Ph.D., ORISE, CDER/OPQ/OTR/DPA Latevi Lawson, Ph.D., ORISE, CDER/OPQ/OTR/DPA Laura Pogue, Ph.D., Method Verification Coordinator, CDER/OPQ/OTR/DPA Subject: Method Verification for NDA 208447: Zejula (niraparib) 100 mg capsule The following methods were evaluated and are acceptable for quality control and regulatory purposes:
1. AM-1842 FTIR Identification of Niraparib Tosylate Monohydrate Drug Substance 2. AM-1843 FTIR Identification of Niraparib Capsules, 100 mg 3. AM-1921 HPLC for Identity, Assay and Impurities for Niraparib Tosylate
Monohydrate Drug Substance 4. AM-1971 HPLC ID, Assay and Related Impurities for Niraparib Capsules, 100 mg 5. AM-1814 HPLC Chiral Purity Method for Niraparib Tosylate Monohydrate Drug
Substance 6. AM-1974 HPLC Dissolution Method for Niraparib Capsules, 100 mg 7. AM-1884 Determination of Residual Solvents in Niraparib Tosylate Monohydrate
Drug Substance by Gas Chromatography The Division of Pharmaceutical Analysis (DPA) has no comments pertaining to the methods. Original analyst worksheets can be viewed using this ECMS link: http://ecmsweb.fda.gov:8080/webtop/drl/objectId/090026f880fb2cfd
Summary of Analysis NDA 208447
Page 2 of 2
Method Test Item Specification Result PASS / FAIL
AM‐1842 FTIR
Identification of
Niraparib Tosylate
Monohydrate
Drug Substance
Identification:
Niraparib Tosylate
Monohydrate
Conforms to the Niraparib Tosylate
Monohydrate reference standard spectrum
Conforms to the Niraparib Tosylate
Monohydrate reference standard spectrumPASS
AM‐1843 FTIR
Identification of
Niraparib
Capsules, 100 mg
Identification:
Niraparib Tosylate
Monohydrate
Spectrum of sample exhibits adsorption
bands at approximately 1660, 1520 and 820
reciprocal centimeters when compared to
ref STD
Spectrum of sample exhibits adsorption
bands at 1659, 1525 and 818 reciprocal
centimeters; ref STD bands at 1659, 1524,
818 reciprocal centimeters
PASS
Identification:
Niraparib
Mean retention time (RT) of the main peak is
within of the mean system suitability RT
for Nir parib Tosylate Monohydrate ref STD
Mean retention time (RT) of the main peak
shows 0% difference of the mean system
suitability RT for Niraparib Tosylate
Monohydrate ref STD
PASS
Identification: Mean retention time (RT) of the main peak is
within of the mean system suitability RT
for ref STD
Mean retention time (RT) of the main peak
shows 0% difference of the mean system
suitability RT for ref
STD
PASS
Assay: Niraparib Tosylate
Monohydrate98.9% w/w PASS
Related Impurities: (Achiral)
Specified Impurities A, B & ENMT % w/w (A, B & E) Impurities A, B & E each < 0.05% w/w PASS
Related Impurities: (Achiral)
Individual Unspecified
Impurity
NMT % w/w < 0.05% w/w PASS
Total Impurities (Achiral) NMT % w/w < 0.05% w/w PASS
Identification
Niraparib
The RT of the main peak in the sample
conforms to that for the Niraparib ref STD
The RT of Niraparib ref STD is 17.6 min and
the RT of Niraparib in the sample is 17.6 minPASS
Assay: Niraparib Tosylate
Monohydrate% of the label claim (%LC) 98.8% LC PASS
Degradation Products:
Impurity A, Individual
Unspecified Degradation
Product, Total Degradation
Products
Impurity A NMT % w/w
Individual Unspecified Degradation Product
NMT % w/w
Total Degradation Products NMT % w/w
Impurity A < 0.1% w/w
Individual Unspecified Degradation Product
< 0.1% w/w
Total Degradation Products < 0.1% w/w
PASS
AM‐1814 HPLC
Chiral Purity
Method for
Niraparib Tosylate
Monohydrate
Drug Substance
Chiral Impurity: Niraparib
Tosylate Monohydrate
enantiomer
NMT % a/a 0.11% a/a PASS
AM‐1974 HPLC
Dissolution
Method for
Niraparib
Capsules, 100 mg
Dissolution Q = at 45 minutes AVG Q = 97.7% at 45 minutes PASS
AM‐1884
Determination of
Residual Solvents
in Niraparib
Tosylate
Monohydrate
Drug Substance by
Gas
Chromatography
ND
ND
ND
1595 ppm
ND
PASS
AM‐1921 HPLC for
Identity, Assay
and Impurities for
Niraparib Tosylate
Monohydrate
Drug Substance
AM‐1971 HPLC ID,
Assay and Related
Impurities for
Niraparib
Capsules, 100 mg
(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)
MichaelTrehy
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Date: 2/10/2017 11:38:01AM
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OFFICE OF PHARMACEUTICAL QUALITY FILING REVIEW
B. NOTEWORTHY ELEMENTS OF THE APPLICATION Yes No Comment
14. Oral disintegrating tablet1
15. Modified release product1
16. Liposome product1
17. Biosimiliar product1
18. Combination Product _____________________19. Other_________________
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OFFICE OF PHARMACEUTICAL QUALITY FILING REVIEW
C. FILING CONSIDERATIONS Drug Substance Drug Product Appendices
o Facilities and Equipmento Adventitious Agents Safety
Evaluationo Novel Excipients
Regional Informationo Executed Batch Recordso Method Validation Packageo Comparability Protocols
FACILITY INFORMATION3. Are drug substance manufacturing sites, drug
product manufacturing sites, and additional manufacturing, packaging and control/testing laboratory sites identified on FDA Form 356h or associated continuation sheet? For a naturally-derived API only, are the facilities responsible for critical intermediate or crude API manufacturing, or performing upstream steps, specified in the application? If not, has a justification been provided for this omission? For each site, does the application list: 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)
4. Is a statement provided that all facilities are ready for GMP inspection at the time of submission?For BLA: Is a manufacturing schedule provided? Is the schedule feasible to conduct an
inspection within the review cycle?DRUG SUBSTANCE INFORMATION
5. For DMF review, are DMF # identified and authorization letter(s), included US Agent Letter of Authorization provided?
6. Is the Drug Substance section [3.2.S] organized adequately and legible? Is there sufficient information in the following sections to conduct a review?
general information
OFFICE OF PHARMACEUTICAL QUALITY FILING REVIEW
C. FILING CONSIDERATIONS manufacture
o Includes production data on drug substance manufactured in the facility intended to be licensed (including pilot facilities) using the final production process(es)
o Includes descriptions of changes in the manufacturing process from material used in clinical to commercial production lots – BLA only
o Includes complete description of product lots and their uses during development – BLA only
characterization of drug substance control of drug substance
o Includes data to demonstrate comparability of product to be marketed to that used in the clinical trials (when significant changes in manufacturing processes or facilities have occurred)
o Includes data to demonstrate process consistency (i.e. data on process validation lots) – BLA only
reference standards or materials container closure system stability
o Includes data establishing stability of the product through the proposed dating period and a stability protocol describing the test methods used and time intervals for product assessment
DRUG PRODUCT INFORMATION7. Is the Drug Product section [3.2.P] organized
adequately and legible? Is there sufficient information in the following sections to conduct a review? Description and Composition of the Drug
Product Pharmaceutical Development
o Includes descriptions of changes in the manufacturing process from material used in clinical to commercial production lots
o Includes complete description of product lots and their uses during development
Manufacture o If sterile, are sterilization validation studies
submitted? For aseptic processes, are bacterial challenge studies submitted to support the proposed filter?
Control of Excipients Control of Drug Product
In the presubmission, there is only 6 month long term stability data in the NDA. The applicant had agreed to submit 12 onths stability data within 30 day of the NDA submission (initial clock starting point) in a preNDA meeting held on 9/21/2016.
OFFICE OF PHARMACEUTICAL QUALITY FILING REVIEW
C. FILING CONSIDERATIONSday letter.
10. Does the application include a biowaiver request? If yes, are supportive data provided as per the type of waiver requested under the CFR to support the requested waiver? Note the CFR section cited.
11. For a modified release dosage form, does the application include information/data on the in-vitro alcohol dose-dumping potential?
The proposed product is an immediate release capsule.
12. For an extended release dosage form, is there enough information to assess the extended release designation claim as per the CFR?
The proposed product is an immediate release capsule.
13. Is there a claim or request for BCS I designation? If yes, is there sufficient permeability, solubility, stability, and dissolution data?
REGIONAL INFORMATION AND APPENDICES14. Are any study reports or published articles in a
foreign language? If yes, has the translated version been included in the submission for review?
15. Are Executed Batch Records for drug substance (if applicable) and drug product available?
16. Are the following information available in the Appendices for Biotech Products [3.2.A]? facilities and equipment
o manufacturing flow; adjacent areaso other products in facilityo equipment dedication, preparation,
sterilization and storageo procedures and design features to prevent
contamination and cross-contamination adventitious agents safety evaluation (viral and
non-viral) e.g.:o avoidance and control procedureso cell line qualification o other materials of biological origino viral testing of unprocessed bulko viral clearance studieso testing at appropriate stages of production
novel excipients17. Are the following information available for Biotech
Products: Compliance to 21 CFR 610.9: If not using a
test method or process specified by regulation, data are provided to show the alternate is equivalent to that specified by regulation. For example:
o LAL instead of rabbit pyrogeno Mycoplasma
Compliance to 21 CFR 601.2(a): Identification by
OFFICE OF PHARMACEUTICAL QUALITY FILING REVIEW
C. FILING CONSIDERATIONSlot number and submission upon request, of sample(s) representative of the product to be marketed with summaries of test results for those samples
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XiaoChen
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Date: 12/16/2016 09:37 35AM
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