CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
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`APPLICA TION NUMBER:
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`2 1 -976
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`CHEMISTRY REVIEW! S!
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`

`

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`' ”15%;;HEMISTRY' REVIEWS
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`Chemistry Review Data Sheet
`
`NDA #21-976
`
`PREZISTATM
`
`(darunavir)
`Tablets
`
`300 mg
`
`Tibotec, Inc.
`
`CMC Review
`
`Rao V. Kambhampati, Ph.D.
`Senior Regulatory Review Scientist
`ONDQA, DPA II, Branch IV
`
`Page 1 of 46
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` ;} CHEMISTRY REVIEW .
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`Chemistry Review Data Sheet
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`Chemistry Review Data Sheet
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`1. NDA# 21-976 .
`
`2. REVIEW #: 1
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`3. REVIEW DATE: 6/23/2006
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`4. REVIEWER: Rao V. Kambhampati, Ph.D.
`
`5. PREVIOUS DOCUMENTS: N/A
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`6. SUBMISSION(S) BEING REVIEWED:
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`
`
`
`Document Date
`Submission( 5) Reviewed
`
`
`
`fle-submissionRRZ 002
`4/Nov/2005
`' —'|
`
`
`
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`22/Dec/2005
`
`
`
`
`
`
`
`Amendment N 000 BC
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`
`
`
`
`
`19/Jun/2006
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`
`
`
`
`
`
`_
`
`.
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`
`
`
`
`1020 Stony Hill Road, Ste 300
`
`
`
`
`
`
`
`Re resentative'
`p
`'
`
`Jenny Z. Lin, Pharm. D.
`Mana er, Re ulato Affairs
`
`1,
`
`.
`
`'
`
`_
`
`Telephone:
`609-730-7516
`-
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`
`
`
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`8. DRUG PRODUCT NAIVIE/CODE/TYPE:
`
`a) Proprietary Name: PREZIST TM
`b) Non-Proprietary Name (USAN): darunavir
`0) Code Name/#: TMC 114, TMC 114 ethanolate, TMC 114 monoethanolate, R319064, INJ-
`25875382, darunavir ethanolate.
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 1
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`, Page 2 of 46
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`1"
`CHEMISTRY REVIE:
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`Chemistry Review Data Sheet
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`0 Submission Priority: P
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`9. LEGAL BASIS FOR SUBMISSION: N/A'
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`10.
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`PHARMACOL CATEGORY: Antiviral (protease inhibitor)
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`11.
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`DOSAGE FORM: Tablet
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`12.
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`STRENGTH/POTENCY: 300 mg (each tablet contains darunavir ethanolate
`equivalent to 300 mg of the free form of darunavir)
`
`13.
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`ROUTE OF ADMINISTRATION: Oral
`
`14.
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`RX/OTC DISPENSED:
`
`_,_._____
`X RX
`
`OTC
`
`15.
`
` SPOTS SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM :
`
`
`SPOTS product — Form Completed
`
`
`X
`Not a SPOTS product
`
`16.
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`Chemical Name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-
`hydroxy-1-(phenylmethyl)propyl]—carbamic acid (3R,3aS,6aR)—
`hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate
`CAS Reg. No.: N/A (206361-99-1 for free darunavir)
`Molecular Formula: C27H37N3O7S°C2H50H
`Molecular Weight: ‘
`Structural Formula: _
`
`
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`Page 3 of 46
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`, ,HEMISTRY REVIEW,
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`Chemistry Review Data Sheet
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`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`‘
`
`l1
`
`ll
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`18. STATUS:
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`
`
`
`'
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`Acceptable
`
`3/29/06
`
`J.D. Ambrog10(HFD322), DMPQ,
`oc
`
`
`
`
`
`
`6/21/06
`
`Rao Kambhampati, Ph.D.
`
`
`
`
`
`
`
`
`
`_rAademarkReview-cce_able_4/7/06 DMETS (HFD-420), ODS
`
`
`
`Acceptable (Categorical
`Exclusion)
`Acceptable
`
`Biopharm for
`Dissolution Method
`
`including acceptance
`criteria
`
`Methods Valldat1on
`
`6/21/06
`
`Vikram Arya,_ Ph.D.
`
`
`
`__6/21/_06 _RaoKambharLt', 7
`
`Page 4 of 46
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` /
`SCHEMISTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NDA 21-976
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`. Recommendation'and Conclusion on Approvability
`From the chemistry, manufacturing and controls (CMC) standpoint, the NDA #21-976 is
`recommended for approval.
`
`. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approval
`N/A
`
`Summary of Chemistry Assessments
`
`. Description of the Drug Substance(s) and Drug Product(s)
`The Applicant intends to seek approval of the FDA for PREZISTATM (darunavir) Tablets
`for co-administration with 100 mg of ritonavir, and with other active antiretroviral agents
`fOr the treatment of HIV infection in antiretroviral treatment-experienced adult patients._
`Each Prezista (darunavir) tablet contains darunavir ethanolate f — ) equivalent to 300
`mg of the free form of darunavir. The tablets are orange, oVal-shaped, film-coated, and
`debossed with “300” on one side and “TMC114” on the other side. The tablets are
`
`packaged in 160-mL bottles of 120 count.
`
`'
`
`All information regarding the chemistry, manufacturing and controls (CMC) for
`darunavir drug substance was cross-referenced to the Janssen Pharmaceutica NV’s —- "-
`-— and a Letter of Authorization (LOA) was submitted to the NDA. The DMF and its
`amendments there to, contained adequate CMC information for darunavir drug substance.
`
`The drug product is a film-coated tablet. The total weight of each tablet is 650.20 mg.
`The core of each tablet contains — 7 of darunavir ethanolate which is equivalent to
`300 mg of free darunavir as the active ingredient and the following excipients,
`.__—_—~ microcrystalline cellulose and
`.- colloidal silicon dioxide) ——- , crospovidone —— and magnesium
`stearate —— The film—coating contains Opadry 11 Orange “ The
`commercial darunavir tablets are manufactured by Janssen 'Ortho L.L.C., Gurabo (Puerto
`Rico). The secondary packaging is performed by Ortho-McNeil Pharmaceutical, Inc.,
`Raritan, NJ. The stability testing of the marketed product will be performed by Janssen
`Pharmaceutica Inc., Titusville, NJ. Tibotec and all these companies are the affiliated
`companies of Johnson & Johnson. The initially intended commercial batch size was —-
`kg but it was later revised to — 7
`, The primary stability data were provided for -—
`registration batches of — each. The manufacturing process involves the following
`steps; .
`-M
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`Page 5 of 46
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` M” ‘
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`HEMISTRY REVIEW
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`Executive Summary Section
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`— The in—process controls included adequate tests and acceptance
`criteria. The tablet release specifications included —_————I
`HPLC), assay 1, f— , chromatographic purity (each individual degradation
`product NMT -- and Total degradation products NMT — 1, weight variation (USP
`<905>), and dissolution (NLT' 'I' of darunavir —— . Upon comment, in
`the amendment (6/19/06) the Total degradation products content was tightened from
`
`initial fl
`Adequate description was provided for the analytical methods
`9 .— and dissolution). The method validation was conducted on ~
`‘#
`—__———-
`' which is acceptable because this change does not affect the
`test results. Batch analyses data were provided for — NDA registration batches \—
`kg) that were manufactured at the proposed commercial site (Janssen-Ortho, Gurabo, PR)
`and for - batches that were manufactured at Johnson & Johnson Pharmaceutical
`Research and Development (J&JPRD) at Spring House, PA. In addition, upon comment,
`batch analyses data were provided in the amendment (6/ 19/06) for. full production scale
`-— batches that were made at Gurabo which also included - process validation
`batches. It was demonstrated that the darunavir tablets can be made with consistent
`quality and purity. The container/closure system consists of —-————
`
`a*
`
`However, the 120 count bottles Will
`only be marketed at this point. Adequate description, specifications, and test results were
`provided for container/closure Components. The initial submission (11/4/05) contained -
`months of long term and accelerated stability data for — primary stability batches. The
`—" long-term updated data were provided in the NDA amendment (2/27/06). In '
`addition, in the initial submission, ‘- long-term and — accelerated supportive
`stability data-were provided for one batch each of the 300 mg and 400 mg strength tablets
`which was followed by — long-term updated data in the 2/27/06 amendment.
`Based on the real time stability data and statistical analysis of the data, the applicant
`proposed an expiration dating period of 18 months when darunavir tablets are stored at
`25°—30°C.
`
`.
`
`.
`
`B. Description of How the Drug Product is Intended to be Used
`The PREZISTATM (darunavir) tablets are administered orally. The recommended’dose
`for adults is 600 mg (two 300 mg tablets) twice daily taken with ritonavir 100 mg twice
`daily and with food. Ritonavir is used as a pharmacokinetic enhancer of Prezista. The
`tablets are packaged in l60—mL — bottles of 120 count. The tablets are recommended
`to be stored at 25°C (77°F); with excursions permitted to 15° to 30°C (59° to 86°F). The
`expiration dating period is —_ when stored at 25°-30°C (59°-86°F).
`
`C. Basis for Approvability or Not-Approval Recommendation
`The original NDA submission and amendments there to, provided adequate information
`on the chemistry, manufacturing, and controls (CMC) for the production of PREZISTA
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`Page 6 of 46,
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`CHEMISTRY REVIE »
`
`Executive Summary Section
`
`(darunavir) tablets. The DMF ‘- and amendments there to found to contain adequate
`CMC information for darunavir drug substance.
`
`The manufacturing and packaging processes and in-process controls used for the drug
`product are acceptable. Adequate batch analysis data were provided for the drug product
`which included data for full production scale and ~ process validation batches. The
`specification for the drug product included adequate tests, and the revised acceptance
`criteria are acceptable. The stability data included " fl'
`: real-time long—term stability
`data for 0 primary registration batches and d. long-term data for one
`supportive stability batch and, and statistical analysis which projected an expiration
`period of a- months for 120-count bottles. On the basis of the real time data and
`statistical analysis of the data, the proposed expiration dating period of 18 months is
`’ acceptable when tablets are stored at 25°-30°C.
`
`The trade name, PREZISTATM,.was found to be acceptable by the DMETS (HFD-420),
`DDMAC, and DAVP (HFD-530). The established (USAN) name for the drug substance
`is darunavir. Some changes were recommended to the package insert and bottle and
`carton labels and those changes will be incorporated in the final printed labeling
`documents by the Applicant.
`
`The manufacturing, packaging, and release testing facility and the commercial stability
`'
`testing facility for darunavir tablets were found to be acceptable by DMPQ (HFD-324).
`The dissolution method including the acceptance criteria is acceptable from the 'CMC and
`from the biopharm perspective (Vikram Arya, Ph.D.). As according to the current policy,
`the analytical methods validation is not required because the dosage form is simple and it
`does not involve any unusual/special testing methods. The Applicant’s request for an
`exemption from the EA requirement under categorical exclusion is acceptable.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Signed in DFS by Rao V. Kambhampati, Ph.D., Senior Regulatory Review Scientist
`(Chemist).
`
`B.
`
`Endorsement Block
`
`Signed in DFS by Norman Schmufif Ph.D., Branch Chief Branch IV, DPA II, 0NDQA.
`
`CC Blockcc:
`,
`Org. NDA 21-976
`vHFD-800/Branch Chief/NSchmuff
`HFD-530/PM/EThompson
`
`.
`HFD-800/Chem Reviewer/RKambhampati
`HFD-SOO/PAL/SMiller
`HFD—800/PM/KStiller
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`Page 7 of 46
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` 3 9 Page(s) Withheld
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`+4 § 552(b)(4) Trade Secret / Confidential
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`§ 552(b)(5) Deliberative Process
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`§ 552(b)(5) Draft Labeling
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`’Withheld Track Number: Chemistry-
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`I
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`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Rao Kambhampati
`6/23/2006 03:44:17 PM
`CHEMIST
`
`Recommended for approval.
`Please sign off and file.
`
`Norman Schmuff
`
`6/23/2006 04:04:40 PM
`CHEMIST
`
`