208447Orig1s000 - Food and Drug Administration · Division of Pharmaceutical Analysis 645 S....

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208447Orig1s000

CHEMISTRY REVIEW(S)

XiaoChen

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Date: 3/09/2017 10:04:55AM

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XiaoChen


Date: 3/09/2017 09:28:06PM



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

Digitally signed by Michael Trehy

Date: 2/10/2017 11:38:01AM

GUID: 508da7370002b1e9d13b216a10507f03


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_________________



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


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.


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


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


XiaoChen


Date: 12/16/2016 09:37 35AM



208447Orig1s000 - Food and Drug Administration · Division of Pharmaceutical Analysis 645 S....

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