022496Orig1s000 - Food and Drug Administration · 2012. 6. 4. · 2011-07-13 Adequate 2011-09-23 Adequate 2011-09-16 Adequate 2003-07-10 Acceptable for 2011-01-06 Adequate B. Other

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

022496Orig1s000

CHEMISTRY REVIEW(S)

Chemistry Review Cover Sheet

NDA 22496 Exparel (bupivacaine)

liposomal injection

Arthur B. Shaw, Ph. D. ONDQA/DNDQA3/DAAAP

Reference ID: 3019727

Chemistry Review #2 NDA 22496 Page 2

Table of Contents I. Recommendations ....................................................................................................................6

1. Recommendation and Conclusion on Approvability: ....................................................................6 2. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk

Management Steps, if Approvable. ..................................................................................................6

II. Summary of Chemistry Assessments .....................................................................................6 A. Description of the Drug Product(s) and Drug Substance(s) .............................................................6 1. Drug Substances ...............................................................................................................................6 2. Drug Product ....................................................................................................................................6 B. Description of How the Drug Product is Intended to be Used .........................................................8 C. Basis for Approvability or Not-Approval Recommendation ...........................................................9

III. Administrative..........................................................................................................................9

I. Review of Common Technical Document-Quality (CTD-Q) Module 3.2: Body of Data .........................................................................................................................................10 S DRUG SUBSTANCE ....................................................................................................................10 S.1 General Information: ...................................................................................................................................................... 10 S.2 Manufacture .................................................................................................................................................................... 10 S.3 Characterization: ............................................................................................................................................................ 10 S.4 Control of Drug Substance.............................................................................................................................................. 10 S.5 Reference Standards or Materials.................................................................................................................................... 12 S.6 Container Closure System ............................................................................................................................................ 102 S.7 Stability:.......................................................................................................................................................................... 13

P DRUG PRODUCT.........................................................................................................................13 P.1 Description and Composition of the Drug Product ......................................................................................................... 13 P.2 Pharmaceutical Development:......................................................................................................................................... 16 P.3. Manufacture .................................................................................................................................................................... 23 P.4 Control of Excipients ...................................................................................................................................................... 32 P.5 Control of Drug Product.................................................................................................................................................. 35 P.6 Reference Standards or Materials.................................................................................................................................... 64 P.7 Container Closure ........................................................................................................................................................... 64 P.8 Stability........................................................................................................................................................................... 65

R REGIONAL INFORMATION ....................................................................................................................................... 71 . LABELING ................................................................................................................................................................... 71



1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide

Molecular weight: 288.43

Molecular formula: C18H28N2O

CAS RN 2180-92-9 and 38396-39-3

17. RELATED/SUPPORTING DOCUMENTS:

A. DMFs: Reviewed: DMF Holder DMF Subject Review Date Comment

Bupivacaine 2011-07-11 Adequate IR Letter 2011-08-11 No response

Bupivacaine 2011-07-06 Adequate IR Letter 2011-07-13 Response under review

Bupivacaine HCl 2011-04-06 Used to support DMF

No control of

IR letter 2011-04-15 2011-08-19 Adequate 2011-07-13 Adequate 2011-09-23 Adequate 2011-09-16 Adequate 2003-07-10 Acceptable for 2011-01-06 Adequate

B. Other Documents: NDA 16964 Marcaine (bupivacaine HCl) injection 18. STATUS: CONSULTS/ CMC RELATED REVIEWS: Microbiology: ACCEPTABLE 2011-09-27 Biopharm review: ACCEPTABLE 2011-08-11 EA waiver requested in 1.12.14. Granted ACCEPTABLE Inspection: All sites are satisfactory.


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C. Basis for Approvability or Not-Approval Recommendation The NDA can be approved at this time from a CMC point of view. Administrative.

See DARRTS signatures and cc’s


63 PAGES HAVE BEEN WITHHELD IN FULL AS b4 (CCI/TS) IMMEDIATELY FOLLOWING THIS PAGE

---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

ARTHUR B SHAW09/28/2011

PRASAD PERI09/28/2011I concur


Chemistry Review Cover Sheet

NDA 22496 Exparel (bupivacaine)

liposomal injection

Arthur B. Shaw, Ph. D. ONDQA/DNDQA3/DAAAP



Table of Contents I. Recommendations ....................................................................................................................7

1. Recommendation and Conclusion on Approvability: ...................................................... 7 2. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk

Management Steps, if Approvable. .................................................................................... 7

II. Summary of Chemistry Assessments .....................................................................................7 A. Description of the Drug Product(s) and Drug Substance(s) ............................................... 7 1. Drug Substances ................................................................................................................. 7 2. Drug Product ...................................................................................................................... 7 B. Description of How the Drug Product is Intended to be Used ......................................... 10 C. Basis for Approvability or Not-Approval Recommendation ........................................... 10

III. Administrative........................................................................................................................10

I. Review of Common Technical Document-Quality (CTD-Q) Module 3.2: Body of Data .........................................................................................................................................11 S DRUG SUBSTANCE ...................................................................................................... 11 S.1 General Information :...................................................................................................................................................... 11 S.2 Manufacture: ................................................................................................................................................................... 11 S.3 Characterization: ............................................................................................................................................................. 13 S.4 Control of Drug Substance.............................................................................................................................................. 18 S.5 Reference Standards or Materials: .................................................................................................................................. 28 S.6 Container-Closure ........................................................................................................................................................... 28 S.7 Stability:.......................................................................................................................................................................... 30 P DRUG PRODUCT........................................................................................................... 31 P.1 Description and Composition of the Drug Product ......................................................................................................... 31 P.2 Pharmaceutical Development:......................................................................................................................................... 34 P.3. Manufacture .................................................................................................................................................................... 85 P.4 Control of Excipients ...................................................................................................................................................... 98 P.5 Control of Drug Product................................................................................................................................................ 102 P.7 Container Closure System:............................................................................................................................................ 178 P.8 Stability......................................................................................................................................................................... 180 R REGIONAL INFORMATION ..................................................................................................................................... 203 II. LABELING................................................................................................................................................................... 203 III. DRAFT COMMENTS TO BE SENT TO APPLICANT: :............................................................................................ 204



Amendment 2011-07-15 29 27 Withdraw of drug product

Amendment 2011-07-22 28 30 Add spec for from

Amendment 2011-07-25 29 31 Response to Obs 2 in 483

Amendment 2011-7-26 30 32 Confirm application for USAN

Amendment 2011-07-27 31 33 Add spec for related substances

Amendment 2011-07-27 32 34 Amend in vitro release method

7. NAME & ADDRESS OF APPLICANT AND AGENT:

Applicant Name Pacira Pharmaceuticals, Inc. Address 10450 Science Center Dr.

San Diego, CA 92121 Representative Name Dwain K. Allen, Director, Regulatory Affairs Phone 858-625-2424 ext. 3262

8. DRUG PRODUCT NAME/CODE/TYPE:

a) Proposed Proprietary Name: Exparel b) Non-Proprietary Name (INN, BAN): bupivacaine

Note that there is no USAN for bupivacaine. There is one for bupivacaine hydrochloride. The applicant has requested a name from the USAN council.

c) Chem. Type/Submission Priority • Chem. Type: 4 • Submission Priority: S

9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)

10. PHARMACOL. CATEGORY: analgesic

11. DOSAGE FORM: Extended release liposomal suspension

The dosage form name in the label is

Note: It is not clear whether the drug product meets the criteria for This is under review by the relevant disciplines.

COMMENT: Change the dosage form name in the label to

12. STRENGTH/POTENCY: See discussion below

13. ROUTE OF ADMINISTRATION:

14. Rx/OTC DISPENSED: __X_Rx ___OTC

15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM): None


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16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:

(RS)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide;

1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide

Molecular weight: 288.43

Molecular formula: C18H28N2O

CAS RN 2180-92-9 and 38396-39-3

17. RELATED/SUPPORTING DOCUMENTS:

A. DMFs: Reviewed: DMF Holder DMF Subject Review Date Comment

Bupivacaine 2011-07-11 Adequate IR Letter 2011-08-11

Bupivacaine 2011-07-06 Adequate IR Letter 2011-07-13

Bupivacaine HCl 2011-04-06 Used to support IND

No control of

IR letter 2011-04-15 2011-08-11 Deficient. Def Letter

2011-08-11 2011-07-13 Acceptable 2011-02-11 Deficient. Def letter

2011-02-25 Amendment 2011-05-17 Incomplete

2011-07-13 Acceptable IR Letter 2011-08-11

2003-07-10 Acceptable for D7777 2011-01-06 Acceptable

B. Other Documents: NDA 16964 Marcaine


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PRASAD PERI08/14/2011I concur


DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

METHODS VALIDATION REPORT SUMMARY

TO: Arthur Shaw, Reviewing Chemist, HFD-800

E-mail Address: [email protected] Phone: (301)-796-1460 Fax: (301)-796-9787

FROM: FDA Division of Pharmaceutical Analysis, HFD-920

James Allgire Room 1002

1114 Market Street St. Louis, MO 63101 Through: B. J. Westenberger, Deputy Director, HFD-920 Phone: (314)-539-3869 SUBJECT: Methods Validation Report Summary

Application Number: NDA 22496 Name of Product: Exparel (bupivacaine liposomal extended release) Injection

Applicant: Pacira Pharmaceuticals, Inc.

Applicant’s Contact Person: Dwain K. Allen, Director, Regulatory Affairs

Address: 10450 Science Ctr. Dr., San Diego, CA 92121 Telephone: 858-625-2424 ext. 3262 Fax: No Fax email: [email protected] Date NDA Received by DPA: 3/25/2011

Date Samples Received by DPA: 4/12/2011

Date Analytical Completed by DPA: 5/18/2011

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: The cover memo and summary of results are attached.


Summary of Results NDA 22-496 Method: SKY0402 In Vitro Release Assay, Document 053-40008.006, PCDOC# 130969.01 Time point %Release Avg(3) %Release SD %RSD Specifications Initial 9.6, 8.3, 8.4 8.8 0.7 8.3 4h 18.5, 19.9, 18.8 19.1 0.8 3.9 24h 48.8, 50.7, 48.3 49.3 1.2 2.5 48h 66.4, 65.1, 64.0 65.2 1.2 1.9 72h 72.4, 78.2, 81.2 77.3 4.4 5.8 Method: Particle Size Analysis of SKY0402, Document 053-40004.005, PCDOC# 12952.01 Percentile Particle Size Avg(3) Particle Size SD %RSD Specifications D10 (µm) D50 (µm) D90 (µm)


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JAMES F ALLGIRE05/18/2011

BENJAMIN J WESTENBERGER05/23/2011


Version 1/25/2005 Methods Validation Consult Request Page 1

DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

METHODS VALIDATION REQUEST

TO: FDA Division of Pharmaceutical Analysis, HFD-920

Attn: Nick Westenberger Room 1002

1114 Market Street St. Louis, MO 63101

FROM: Arthur Shaw, Reviewing Chemist, HFD-800

E-mail Address: [email protected] Phone: (301)-796-1460 Fax.: (301)-796-9787

Through: Danae Christodolou, Chemistry Team Leader, HFD-800 Phone: (301)-796-1342 and Michael Folkendt, ONDC Methods Validation Coordinator, HFD-800 Phone: 301-827-5173 SUBJECT: Methods Validation Request

Application Number: NDA 22496 Name of Product: Exparel (bupivacaine liposomal extended release) Injection

Applicant: Pacira Pharmaceuticals, Inc.

Applicant’s Contact Person: Dwain K. Allen, Director, Regulatory Affairs

Address: 10450 Science Ctr. Dr., San Diego, CA 92121 Telephone: 858-625-2424 ext. 3262 Fax: No Fax email [email protected] Date NDA Received by CDER: 9/28/2010 Chemical/Therapeutic Type: 3S

Date of Amendment(s) containing the MVP: 09/28/2010 Special Handling Required: No

DATE of Request: March 2, 3011 DEA Class: N/A

Requested Completion Date: 4/15/2011 Format of Methods Validation Package

PDUFA User Fee Goal Date: 7/28/2011 Paper Electronic Mixed

We request suitability evaluation of the proposed manufacturing controls/analytical methods as described in the subject application. Please submit a letter to the applicant requesting the samples identified in the attached Methods Validation Request Form. Upon receipt of the samples, perform the tests indicated in item 3 of the attached Methods Validation Request Form as described in the MV package. We request your report to be submitted in DFS promptly upon completion, but not later than 45 days from date of receipt of the required samples, laboratory safety information, equipment, components, etc. We request that you notify the reviewing chemist of the date the validation process begins. If the requested completion date cannot be met, please promptly notify the reviewing chemist and the ONDC Methods Validation Coordinator. 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 DFS. Send the complete report, with the DFS signed Methods Validation Report Summary, by overnight courier to the above reviewing chemist. All information relative to this application is to be held confidential as required by 21 CFR 314.430. ATTACHMENT(S): Methods Validation Request Form, NDA Methods Validation Package (if not available in the EDR).


Version 1/25/2005 Methods Validation Consult Request Page 3

Methods Validation Request Criteria

MVP Request

Category Description

1 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)

2

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)

3 Methods for biological and biochemical attributes (e.g., peptide mapping, enzyme-based assay, bioassay)

4 Certain methods for physical attributes critical to the performance of a drug (e.g., particle size distribution for drug substance and/or drug product)

5 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

6 Methods for which there are concerns with their adequacy (e.g., capability of resolving closely eluting peaks, limits of detection and/or quantitation)

7 Methods that are subject to a “for cause” reason.



SWATI A PATWARDHAN03/03/2011


DANAE D CHRISTODOULOU03/07/2011

MICHAEL M FOLKENDT03/07/2011


Initial Quality Assessment Office of New Drug Quality Assessment

Division III, Branch VIII Division of Anesthesia, Analgesia and Addiction Products

OND Division: Anesthesia, Analgesia and Addiction NDA: 22496 Chemical Classification 3S Applicant: Pacira Pharmaceuticals Inc. Stamp date: September 28, 2010 PDUFA Date: July 28, 2011 Trademark: EXPAREL™ Established Name: Bupivacaine extended-release liposomal injection Dosage Form: Liposomal injection(s), Route of Administration: Local infiltration into the surgical wound Indication: Post-surgical analgesia Pharmaceutical Assessment Lead: Danae D. Christodoulou, Ph.D. YES NO ONDQA Fileability: √ Comments for 74-Day Letter: √


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17

lipids, which are critical excipients to the liposomal formulation; and the drug product presents complexity with respect to stability and compatibility atrributes. Consults: Microbiology consult was requested. Biopharmaceutics assignment was requested. The primary reviewers should initiate Toxicology consults for the impurities/degradants and extractables/leachables evaluation.

Danae D. Christodoulou, Ph.D. 11/24/2010 CMC Lead, ONDQA Date Prasad Peri, Ph.D. 11/24/2010 Acting Branch VIII Chief, ONDQA Date


19

7.

Are drug substance manufacturing sites identified on FDA Form 356h or associated continuation sheet? 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)

X

8.

Are drug product manufacturing sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including






X

9.

Are additional manufacturing, packaging and control/testing laboratory sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including






X Clarifications and communications with OC.



DANAE D CHRISTODOULOU11/24/2010Initial Quality Assessment

ERIC P DUFFY11/29/2010
