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CENTER FOR DRUG EVALUATION ANDRESEARCHAPPLICATION NUMBER:201917Orig1s000CHEMISTRY REVIEW(S)

CHEMISTRY REVIEW TEMPLATEChemistry Assessment SectionNDA 201-917INCIVEK (telaprevir) TabletsVertex Pharmaceuticals, Inc.Christopher Hough, Ph.D.Bogdan Kurtyka, Ph.D.George Lunn, Ph.D.Lin Qi, Ph.D.Division of Anti-Viral ProductsREVIEW #: 2REVIEW DATE: 20-May-2011Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment SectionSUBMISSIONS BEING REVIEWED:Submission(s) ReviewedDocument 04-Apr-201114-Apr-201110-May-2011NAME & ADDRESS OF APPLICANT:Name:Address:Representative:Vertex Pharmaceuticals Incorporated130 Waverly StreetCambridge, MA 02139John F. Weet, Ph.D.Vice-President, Regulatory AffairsTelephone:617 444 7789DRUG PRODUCT NAME/CODE/TYPE:a) Proprietary Name:N/Ab) Non-Proprietary Name (USAN):Telaprevirc) Code Name/# (ONDC only):VX-950d) Chem. Type/Submission Priority (ONDC only): Chem. Type:1 Submission Priority:PDMFs:DMF # TYPEHOLDERITEMREFERENCED(b) (4)(b) (4)IIIIIVReference ID: COMMENTSREVIEWLOA datedCOMPLETEDApr 25, 201107/07/2010(G.Lunn)May 11, 201107/06/2010(B.Kurtyka)4/19/1106/12/2009

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(Reviewed byLin 21/20091Action codes for DMF Table:1 – DMF Reviewed.4 – Sufficient information in application1.RecommendationsA. Recommendation and Conclusion on ApprovabilityThis NDA has provided sufficient information to assure identity, strength, purity, and quality of(b) (4)the drug substance,, and drug product. The labels andlabeling have been finalized, and have adequate information as required. An OverallRecommendation of Acceptable has been made by the Office of Compliance. AppropriateReference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)responses to information requests for DMFwere received on March 28, 2011, and thatDMF is now adequate and supports this NDA. Therefore, from the CMC perspective, this NDAis recommended for approval.B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/orRisk Management Steps, if ApprovableNone2. Summary of Chemistry AssessmentsA. Description of the Drug Product(s) and Drug Substance(s)A Quality by Design approach has been used for the manufacture of telaprevir drug substance.Each step in the procedure has been evaluated and for each parameter a Normal Operating Range(NOR) and a Proven Acceptable Range (PAR) have been determined on the basis of experimentsin which the parameter was varied. These experiments are described in detail and the NORs andPARs are acceptable. The critical/non-critical nature of each step was also assessed. The drugsubstance is manufactured following the process description together with the knowledge of theNOR and the PAR. Together this information is used to produce the manufacturing batchrecord. The NOR is given in the batch record and the PAR is available in the Process SupportDocument. As experience is gained the process can be adapted. Adequate specifications areprovided for the starting materials, solvents, and reagents.(b) (4)An acceptable drug substance specification that has tests for appearance, identity, assay,(b) (4)(b) (4)impurities,, heavy metals, and residue on ignition is provided.The specified impuritieshave been qualified based on toxicological studies. The analytical methods are described at anacceptable level of detail and have been validated.Satisfactory stability data obtained at 25 C/60% RH, 30 C/65% RH, and 40 C/75% RH for up to24 months are provided for 9 batches. There are no out of specification results and no trends.(b) (4). Two attributes critical to final product quality, particle size and bulk density, are tested foreach batch according to the specification. Established specification limits assure proper safety,Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)bioavailability and efficacy of the final drug product.Telaprevir drug product is an immediate-release tablet for oral administration. Each tabletcontains 375 mg of telaprevir drug substance, with a total target weight of 1 g. The tablet iscapsule-shaped, film-coated purple and debossed with the characters “V 375” on one side. Eachtablet contains as inactive ingredients colloidal silicon dioxide, croscarmellose sodium, dibasiccalcium phosphate (anhydrous), hypromellose acetate succinate, microcrystalline cellulose,(b) (4)sodium lauryl sulfate, and sodium stearyl fumarate. In addition,contains FD&C(b) (4)Red No. 40, FD&C Blue No. 2, polyethylene glycolpolyvinyl alcohol, talc, and titaniumdioxide.(b) (4)A QbD approach was applied to the drug product manufacturing process to define the NOR andPAR for material attributes and operating parameters of each unit operating process. Excipientswere selected to provide a chemically and physically stable formulation with optimizedperformance. The applicant described in detail how some ranges were determined and how theprocess parameters were classified as critical, key, or non-critical by DoEs, process capabilityratio (Cpk), stability models, and tablet lot histories. Detailed manufacturing process descriptionand controls were provided in the master batch record.A conventional specification, which includes tests for appearance, identity, assay, impurities,(b) (4)dosage uniformity by weight variation, physical form, dissolution, and, is provided(b) (4)for the tablet. As part of the control strategy, in-process controls/checks are established, including average tablet hardness (critical), average tablet weight, and average tabletthickness. The analytical methods are reasonably well described and have been validated.(b) (4)The tablets are packaged in a 3 x 2-tableblister packs or a 168-count400 cc high-density polyethylene (HDPE) in induction sealed bottle containing a desiccant. Theblister packs are child resistant and are packaged in cartons containing a 1-week supply. Fourweekly cartons are packed in a 28-day packer. The bottle is for institutional use and is notrequired to be child resistant. The bottle contains a 28-day supply for a single patient. Up to 24months of stability data obtained at 25 C/60% RH are provided and a shelf life of 24 months isproposed for the tablets.(b) (4)Telaprevir drug substance,, and drug product are manufactured in anumber of facilities around the world. An Establishment Evaluation Request was submitted andan Overall Recommendation of Acceptable has been made.B. Description of How the Drug Product is Intended to be UsedReference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment SectionINCIVEK is a HCV NS3-4A protease inhibitor indicated, in combination with peginterferon alfaand ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients withcompensated liver disease, including cirrhosis, who are treatment naïve or who have beenpreviously treated, including prior null responders, partial responders, and relapsers.Telaprevir tablets must not be administered as monotherapy and must only be prescribed withboth peginterferon alfa and ribavirin. The recommended dose of INCIVEK tablets is 750 mg(two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food. The total daily doseis 6 tablets (2250 mg).C. Basis for Approvability or Not-Approval RecommendationThe applicant has provided sufficient information on raw material controls, manufacturingprocesses and process controls, and adequate specifications for assuring consistent product(b) (4)quality of the drug substance,, and drug product. The NDA also hasprovided sufficient stability information on the drug product to assure strength, purity, andquality of the drug product during the expiration dating period.CMC recommendations for the package insert, bottle, blister and carton labels were included inthe labeling review process. Labels and labeling have now been finalized and include therequired information.Approval is recommended from the CMC perspective.3.Review Of Common Technical Document-Quality (Ctd-Q) Module 1A. Labeling & Package InsertReference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment SectionThe following is a summary of the labeling review, and includes comments discussed aspart of the multidisciplinary labeling review.1(b) (4)7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediatelyfollowing this pageReference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment SectionProprietary name, established name (font size,prominence)Dosage strengthNet quantity of dosage form“Rx only” displayed prominently on the main panelLot number and expiration dateStorage conditionsBar code (21CFR 201.25)NDC number (21 CFR 207.35(b)(3)(i))(Appearprominently in the top third of the principal displaypanel or it may appear as part of and contiguous toany bar-code symbol)Manufacturer/distributor's nameQuantitative ingredient information (injectables)Statement of being sterile (if applicable)“See package insert for dosage information”Special instructions (“Keep out of reach ofchildren” is required for OTC in CFR. Optional forRx drugs)Refer to DMEPA review.375 edNANAincludedincludedEvaluation: The container and carton labels are acceptable from a CMC perspective.4.EES ReportEES Report as of 5/19/11.Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)BEST AVAILABLE COPY(b) (4)Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)(b) (4)(b) (4)BEST AVAILABLE COPY(b) (4)Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)Reference ID: 2949959

CHEMISTRY REVIEW TEMPLATEChemistry Assessment Section(b) (4)(b) (4)(b) (4)5. SignaturesReviewers’ SignaturesChristopher Hough, Ph.D. {Signed Electronically in DFS}Bogdan Kurtyka, Ph.D. {Signed Electronically in DFS}George Lunn, Ph.D. {Signed Electronically in DFS}Lin Qi, Ph.D. {Signed Electronically in DFS}Endorsement BlockCMC-Lead:Stephen P. Miller, Ph.D. {Signed Electronically in DFS}CC BlockProject Managers:Reference ID: 2949959Don Henry; Myung-Joo P. Hong

----This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the ----------------------------GEORGE LUNN05/20/2011Compliance has provided an overall recommendation of Acceptable and so this application is nowrecommended for approval from the CMC point of view.LIN QI05/20/2011BOGDAN KURTYKA05/20/2011STEPHEN P MILLER05/20/2011I concur - this NDA is recommended for approval from the CMC perspectiveReference ID: 2949959

CHEMISTRY REVIEWNDA 201-917INCIVEK (telaprevir) TabletsVertex Pharmaceuticals, Inc.Christopher Hough, Ph.D.Bogdan Kurtyka, Ph.D.George Lunn, Ph.D.Lin Qi, Ph.D.Division of Anti-Viral ProductsReference ID: 2938185

CHEMISTRY REVIEWTable of ContentsTable of Contents .2Chemistry Review Data Sheet.4The Executive Summary .9I. Recommendations .9A. Recommendation and Conclusion on Approvability . 9B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or RiskManagement Steps, if Approvable. 9II. Summary of Chemistry Assessments.9A. Description of the Drug Product(s) and Drug Substance(s) . 9B. Description of How the Drug Product is Intended to be Used. 11C. Basis for Approvability or Not-Approval Recommendation. 11III. Administrative.12A. Reviewer’s Signature. 12B. Endorsement Block. 12C. CC Block . 12Chemistry Assessment .13I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of 7P.8P(b) (4)DRUG SUBSTANCE [Telaprevir,] .

and controls were provided in the master batch record. A conventional specification, which includes tests for appearance, identity, assay, impurities, dosage uniformity by weight variation, physical form, dissolution, and , is provided for the tablet. As part of the control