`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202895Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`NDA 202-895
`
`PrezistaTM
`
`(darunavir)
`
`Oral Suspension
`100 mg per mL
`
`Tibotec, Inc.
`
`Mark R. Seggel
`ONDQA
`
`Division of New Drug Quality Assessment II
`Branch V
`
`Reference ID: 3022480
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................6
`
`1. Recommendations ..................................................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 6
`
`H. Summary of Chemistry Assessments ....................................................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`111. Admm'islrative ...................................................................................................................................................... 10
`
`A. Reviewer’s Signature ...................................................................................................................... 10
`
`B. Endorsement Block ......................................................................................................................... 10
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... 1 1
`
`1. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data ...................................... 11
`
`S
`
`P
`
`DRUG SUBSTANCE ................................................................................. 11
`
`DRUG PRODUCT ...................................................................................... 11
`
`R5 Control of Drug Product ...................................................................................................................................... 11
`
`P. 5 .1
`
`Specification .......................................................................................................................... l 1
`
`R7 Container Closure System .................................................................................................................................... 12
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................................... 15
`
`A. Labeling & Package Inseit ............................................................................................................. 15
`
`111. List Of Deficiencies To Be Communicated.......................................................................................................... 20
`
`Reference ID: 3022480
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 202-895
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 28-SEP-201 1
`
`4. REVIEWER: Mark R. Seggel
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents (eC'ID)
`(0000)
`Original submission
`(0003)
`Amendment (mfg. facilities)
`Amendment (response to info. request) (0019)
`Amendment (response to info. request) (0024)
`Amendment (response to info. request) (0025)
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; 5) Reviewed (eC’ID)
`(0030)
`Amendment (labeling)
`(0031)
`Amendment (CMC)
`Amendment (alternative dosing pipette) (0032)
`Amendment (labeling)
`(0033)
`Amendment (labeling)
`(0034)
`Amendment (alternative dosing pipette) (0035)
`Amendment (labeling)
`(0036)
`Amendment (syringe graphics)
`(0037)
`Amendment (labeling)
`(0040)
`
`7. NANIE & ADDRESS OF APPLICANT:
`
`Document Date
`29—MAR—201 l
`26-APR—201 l
`29—JUL-201 1
`1 8-AUG-20 l l
`19-AUG—201 1
`
`Document Date
`08-SEP—201 1
`09—SEP—20 l l
`09—SEP—201 1
`09-SEP-201 1
`12-SEP-20 1 1
`14-SEP-201 1
`2 l -SEP-201 1
`22-SEP-201 1
`28-SEP-201 1
`
`920 US. Highway 202.
`Address: PO. Box 300
`Raritan. NJ 08869—0602
`
`908-707-3451
`
`Re resentative(s)' Charles Zezza. PhD
`p
`' Director. Global Re lato Affairs
`
`8. DRUG PRODUCT NAME/CODE/I‘YPE:
`
`a) Proprietary Name: PrezistaTM
`b) Non-Proprietary Name (USAN): Darunavir
`c) Code Name/#: 'IMC 1 14 (TMC114 ethanolate); R319064; JNJ-25875382; 54179
`W": 206361-99-1
`(1) CAS Registry Number: ethanolate: 635728-49-3;
`
`Reference ID: 3022480
`
`Page 3 of 20
`
`

`

`
`
`Chemistry Review Data Sheet
`
`e) Chem. Type/Submission Priority:
`i. Chem. Type: 3
`ii. Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)
`
`10. PHARMACOL. CATEGORY: Antiretroviral/Systemic/I-IIV/Protease inhibitor
`
`(7030220)
`
`11. DOSAGE FORM: Suspension
`
`12. STRENGTH/POTENCY: 100 mg per mL
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON—LINE TRACKlNG SYSTEM)
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT
`
`Chemical Names:
`
`[(lS,2R)—3-[[(4—aminophenyl)sulfonyl](2—methylpropyl)amino]-2—hydroxy—l—(phenylmethyl)—
`1.
`propyl]-carbamic acid (3R,3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-yl ester
`2. Carbamic acid, [(1S,2R)-3-[[(4-amin0phenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-l-
`(phenyhnethyl)propyl]—, (3R,3aS,6aR)—hexahydrofi1ro[2,3-b]furan-3—yl ester
`
`USAN/INN: Danmavir
`
`Structural Formula:
`
`Molecular Formula and Molecular Weight:
`Darunavir
`C27H37N307S
`Darunavir ethanolate
`C27H37N307S-C2H60
`
`547.66
`593.73
`
`"”“’ by weight)
`
`Note: The labeled strength, 100 mg/mL, is based on the weight of danmavir.
`
`Reference ID: 3022480
`
`Page 4 of 20
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`DNIF #
`
`
`
`CED CODE1
`
`HOLDER
`
`18825
`
`H
`
`anssen
`I' harmaceutica
`|
`(J&J PR&D)
`
`II arunavir API
`
`1
`
`Adequate
`
`3 l-AUG—201 l
`
`overing M (4)
`». d particle size
`ontrol
`
`(b) (4)
`
`
`
`Action codes for DMF Table:
`1 — DMF Reviewed
`Other codes indicate why the DMF was not reviewed, as follows:
`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:
`APPLICATION NUT/[BER
`
`NDA 21-976
`
`18. STATUS
`
`SUBJECT
`
`Darlmavir Tablets: A roved 23-JUN—2006
`
`
`CONSULTS/ CMC
`DATE
`RECOMMENDATION
`RELATED REVIEWS
`_ /A —
`O I'erall Recommendation: Acc table
`20-MAY-2011
`
`_ /A —
`0NDQA Biopharmaceutics |
`terim dissolution test acceptance
`01-SEP-2011
`riterion acc otable
`:3
`
`NC
`ethods Validation
`
`I MEPA
`
`i
`| abeling revisions recommended:
`se of standard oral syringe and bottle
`
`31—AUG—2011
`
`da tor/ .lu recommended.
`
`REVIEWER
`
`II . Smith
`
`|
`
`I
`
`. Seggel
`
`. Holmes
`
`
`
`I abelin. revisions recommended
`
`28-SEP-2011
`
`“
`
`_— - Se e1
`Q uali Microbiolo 3
`I' ecommend a o roval
`. Metcalf
`
`19. GOAL DATES
`
`PDUFA Goal:
`
`30—SEP-2011
`
`Reference ID: 3022480
`
`Page 5 of 20
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202-895
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA, as amended, has provided sufficient information to assure identity, strength,
`quality, purity, potency and bioavailability of the drug product. The labels have
`adequate information as required. The issues regarding the dosing device and labeling
`identified in Chemistry Review #1 have been resolved. The Office of Compliance has
`issued an overall recommendation of ‘Acceptable’ based on the satisfactory cGMP
`status of the manufacturing facilities. Therefore, from the CMC perspective, this NDA
`is recommended for approval.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`Tibotec and the ONDQA Biophalmaceutics review team have agreed to the
`establishment of an Interim dissolution test acceptance criterion. A Q of {23% at 45
`minutes will be in place while Tibotec continues to collect dissolution profiles at
`release and on stability for one (1) year following approval. Per a Post—Marketing
`Commitment, Tibotec will report the results and propose a final regulatory specification
`for review. See this reviewer’s Biopharmaceutics review for background information.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`“(4), white to off-white
`PREZISTA (darlmavir) Oral Suspension, 100 mg/mL is a
`opaque, strawberry-cream flavored liquid containing the equivalent of 100 mg
`danmavir per mL. The suspension is supplied in amber—colored multiple-dose bottles
`containing 200 mL of the liquid. Note that while the product is manufactured from
`darlmavir ethanolate, in aqueous systems such as the suspension, the ethanolate
`undergoes conversion to the iso-structural hydrate. This interconversion does not affect
`bioavailability.
`
`Darunavir is currently available in tablet form (NDA 21-976). The first approved tablet
`strength was 300 mg (AP 23-JUN-2006). Subsequently, a 600 mg tablet was approved
`(25-FEB-2008); this is the current RLD. A 400 mg tablet was approved on 21-OCT-
`2008. This was followed by approval of 75 mg and 150 mg tablets on l8—DEC-2008.
`The 300 mg tablet is no longer marketed in the US. Darunavir oral suspension was
`developed in order to address the needs of pediatric patients unable to swallow Prezista
`
`Reference ID: 3022480
`
`Page 6 of 20
`
`

`

`
`
`Executive Summary Section
`
`(darunavir) Tablets and to provide a product suitable for young children (age 3-6
`years).
`
`Initially, development focused on a (4,mg/mL formulation, but a 100 mg/mL product
`was preferable, allowing a smaller volume to provide the required dose.
`
`The overall drug product quality control strategy encompasses everything from drug
`substance characteristics, excipient selection and controls, product composition,
`manufacturing process controls, release testing, container-closure system
`characteristics, and stability testing.
`
`Inactive ingredients in darlmavir oral suspension consist of hydroxypropyl cellulose
`M“) microcrystalline cellulose and
`(mu) (
`(m4);
`selected to give a product with
`
`(m4)
`(m4)
`
`(m0), citric acid monohydrate,
`sucralose, masking flavor, strawberry cream flavor (darunavir has an
`(m4)
`(m4) hydrochloric acid and purified water. All are commonly used in
`oral formulations and are of suitable quality for use in this product. All except the
`flavors are controlled in accordance with compendial monographs.
`
`The manufacturing process is relatively straightforward; essentially a
`
`mm
`
`The regulatory specification for Prezista Oral Suspension includes tests for identity,
`assay, chromatographic impurities, pH (critical for optimal
`(mu) efiectiveness),
`deliverable volume, and dissolution rate (an interim acceptance criterion for dissolution
`has been established; see this reviewer’s ONDQA Biopharmaceutics review of the
`dissolution test method and data). The specification also includes an assay of
`methylparaben,
`(mar
`
`M“),
`Darlmavir oral suspension is packagedin an amber glass bottle with
`M’ cap. This container—closure system provides adequate protection of the
`product (including light protection, as some components of the flavors may be light
`sensitive). The
`(ma) closure provides an appropriate level of safety. A 6-mL
`oral syringe and bottle adapter are included in the carton with each bottle.
`
`(II) (4)
`
`The stability of three registration batches of darunavir oral suspension at 25°C/40% RH
`has been followed through 12 months. No significant changes in product quality
`attributes are noted, although there is a slight decrease in percent dissolved at 30
`minutes (see ONDQA Biophannaceutics review). These studies are ongoing to
`confirm the proposed 24-month expiration dating period of the drug product.
`
`Reference ID: 3022480
`
`Page 7 of 20
`
`

`

`
`
`Executive Summary Section
`
`Storage lmder refrigeration and freezing conditions were conducted. Refiigeration can
`result in precipitation of methylparaben, and thus should be avoided. Temperature
`cycling studies were also conducted. No adverse effects were noted. Initial results
`from an ongoing simulated in—use study indicate that repeated opening of the bottle and
`removal of a dose does not adversely affect the quality of the product.
`
`an“) effectiveness testing demonstrated that the product meets
`(m4) criteria for oral products made with an aqueous base. Adequate product
`the
`quality microbiology controls have been established, and include tests for
`(mu)
`
`Quality Microbiology review for details.)
`
`.
`.
`Damnav1r API 1s
`
`(see Product
`
`4
`(m )
`
`). The chemistry, manufacture and control (CMC) of darunavir
`ethanolate drug substance used in the manufacture of both damnavir tablets and
`danmavir oral suspension is documented in Janssen Pharmaceutica’s DMF 18825.
`Darlmavir is only very slightly
`(m4) . Other than a
`(am)
`
`Drug substance particle size, although not particularly critical to bioavailability, can
`«and Hence, the drug substance is
`mm
`in the manufacture of the suspension.
`
`the CMC is the same.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Prezista is indicated for the treatment of HIV-1 infections in adult patients. It is also
`indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and
`older. Prezista must be co—administered with ritonavir and with other antiretroviral
`
`agents. Darunavir is taken twice daily with food. In patients weighing 10 to 15 kg (22
`to 33 pounds), the weight-based dose is {2; mg/kg (equivalent to
`«mo
`mL of the oral suspensionD. Dosing of patients greater than 15 kg is also described.
`The maximum dose of 800 mg (8 mL; for adults unable to swallow the tablets) should
`be taken as two 4 mL administrations with the included oral dosing syringe.
`
`(m4)
`Prezista Oral Suspension is supplied in amber glass bottles with
`caps. A 6-mL
`M“) oral syringe and bottle adapter will be supplied with the
`bottle. (Note: The originally proposed
`(m4) will not be used with product in
`the US.) The patient or caregiver will press fit the adapter into the bottle neck. The tip
`of the syringe is inserted into the adapter and the bottle inverted. The required dose is
`withdrawn into the syringe. The syringe is removed from the adapter and the dose
`administered.
`
`Reference ID: 3022480
`
`Page 8 of 20
`
`

`

`
`
`Executive Summary Section
`
`Prezista Oral Suspension is labeled for storage at 25°C (77°F); with excursions
`permitted to 15°-30°C (59°-86°F). The label also indicates that the product should not
`be refrigerated or frozen. Exposure to excessive heat is to be avoided. The suspension
`is to be stored in the original container, and should be shaken well before each usage.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The applicant has provided sufficient information on raw material controls,
`manufacturing processes and process controls, and adequate specifications for assuring
`consistent product quality of the drug substance and drug product. The applicant also
`has provided sufficient stability information on the drug product to assure strength,
`purity, and quality of the drug product during the expiration dating period.
`
`The proposed dissolution test acceptance criterion, Q= 223% at 30 minutes was
`considered unacceptable. While the available release and stability data suggest that Q =
`33% at 30 minutes is appropriate (although some Stage 2 testing may be necessary),
`Tibotec concludes that an unacceptably high overall failure rate will occur at the
`proposed 24-month expiry (see Biopharmaceutics review). An Interim acceptance
`criterion of Q = 8% at 45 minutes has been established. This will ensure that a mean
`of at least 3% of the drug product is dissolved. A Post-Marketing Commitment
`(PMC) addresses the requirements for collecting data for one year and proposal of a
`final regulatory acceptance criterion.
`
`ma)
`Prezista Oral Suspension is supplied in amber glass bottles with
`caps. A dosing device is supplied with each bottle of oral suspension. The originally
`proposed
`(”"4” reviewed in Chemistry Review #1 will not be used with
`product in the US. DMEPA determined that the design of that
`m“) was inconsistent
`with what patients in the US. are familiar with and was likely to lead to confusion and
`dosing errors. An alternative oral syringe and adapter was subsequently proposed and
`is docmnented in the present review. A 6-mL
`(m4) oral syringe and bottle
`adapter will be supplied with the bottle. The materials of construction comply with {'3
`’ which
`(5) w
`Dosing accuracy of the oral syringe
`
`is within i5% across the dosage range of 2.6 mL to 6 mL. Reference is also made to
`Type HI DMF
`(hm) covering the oral syringe and bottle adapter. DMEPA finds the
`proposed oral syringe acceptable.
`
`Labeling for this product consists of the bottle label, carton, package insert, patient
`information, directions for use (lacking at the time Chemistry Review # was completed)
`and syringe graphics. All labels have the required Description, How Supplied and
`Storage information. The trademark, Prezista, was previously found acceptable for
`Tibotec’s formulations of darunavir (i.e., Prezista Tablets). DMEPA and DRISK have
`provided reconnnendations for revisions to all components of the labeling. For
`example, it was recommended that the strength be expressed as “100 mg per mL” rather
`than “100 mg/mL”. In addition, DMEPA recommended that the storage and handling
`statements (e.g., ‘Do not refrigerate or freeze’) be made more prominent. See DMEPA
`
`Reference ID: 3022480
`
`Page 9 of 20
`
`

`

`
`
`Executive Summary Section
`
`review dated 31—AUG—201 l and DRISK reviews dated 06—SEP—2011 and 28—Sep—20] 1.
`From the CMC perspective, all labeling recommendations made to date are acceptable.
`
`Finally, all manufacturing, packaging and testing facilities have acceptable site
`recommendations. An overall recommendation of Acceptable was issued by the Office
`of Compliance on 20-MAY-2011 (see Chemistry Review #1).
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`{see electronic signature page}
`
`B. Endorsement Block
`
`{see electronic signature page}
`
`C. CC Block
`
`{see darrts}
`
`10 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3022480
`
`Page 10 of 20
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARK R SEGGEL
`09/29/2011
`
`RAPTI D MADURAWE
`09/29/2011
`
`Reference ID: 3022480
`
`

`

`
`
`NDA 202-895
`
`.
`Prelista
`
`TM
`
`(darunavir)
`
`Oral Suspension
`100 mg/mL
`
`Tibotec, Inc.
`
`Mark R. Seggel
`ONDQA
`
`Division of New Drug Quality Assessment II
`Branch V
`
`Reference ID: 3010703
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................5
`
`The Executive Summary .........................................................................................8
`
`I. Recommendations ..................................................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 8
`
`II. Summary of Chemistry Assessments ....................................................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 10
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 11
`
`HI. Administrative ...................................................................................................................................................... 12
`
`A. Reviewer’s Signature ...................................................................................................................... 12
`
`B. Endorsement Block ......................................................................................................................... 12
`
`C. CC Block ........................................................................................................................................ 12
`
`Chemistry Assessment ........................................................................................... 13
`
`1. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data ...................................... 13
`
`S
`
`DRUG SUBSTANCE ................................................................................. 13
`
`8.1 General Information ............................................................................................................................................ 13
`
`S. 1.1
`
`Nomenclature ........................................................................................................................ 13
`
`S. 1.2
`
`Structure ................................................................................................................................ 14
`
`8.1.3
`
`General Properties ................................................................................................................. 14
`
`82 Manufacture.......................................................................................................................................................... 15
`
`8.2.1
`
`Manufacturers ...................................................................................................................... 15
`
`8.3 Characterization.................................................................................................................................................... 16
`
`8.4 Control of Drug Substance ................................................................................................................................... 16
`
`8.4.1
`
`Specification .......................................................................................................................... 16
`
`Reference ID: 301 0703
`
`

`

`'"fl‘t
`
`CHEMISTRY REVIEW #1
`
`'"fi'fi
`
`S.4.2
`
`Analytical Procedures ........................................................................................................... 17
`
`8.4.3
`
`Validation of Analytical Procedures ..................................................................................... 17
`
`8.4.4
`
`Batch Analyses ...................................................................................................................... 17
`
`8.4.5
`
`Justification of Specification ................................................................................................. 17
`
`8.5 Reference Standards or Materials ......................................................................................................................... 17
`
`8.6 Container Closure System .................................................................................................................................... 17
`
`8.7 Stability ................................................................................................................................................................ 17
`
`P
`
`DRUG PRODUCT ...................................................................................... 18
`
`RI
`
`Description and Composition of the Drug Product ......................................................................................... 18
`
`P2 Pharmaceutical Development ............................................................................................................................... 19
`
`P21
`
`Components of the Drug Product .......................................................................................... l9
`
`Drug Substance .......................................................................................................................................... l9
`P.2.l.l
`Excipients .................................................................................................................................................. 20
`P.2.1.2
`P22
`Drug Product ......................................................................................................................... 21
`
`Formulation Development ......................................................................................................................... 21
`P.2.2.l
`Over-ages .................................................................................................................................................... 22
`P.2.2.2
`Physicochemical and Biological Properties ............................................................................................... 22
`P.2.2.3
`Attachment A: Nanotechnology product evaluating questions: ..................................................................................... 22
`P23
`Manufacturing Process Development ................................................................................... 23
`
`P.2.4
`
`Container Closure System ..................................................................................................... 24
`
`P25
`
`Microbiological Attributes .................................................................................................... 24
`
`P26
`
`Compatibility......................................................................................................................... 24
`
`P3 Manufacture.......................................................................................................................................................... 25
`
`P.3.l
`
`Manufacturers ....................................................................................................................... 25
`
`R32
`
`Batch Formula ....................................................................................................................... 25
`
`P33
`
`Description of Manufacturing Process and Process Controls ............................................... 26
`
`P.3.4
`
`Controls of Critical Steps and Intermediates......................................................................... 28
`
`PA Control of Excipients............................................................................................................................................ 29
`
`P5 Control of Drug Product ....................................................................................................................................... 30
`
`P.5.1
`
`Specification(s) ..................................................................................................................... 30
`
`P.5.2
`
`Analytical Procedures ........................................................................................................... 31
`
`P53
`
`Validation of Analytical Procedures ..................................................................................... 33
`
`P54
`
`Batch Analyses ...................................................................................................................... 34
`
`P55
`
`Characterization of Impurities ............................................................................................... 34
`
`P56
`
`Justification of Specification(s) ............................................................................................. 35
`
`Reference ID: 301 0703
`
`

`

`“"E'fi
`
`CHEMISTRY REVIEW #1
`
`”1"?
`
`R6 Reference Standards or Materials ......................................................................................................................... 38
`
`R7 Container Closure System .................................................................................................................................... 38
`
`R8 Stability ................................................................................................................................................................ 40
`
`P.8.l
`
`Stability Summary and Conclusion ....................................................................................... 40
`
`R82
`
`Postapproval Stability Protocol and Stability Commitment .................................................. 41
`
`P.8.3
`
`Stability Data ......................................................................................................................... 42
`
`A APPENDICES ..................................................................................................................................................... 44
`
`Al
`
`A2
`
`A3
`
`Facilities and Equipment (biotech only) ............................................................................... 44
`
`Adventitious Agents Safety Evaluation ................................................................................ 44
`
`Novel Excipients ................................................................................................................... 44
`
`R REGIONAL INFORMATION ............................................................................................................................ 44
`
`R1 Executed Batch Records ............................................................................................................... 44
`
`R2 Comparability Protocols ............................................................................................................... 44
`
`R3 Methods Validation Package ........................................................................................................ 44
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................................... 45
`
`A. Labeling & Package Insert ............................................................................................................. 45
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 49
`
`111. List OfDeficiencies To Be Communicated.......................................................................................................... 50
`
`Iv. Miscellaneous Attachments .................................................................................................................................. 52
`
`Attachment B. EES Report .................................................................................................................. 52
`
`Reference ID: 301 0703
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 202—895
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 06—SEP—2011
`
`4. REVIEWER: Mark R. Seggel
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Not Applicable
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions 5! Reviewed (eCTD)
`(0000)
`Original submission
`(0003)
`Amendment (mfg. facilities)
`Amendment (response to info. request) (0019)
`Amendment (response to info. request) (0024)
`Amendment (response to info. request) (0025)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`Document Date
`29—MAR—201 1
`26-APR-201 l
`29-JUL-201 1
`1 8-AUG-20 1 1
`19-AUG-20 1 1
`
`Address:
`
`920 US. Highway 202
`P.O. Box 300
`Raritan. NJ 08869-0602
`
`Representat1ve(s). Director Global Re . to Aflairs 908-707-3451
`
`.
`
`_ Charles Zezza. PhD
`
`8. DRUG PRODUCT NAME/CODE/I'YPE:
`
`a) Proprietary Name: PrezistaTM
`b) Non-Proprietary Name (USAN): Darunavir
`c) Code Name/#: TMC114 (TMC114 ethanolate);
`d) CAS Registry Number: xxx
`e) Chem. Type/Submission Priority:
`i. Chem. Type: 3
`ii- Submission Priority: P
`
`9.