is lit ?2 Hetlioz (tasimelteon) Capsules NDA 205677 Summary Basis for Recommended Action from Chemistry, Manufacturing, and Controls Applicant: Vanda Pharmaceuticals 2200 Pennsylvania Avenue NW Suite 300E Washington, D.C. 20037 Indication: For the treatment of non 24-hour disorder in totally blind subjects. Presentation: The product will be available as a single 20 mg strength capsules. The capsules are size 1, dark blue, hard gelatin capsules printed with “VANDA 20 mg” in white. The capsules are packaged in 60cc HDPE bottles with (b) (4) each bottle containing 30 capsules, EER Status: Overall recommendation is “Acceptable” as of 11-Dec-2013. Consults: ONDQA Biopharmaceutics – Acceptable (Dr. Kareen Riviere’s review dated 10/30/2013). Microbiology- Acceptable (Bryan S. Riley, 6-Jun-2013) Methods Validation – Requested on 16-Dec-13. The NDA may be approved prior to completion of methods validation by DPA. EA – Categorical exclusion granted. Post-Approval Agreements: None 1 Reference ID: 3425101 Drug Substance: The drug substance, tasimelteon, is a new molecular entity. The drug substance is a white to off-white M4) with molecular weight of 245.32. The molecule has two chiral centers and 1R,2R-isomer is being developed for this NDA. The drug substance is non-hygroscopic. The drug substance can potentially exist in (m4) The drug substance is manufactru?ed by (W) The involves The drug substance quality is ensured through in-process controls throughout the manufactru?ing process and the appropriate ?nal drug substance speci?cation. The drug substance acceptance speci?cation includes tests and acceptance criteria for drug substance critical quality attributes, e. appearance, identi?cation, assay, impurities, chiral pru'ity, particle size distribution, residual solvents, heavy metals, microbial limits, (mm The analytical procedures have been adequately described and validated to control the quality of the drug substance. The stability of the drug substance has been demonstrated through appropriate stability studies to support a retest period of (hm) Drug product: Hetlioz (tasimelteon) capsules are an immediate release product to be marketed in single 20-mg strength. The drug product formulation uses standard compendial excipients, e. lactose, cellulose, colloidal silicon dioxide, crosscar?mellose sodium, and magnesium stearate. The manufactru?ing process includes (no) The manufactluing process has appropriate in-process controls to ensru?e the quality of the drug product. The product quality is further ensru?ed through end product testing. The end product speci?cation includes testing for appearance, identi?cation (by UV and HPLC), assay, content uniformity, related substances, dissolution, disintegration, (m4) and microbial limits tests. All analytical procedures for the drug product are adequately described and validated. The provided stability data support the proposed 30-month expiration period for this product. The product is labeled to be protected from exposru?e to light and moistru'e. The drug product is stored at with excursions permitted Conclusion: Adequate from CMC perspective. Additional Items: All associated Drug Master Files are acceptable or the pertinent information has been adequately provided in the application. Reference ID: 3425101 Overall Conclusion: The application is recommended for “Approval” from CMC perspective. Ramesh K. Sood, Ph.D. Acting Director, DPA I/ONDQA 3 Reference ID: 3425101 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAMESH K SOOD 12/19/2013 Reference ID: 3425101 CHENIISTRY REVIEW NDA 205677 Review #1 Addendum HetliozTM (tasimelteon) Capsules, 20 mg Applicant: Vanda Pharmaceuticals Inc. Wendy I. Wilson-Lee, I/Branch I Quality (CMC) Review For Division of Neurology Products (DNP) Reference ID: 3417349 CHENIISTRY REVIEW hemistly Review Data Sheet NDA 205677 Chemistry Review Data Sheet 1. 205677 2. REVIEW Addendum 3. REVIEW DATE: 12-4-2013 4. REVIEWER: Wendy I. Wilson-Lee, 5. PREVIOUS DOCUMENTS: Previous Documents Document Date N205677 Initial NDA 05/3 1/ 13 N205677 Amendment 0001 (2) 06/18/13 N205677 Amendment 0002 (3) 07/1/13 N205677 Amendment 0003 (4) 07/3/13 N205677 Amendment 0007 (11) 08/20/13 N205677 Amendment 0019 (22) 10/9/13 N205677 Amendment 0020 (23) 10/10/13 N205677 Amendment 0023 (26) 10/25/ 13 N205677 Amendment 0024 (27) 10/28/ 13 N205677 Amendment 0027 (30) 10/30/ 13 N205677 Amendment 0029 (32) 11/12/13 Product Quality Review #1 (R. Kambhampati) 11/ 12/ 13 6. BEING REVIEWED: Submissions Reviewed (Global Submit) Global Submit Date N205677 Amendment 0030 (33) 11/22/13 7. NANIE ADDRESS OF APPLICANT: Name: Vanda Pharmaceuticals Inc. 2200 Ave NW Address: Suite 300E Washington. DC. 20037 Representative: Telephone: 202-734-3400 Page 2 of 12 Reference ID: 3417349 CHENIISTRY REVIEW Chemistry Review Data Sheet NDA 205677 8. DRUG PRODUCT TYPE: 21) Proprietary Name: HetliozTM Capsules b) Non-Proprietary Name (U SAN and INN): Tasimelteon Capsules c) Code Name/# (company): (Vanda); BMS-214778 09(4); and 00(4) (1) Chem. Type/ Submission Priority (ONDC only): 0 Chem. Type: 1 0 Submission Priority: 9. LEGAL BASIS FOR SUBMISSION: NDA (CDA, 21 CFR 314.50), 505 10. PHARMACOL. CATEGORY: Circadian regulator 11. DOSAGE FORM: Capsules 12. 20 mg of tasimelteon/capsule 13. ROUTE OF ADMINISTRATION: Oral 14. DISPENSED: 15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM): SPOTS product Form Completed Not a SPOTS product 16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT: (1R, m{ 0 C15H19N02 245.32 17. SUPPORTING DOCUMENTS: M. DMFs: Page 3 of 12 Reference ID: 3417349 CI-IENIISTRY REVIEW hemistly Review Data Sheet NDA 205677 DNIF ITEM 1 . 2 REVIEW .- TYPE HOLDER REFEREN CED CODE STATLS COMPLETED 111 (um Adequate 9/ 10/12 111 Adequate 10/25/ 12 12/20/10 Adequate HI Adequate 4/ 17/12 lAction 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 Suf?cient information in application 5 Authority to reference not granted 6 DMF not available 7 Other (explain under ?Comments") 2 Adequate. Inadequate. or (There is enough data in the application. therefore the DMF did not need to be reviewed) B. Other Documents: DOCUMENT APPLICATION NUNIBER DESCRIPTION IND 54776 Tasimelteon capsules (Vanda Phannaceuticals Inc.) 18. STATUS: CMC RELATED REVIEWS RECOMMENDATION DATE REVIEWER EES Pending 12/03/13 OMPQ, OC ONDQA Biopharm Dissolution method 10/3 0/ 13 Kareen Riviere. acceptable. LNC (ONDQA) for Not applicable. USAN 10/31/13 Rao Kambhampati. Established Name name available. Methods Validation Pending 10/31/13 DPA. St. Louis DMEPA (Labels and Pending 10/3 1/ 13 Julie V. Neshiewat (DMEPA) Labeling) Proprietary name HetliozTM acceptable 09/ 16/ 13 Carol A. Holquist. (DMEPA) EA Acceptable 10/3 1/ 13 Rao Kambhampati. Product Quality for 6/6/ 13 Bryan S. Riley. (NDMS. OPS) Microbiology approval Page 4 of 12 Reference ID: 3417349 CHENIISTRY REVIEW Executive Summary Section NDA 205677 The Chemistry Review for NDA 205677 The Executive Summarv 1. Recommendations A. Recommendation and Conclusion on Approvability From the Chemistry, Manufacturing, and Controls (CMC) review stand point, the 205677 for HetliozTM (tasimelteon), 20 mg, capsules is recommended for approval provided all the manufactru'ing and testing facilities are acceptable to the Of?ce of Compliance (DC) with an Overall Acceptable Recommendation is issued by the 0C and pending fmal labeling. B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable Not applicable. II. Summary of Chemistry Assessments A. Description of the Drug Product(s) and Drug Substance(s) Drug Substance: Tasirnelteon is the established name for the drug substance. It has a molecular formula of C15H19N02 and molecular weight of 245.32. It has two chiral centers and the applicant chose to develop the trans-lR,2R-isomer. It is a non-hygroscopic, white to off-white powder and has a melting range of It can exist as GM) It is soluble in water (W) and 0.1N-HC1 and freely soluble in isopropanol, PEG 300, and propylene glycol. It exhibits a pH of 8.5 (hm at 0W). It has a partition coef?cient (Po/w) of 2.43 (log P). It is manufactured by (m4) . . 4 The of drug substance rs (hm ?no (N) All the intermediates were clearly identi?ed and speci?cations and batch analysis information were provided for the isolated ones. Some of the acceptance criteria for the intermediates were tightened upon comment. Similarly, the . . . 4 specr?catrons were provrde for the M) drug substance and some of their acceptance criteria were tightened upon comment. Critical process parameters for - 4 Intermediates W4) were provided. The proof-of structlu?e of the drug substance is based on a combination of the spectroscopic data, physic-chemical characteristics, and (mo analysis. All the potential impru?ities arising ??om residual materials and intermediates were identi?ed. In-process control test methods, release methods, and validation reports were provided. All the potential by- products and degradation products were identi?ed. The speci?cation for drug substance included appearance, identi?cation (FTIR, speci?c rotation, chiral HPLC), mp, residue on ignition, heavy metals, elemental impurities, (m4) assay, plu?ity, chiral Page 5 of 12 Reference ID: 3417349 CHENIISTRY REVIEW Executive Summary Section NDA 205677 (4) (4) plu?ity, related substances which were divided into known implu?ities unspeci?ed impm?ities Total implu?ities, residual solvents, (m4) DMF, (m4) and W4) and other tests included (W) particle size, and microbial limits. On the basis of the batch release and stability data, some of the acceptance criteria for the (m4) drug substance were tightened upon comment. All the non-compendial methods were described and method validation reports were provided. Batch analysis information were provided for the batches manufactured at the proposed (m4) facility as well as the previously used W4) and EMS facilities. The drug substance is stored in M4) Stability data were provided for six and fom' ding substance lots that were stored in (W) commercial containers. For foru? W4) lots, the stability data included up to 9 months storage lmder long-term and refrigerated storage conditions and 6 months storage under accelerated conditions. For the six M4) lots, the data included 11p to 18 months storage under long-term conditions and 6 months lmder accelerated conditions. It was demonstrated that the drug substance was stable under these conditions. The requested shelf-life GM) for the 4 . W4) ding substance M) 18 acceptable. (4) Drug Product: The proposed commercial ding product formulation for tasimelteon is Size 1, dark blue opaque, hard gelatin capsules printed with 20 mg? in white, containing 20 mg of tasimelteon per capsule. The components and composition of the each capsule (W) include tasimelteon diug substance as the active pharmaceutical ingredient (20 mg) and the following excipients: lactose (m4) cellulose (hm colloidal silicon (4) (4) dioxide croscarmellose sodium magnesilun stearate (W) The (W) capsule wt is approximately aw) Thirty capsules are packaged in 60-cc white HDPE bottles W4) and then sealed W4) and closed with a (mo closure. All excipients of the capsule (hm provided. The drug product is manufactured and packaged by batch formula for capsules was provided. The manufactlu?ing process involves are of compendial grade. A detailed formulation development report was 09(4) A (4) (4) The ?nal blend is (W) size 1, dark blue opaque, hard gelatin capsules printed with 20 mg? in white. The (W) capsules are packaged into 60-cc high density polyethylene (HDPE) bottles (30-cormt) (m4) caps containing induction seals. Each bottle also contains a (ma) It was demonstrated that the product capsules can be manufactlu?ed with consistent quality and purity. Adequate in-process controls are in place. The speci?cation for drug product capsules included appearance, identi?cation (by UV and HPLC), assay, content 1miformity, related substances (W) dissolution, disintegration, (W) and microbial limits tests. On the basis of lot release and stability data, upon comment, the applicant tightened some of the acceptance criteria. All non-compendial test methods were described and their method validation reports were provided. Batch analysis results were provided for three NDA registration batches, which demonstrated consistent quality and plu?ity. Page 6 of 12 Reference ID: 3417349 CHENIISTRY REVIEW Executive Surmnary Section NDA 205677 The stability data included for three registration batches and three supportive batches. 18 Months of long?term and 6 months of accelerated data were provided for primary batches and 30 months of long-term and 6 months of accelerated data were provided for supportive batches. On the basis of the real time data and statistical analysis, the requested expiration dating period of 30 months when stored at controlled room temperature, is acceptable. C. Description of How the Drug Product is Intended to be Used Hetlioz is a circadian regulator of the master body clock indicated for the treatment of Non-24- Hour Disorder in the totally blind subjects. The recommended dose of Hetlioz is 20 mg per day taken one hour prior to bedtime, preferably at the same time every night. Each bottle of HetliozTM (tasimelteon) contains 30 capsules. Therefore, a 30 cormt bottle will provide a month supply to the patient. Hetlioz 20 mg capsules are available as size 1, dark blue opaque, hard gelatin capsules printed with 20 mg? in white, containing 20 mg of tasimelteon per capsule, in the following quantities: NDC 43068-220-01 Bottles of 30 The recommended storage conditions are: Store Hetlioz 20 mg capsules at controlled room temperatru'e, excursions permitted to 15? - (59? - [See USP Controlled Room Temperature]. Protect Hetlioz 20 mg capsules from exposm?e to light and moisture. D. Basis for Approvability or Not-Approval Recommendation The applicant provided adequate chemistry, manufacturing, and controls (C MC) information for the (hug substance and diug product. The applicant satisfactorily addressed all the de?ciencies that were communicated dining the review. The established name, tasimelteon, is USAN name and it is acceptable. The tradename, HetliozTM is acceptable to DMEPA. The manufactluing process is acceptable from product microbiology reviewer stand point and a review was ?led in DARRTS. The chemistry related portion of the package insert and medication guide and the proposed container and carton labels contain all the required CMC information. All the facilities (m4) are acceptable, therefore, the NDA is recommended for approval provided all the facilities are found to be acceptable by the Of?ce of Compliance and pending ?nal labeling. Administrative A. Reviewer?s Signature Wendy I. WLl/soanee/ Wendy I. Wilson-Lee, B. Endorsement Block Primary Reviewer/Date: Wendy I. Wilson-Lee, 12/3/2013 Senior I/Branch I Secondary Reviewer/Date: Olen Stephens, 12/3/2013 Acting Branch I/Branch I 5 Page(s) has been Withheld in Full as b4 immediately following this page Page 7 of 12 Reference ID: 3417349 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------WENDY I WILSON-LEE 12/04/2013 OLEN M STEPHENS 12/04/2013 Recommendation is pending OC evaluation of manufacturing facilities. Reference ID: 3417349 CHEMISTRY REVIEW NDA 205677 HetliozTM (tasimelteon) Capsules, 20 mg Applicant: Vanda Pharmaceuticals Inc. Rao V. Kambhampati, I/Branch I Quality (CMC) Review For Division of Neurology Products (DNP) Reference ID: 3405492 CHENIISTRY REVIEW hemistiy Review Data Sheet NDA 205677 Chemistry Review Data Sheet 1. 205677 2. REVIEW 1 3. REVIEW DATE: 11-12-2013 4. REVIEWER: Rao V. Kambhampati, 5. PREVIOUS DOCUMENTS: Previous Documents Document Date None 6. BEING REVIEWED: Submissions Reviewed (Global Submit) Global Submit Date N205677 Initial NDA 05/31/13 N205677 Amendment 0001 (2) 06/18/13 N205677 Amendment 0002 (3) 07/1/13 N205677 Amendment 0003 (4) 07/3/ 13 N205677 Amendment 0007 (l 1) 08/20/13 N205677 Amendment 0019 (22) 10/9/13 N205677 Amendment 0020 (23) 10/10/13 N205677 Amendment 0023 (26) 10/25/13 N205677 Amendment 0024 (27) 10/28/13 N205677 Amendment 0027 (30) 10/30/13 N205677 Amendment 0029 (32) 11/12/13 7. ADDRESS OF APPLICANT: Name: Vanda Pharmaceuticals Inc. 2200 Ave NW Address: Suite 300E Washington, DC. 20037 Representative: Telephone: 202-734-3400 Page 2 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Chemistry Review Data Sheet NDA 205677 8. DRUG PRODUCT TYPE: a) Proprietary Name: HetliozTM Capsules b) Non-Proprietary Name (U SAN and INN): Tasimelteon Capsules c) Code Name/# (company): VEC-162 (Vanda); BMS-214778 and (m4) (1) Chem. Type/Submission Priority (ONDC only): 0 Chem. Type: 1 0 Submission Priority: 9. LEGAL BASIS FOR SUBMISSION: NDA (CDA, 21 FR 314.50), 505 10. PHARMACOL. CATEGORY: Circadian regulator 11. DOSAGE FORM: Capsules 12. Y: 20 mg of tasimelteon/capsule 13. ROUTE OF ADMINISTRATION: Oral 14. DISPENSED: LRX OTC 15. SPOTS SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM SPOTS product Form Completed Not a SPOTS product 16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT: (1R, C15H19N02 245.32 17. SUPPORTING DOCUMENTS: Page 3 of 201 Reference ID: 3405492 CHEMISTRY REVIEW Chemistry Review Data Sheet NDA 205677 M. DMFs: DMF ITEM DATE TYPE HOLDER REFEREN STATUS2 REVIEW COMMENTS CED COMPLETED 3 Adequate 9/10/12 111 3 Adequate 12/20/10 Adequate 3 Adequate 4/ 7/ 2 1Action 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 Suf?cient information in application 5 Authority to reference not granted 6 DMF not available 7 Other (explain under 2 Adequate. Inadequate. or (There is enough data in the application. therefore the DMF did not need to be reviewed) B. Other Documents: DOCUMENT APPLICATION NUMBER DESCRIPTION IND 54776 Tasimelteon capsules (Vanda Pharmaceuticals Inc.) 18. STATUS: CMC RELATED RECOMMENDATION DATE REVIEWER REVIEWS EES Pending 10/31/13 OMPQ, OC Page 4 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Chemistry Review Data Sheet NDA 205677 ONDQA Biophaim Dissolution method 10/30/13 Kareen Riviere, acceptable. LNC (ONDQA) for Not applicable. USAN 10/31/13 Rao Kambhampati, Established Name name available. Methods Validation Pending 10/31/13 DPA, St. Louis DMEPA (Labels and Pending 10/31/13 Julie V. Neshiewat (DMEPA) Labeling) Proprietary name Hetlioz1M acceptable 09/16/13 Carol A. Holquist, (DNIEPA) EA Acceptable 10/ 3 1/13 Rao Kambhampati, Product Quality Recommended for 6/6/13 Bryan S. Riley, (NDMS, Microbiology approval OPS) Page 5 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Executive Summaiy Section NDA 205677 The Chemistry Review for NDA 205677 The Executive Summary 1. Recommendations A. Recommendation and Conclusion on Approvability F1om the Chennst1yManufact111ing,and ont1 ols (C MC 1eview stand point, the 205677 for HetliozTM (tasimelteon), 20 mg, capsules lS 1ecommended fo1 app10val p1 ov1ded all the manufacturing and testing facilities are acceptable to the Of?ce of Compliance (0C) and an Overall Acceptable Recommendation is issued by the OC . B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable Not applicable. II. Summary of Chemistry Assessments A. Description of the Drug Product(s) and Drug Substance(s) Substance: Tasimelteon is the established name (USAN) for the substance and it is a New Molecular Entity (NME). It has a molecular fonnula of 15H19N02 and molecular weight of 245.32. It has two chiral centers and the applicant chose to develop the trans- 1R, 2R-isomer. It is a non-hygroscopic, white to off-white c1ystalline powder and has a melting range of . It can exist as aw) It is soluble in water (m4) and 0.1N-HC1 (mo and freely soluble in isopropanol, PEG 300, and propylene glycol. It exhibits a pH of 8.5 (m4) at (mm It has a pa1tition coef?cient (Po/w) of 2.43 (log P). It is manufactlu?drug substance 18 a (W) (4) All the intennediates were clearly identi?ed and speci?cations and batch analysis infonnation were provided for the isolated ones. Some of the acceptance criteria for the intennediates were tightened upon Similarly the speci?cations we1e provided f01 the drug substance and some of their acceptance c11te11a we1e tightened upon Ciitical piocess pa1amete1s f01 Intennediates (hm (hm we1e p1 ovided. The proof-of structure of the drug substance is based on a combination of the spectroscopic data, physic-chemical (4) Page 6 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Executive Summary Section NDA 205677 characteristics, and mm analysis. All the potential impru?ities arising from residual materials and intermediates were identi?ed. In-process control test methods, release methods, and validation reports were provided. All the potential by- products and degradation products were identi?ed. The speci?cation for (W) drug substance included appearance, identi?cation (FTIR, speci?c rotation, chiral HPLC), mp, residue on ignition, heavy metals, elemental impurities, (m4) assay, purity, chiral pru?ity, related substances which were divided into known impurities W4) unspeci?ed impurities MwTotal impru?ities, (m4) residual solvents, (mo DMF, (mo and other tests included particle size, and microbial limits. On the basis of the batch release and stability data, some of the acceptance criteria for the M4) drug substance were tightened upon comment. All the non-compendial methods were described and method validation reports were provided. Batch analysis information were provided for the batches manufactured at the proposed (m4) facility as well as the previously used (m4) and EMS facilities. The drug substance is stored in (tow St b'l' - - 00(4) (5X4) a 1ty data were provrded for and four drug substance lots that were stored in (W) commercial containers. For four (W) lots, the stability data included up to 9 months storage rmder long-term and refrigerated storage conditions and 6 months storage under accelerated conditions. For the six (m4) lots, the data included up to 18 months storage under long-term conditions and 6 months under accelerated conditions. It was demonstrated that the drug substance was stable rmder these conditions. The applicant requested for a shelf-life of (M4) for the drug substance lots which is acceptable. Drug Product: The proposed commercial drug product formulation for tasimelteon is Size 1, dark blue opaque, hard gelatin capsules printed with 20 mg? in white, containing 20 mg of tasimelteon per capsule. The components and composition of the each capsule (W) include tasimelteon drug substance as the active pharmaceutical ingredient (20 mg) and the following excipients: lactose (m4) cellulose W4) colloidal silicon dioxide croscarmellose sodium magnesirun stearate The (W) capsule wt is approximately (m4) Thirty capsules are packaged in 60-cc white HDPE bottles a? (4) and then sealed M4) and closed with a GM) closru?e. All excipients of the capsule (9 are of compendial grade. A detailed formulation development report was provided. The drug product is manufactured and packaged by (I?m A batch formula for (ma) capsules was provided. The manufacturing process involves W4) The ?nal (m4) is size 1, dark blue opaque, hard gelatin capsules printed with 20 omcapsules are packaged into 60-cc high density polyethylene (4) (4) (4) mg? in white. The Page 7 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Executive Surmnary Section NDA 205677 (HDPE) bottles (30-c01mt) with ?(ocaps containing induction seals. Each bottle also contains a W0 It was demonstrated that the drug product capsules can be manufactured with consistent quality and pru?ity. Adequate in-process controls are in place. The speci?cation for drug product capsules included appearance, identi?cation (by UV and HPLC), assay, content uniformity, related substances (m4) dissolution, disintegration, and microbial limits tests. On the basis of lot release and stability data, upon comment, the applicant tightened some of the acceptance criteria. All non-compendial test methods were described and their method validation reports were provided. Batch analysis results were provided for three NDA registration batches, which demonstrated consistent quality and purity. The stability data included for three registration batches and three supportive batches. 18 Months of long-term and 6 months of accelerated data were provided for primary batches and 30 months of long- term and 6 months of accelerated data were provided for supportive batches. On the basis of the real time data and statistical analysis, the applicant requested for an expiration dating period of 30 months when stored at controlled room temperatru?e, which is acceptable. (5) (4) C. Description of How the Drug Product is Intended to be Used Hetlioz is a circadian regulator of the master body clock indicated for the treatment of Non-24-Hour Disorder in the totally blind subjects. The recommended dose of Hetlioz is 20 mg per day taken one hour prior to bedtime, preferably at the same time every night. Each bottle of HetliozTM (tasimelteon) contains 30 capsules. Therefore, a 30 cormt bottle will provide a month supply to the patient. Hetlioz 20 mg capsules are available as size 1, dark blue opaque, hard gelatin capsules printed with 20 mg? in white, containing 20 mg of tasimelteon per capsule, in the following quantities: NDC 43068-220-01 Bottles of 30 The recommended storage conditions are as follows: Store Hetlioz 20 mg capsules at controlled room temperature, excursions permitted to 15? - (59? - [See USP Controlled Room Temperature]. Protect Hetlioz 20 mg capsules from exposure to light and moisture. D. Basis for Approvability or Not-Approval Recommendation The applicant provided adequate chemistry, manufacturing, and controls (C MC information for the drug substance and diug product. The applicant satisfactorily addressed all the de?ciencies that were commrmicated during the review. The established name, tasimelteon, is USAN name and it is acceptable. The tradename, HetliozTM is acceptable to DMEPA. The manufacturing process is acceptable ?'om product microbiology reviewer stand point and a review was ?led in DARRTS. The chemistry related portion of the package insert and medication guide and the proposed container and carton labels contain all the required MC information. All the facilities (m4) are acceptable, therefore, Page 8 of 201 Reference ID: 3405492 CHENIISTRY REVIEW Executive Suimnary Section NDA 205677 the NDA is recommended for approval provided all the facilities are formd to be acceptable by the Of?ce of Compliance. Administrative A. Reviewer?s Signature Rao V. Kambhampati, B. Endorsement Block Primary Reviewer/Date: Rao V. Kambhampati, 1 1/ 12/ 13 Senior I/Branch I Secondary Reviewer/Date: Olen Stephens, 11/12/13 Acting Branch I/Branch I 192 Page(s) has been Withheld in Full as b4 immediately following this page Page 9 of 201 Reference ID: 3405492 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAO V KAMBHAMPATI 11/12/2013 OLEN M STEPHENS 11/12/2013 Reference ID: 3405492 NEW DRUG APPLICATION OMPO REVIEW Initial Manufacturing (CGMP/Facilities) Assessment (IMA) and Filing Review for Pre- Marketing Applications (Original) I. Review Cover Sheet 11. Application Detail Filing Checklist IV. Manufactming Surmnaiy V. Overall Conclusions and Recommendations I. Review Cover Sheet 1. OMPQ Reviewer: Christina apacci-Daniel 2. Number: NDA 205677 Submission Date: 31-May-2013 21St C. Review Goal Date: 30-Nov-2013 PDUFA Goal Date: 3 l-J an-2014 3. PRODUCT PROPERTIES: Trade or Proprietary Name: Hetlioz Established or Non-Proprietary Name (USAN) and strength: Tasimelteon, 20mg Dosage Form: Hard gelatin capsule 4. SUBMISSION PROPERTIES: Review Priority PRIORITY (orphan indication) Applicant Name: Vanda Pharmaceuticals, Inc. Responsible Organization (0ND Division): DNP Sedatives and Hypnotics Reference ID: 3341257 Page 1 of 8 OMPQ Initial Manufacturing (C acilities) Assessment and Filing Review For Pre-Marking Applications II. Application Detail 1. INDICATION: Treatment of Non-24?hom? disorder in the totally blind. 2. ROUTE OF ADMINISTRATION: Oral 3. Y: 20mg 4. DISPENSED: [2le Elorc 5. ELECTRONIC SUBMISSION (yes/no)? Yes 6. PRIORITY CONSIDERATIONS: Parameter Yes No Unk Comment 1. NME PDUFA El Breakthrough Therapy 2. . . I21 Desrgnatron 3. Orphan Drug Priority review Desrgnatron 4. Unapproved New Drug El NCE 5 Medically Necessary l2! Determination Potential Shortage 6 Issues [either alleviating El or non-approval may cause a shortage] 7. Rolling Submission El Drug/ device 8. combination product with consult 9. Complex manufactrn'ing 10 Other expedited l2! for an rmlisted reason) 11 At this time, is a KTM DP manufacturer: OMPQ reviewer to accompany DP warranted for any PAI *If a priority consideration is indicated, please forward to NDMAB BC and TL and do not process associated EERs. Reference ID: 3341257 Page 2 of 8 OMPQ Initial Manufacturing (C acilities) Assessment and Filing Review For Pie-Marking Applications FILING CHECKLIST The following parameters are necessary in order to initiate a full review the application is complete enough to start review but may have de?ciencies). On initial review of the NDA application: A. COMPLETENESS OF FACILITY INFORMATION Parameter Yes No Comment 12. Is a single comprehensive list of all involved facilities available in one location in the application? 13. Is all site information complete contact information, responsibilities, address)? 14. For testing labs, is complete information provided regarding which speci?c test is performed at each facility and what stage of manufacturing? -stability testing not explicitly stated 15. Do all sites indicate they are ready to be inspected (on 356h)? 16. Additional notes (non-?ling issue) 1. Are all sites registered or have FEI 2. Do in EES indicate a request to participate on inspection(s)? 3. Is this ?rst application by the applicant? - (CTL) has no irrspectiorral history -Remainirrg 4 BER facilities have good inspection history -EES comment commrmication with ORA to participate in DP manufactruirrg site PAI *If any information regarding the facilities is missing/omitted, commruricate to Reference ID: 3341257 regarding missing information and copy EESQ. Notify OMPQ management if problems are not resolved within 3 days and it can be a potential ?ling issue. Page 3 of 8 OMPQ Initial Manufactm?ing (C acilities) Assessment and Filing Review For Pie-Marking Applications B. DRUG PHARMACEUTICAL INGREDIENT Parameter Yes No Comment 17. Is the drug substance process or analytics considerably complex? (If 50. comment) IZI (See Part IV) C. DRUG PRODUCT (DP) Parameter Yes No Comment 18. Is the DP production (formulation. processing. ?nishing. ?lling. labeling and packaging. etc) or analytics considerably complex? (See Part IV) l9. Have any Comparability Protocols been requested? IMA CONCLUSION Parameter Yes No Comment 20. Does this application ?t one of the EES Product Speci?c Categories? NME. First FDA Evaluation for one establishment 21. Have EERs been cross referenced against the 35611 and product speci?c pro?le for accru?acy and completion? Have all EERs been updated with fmal PAI 22. From a CGMP/faeilities perspective, is the application ?leable? If the NDA is not ?leable from a product quality perspective. state the reasons and provide ?ling comments to be sent to the Applicant. All sites listed as ready for inspection. Reference ID: 3341257 Page 4 of 8 OMPQ Initial Manufactm?ing (C acilities) Assessment and Filing Review For Pie-Marking Applications IV. Manufacturing Summary: Critical Issues and Complexities Does the submission contain any of the following elements? Nanotechnology RTRT Proposal PET Design Space Other (explain): Manufacturing Highlights 1. Drug Substance Drug/Device Combo Continuous Natlu?ally derived API Parameter Yes Is manufacturing process considered complex imusual 1n1it operations, innovative manufactm'ing technology, 1musual control strategy)? 2. Drug Product Comment (hm) Parameter Yes No Comment I Is manufactm'ing process considered complex 1musual unit operations, iimovative manufactin?ing technology, unusual control strategy)? (4) -Content unifonnity sampling plan -Unique capsule quality sample plan and reject limits Reference ID: 3341257 Page 5 of 8 OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review For Pre-Marking Applications 3. Facility-Related Risks or Complexities (e.g., number of foreign sites, large number of sites involved, etc.) None (b) (4) Page 6 of 8 Reference ID: 3341257 OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review For Pre-Marking Applications (b) (4) Page 7 of 8 Reference ID: 3341257 OMPQ Initial Manufacturing (C acilities) Assessment and Filing Review For Pie-Marking Applications V. Overall Conclusions and Recommendations Is the application filable? (yes/no) YES Are there comments/issues to be included in the 74 day letter, including appropriate identification of facilities? (yes/no) NO for 74 Day Letter 1. 2. 3. REVIEW AND APPROVAL Mahesh Ramanadham 6/26/2013 Don Hemy 7/10/2013 ln?istina apacci-Daniel 7/1 1/2013 Page 8 of 8 Reference ID: 3341257 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CHRISTINA A CAPACCI-DANIEL 07/15/2013 Corrected version DON L HENRY 07/15/2013 Reference ID: 3341257 Initial Quality Assessment Branch I Division of New Drug Quality Assessment I OND Division: NDA: Applicant: Stamp Date: PDUFA Date: Trademark: Established Name: Dosage Form: Route of Administration: Indication: Division of Neurology Products 205677 Vanda Pharmaceuticals, Inc 31-May-2013 31-Jan-2014 Hetlioz is proposed Tasimelteon Capsules Oral Treatment of non-24 hour disorder (circadian rhythm sleep disorder) in the totally blind CMC Lead: Martha R. Heimann, Ph.D. Yes No ONDQA Fileability: Comments for 74-Day Letter: Note: NME, in Program, orphan indication Summary and Critical Issues: Summary Tasimelteon (VEC-162) is an orally acting dual melatonin receptor agonist with selective agonist with selective agonist activity at the MT1 and MT2 receptors. It was originally developed by Bristol-Myers-Squibb, under IND 54776, as BMS-214778. The original indication at the time the IND was submitted was for treatment of primary insomnia. Vanda Pharmaceuticals (Vanda) subsequently acquired the rights to the compound and has investigated its use for a number of circadian rhythm related sleep disorders. This NDA provides for an immediate release capsule formulation containing 20 mg of tasimelteon. The product is intended to be used for the treatment of non-24-hour disorder in the totally blind. The recommended dose is 20 mg per day taken one hour prior to bedtime, preferably at the same time every night. During development, Vanda sought CMC input via an end of Phase 2 CMC-meeting scheduled for October 11, 2007. The firm cancelled the meeting after receiving preliminary comments. Note that FDA did not agree with the firm’s proposals. However, the issues raised are no longer relevant due to subsequent manufacturing changes. A CMC-only pre-NDA meeting was held on October 23, 2012. Key CMC issues were designation of drug substance starting materials (agreed), issues related to agglomeration of the Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 2 drug substance on storage, and limited stability data for substance batches. The ?rm Ins extemive data for tasirmlteon but limited data for batches. FDA and ?1e ?rm agreed tint limited data for the - batches would not be a ?ling issue; retest period will be determined based on review of the provided data. DAM The active ingredient, tasinelteon [chemical mme: is a neutral small molecule with molecular formila C15H19N02 and molecular weight 245.32. The chemical structure of tasimelteon is: dva/??k/ Tasimelteon is sli The drug substance is nam?actured by 3.2.8.2.6-1 on the follow' The proposed commercial batch scale is intended to tasimelteon. The material will be stored and Reference ID: 3334036 NDA 205677 Initial Quality Assessment 0 Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 4 The following points are noted wi?1 regard to drug substance namrfacture: 0 Dining development, the nmmfacturing process has undergone several iterations since the ori 1ND rocess. This includes to the Imnufacturer and Imrmfacturing site Thus, the linkage between pivotal nonclinical and clinical batches and the proposed commercial material should be evaluated carefully. The conmercial tasirmlteon manufacturing process involves rocess. The tasimelteon drug 0 has limited experience with ?le namrfacturin applicant indicates that to date, ?ve batches respectively. The proposed drug substance speci?cation is included in l. The speci?cation includes appropriate tests (identi otenc chiral purity, inorganic inpun'ties, organic inpurities, residual solvents, particle size, etc) and the analytical procedures appear straightforward. The following concerns are noted: The applicant proposes that a mnnber of tests only be performed on- tasimelteon. The acceptability of this approach for parameters such as residual solvents is considered a utter for review. The applicant should be asked to acknowledge that the drug substance should, if tested, conply with all requirements. The a licant proposes that 111me contro as . Giventhe potential for genotoxicity, reliance on an indirect control strategy may not be appropriate. The drug substance prirmry stability package includes long-term R. H.) and accelerated H. data thro six mon?s for three drug substance batches manufactured according to the proposed commercial Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 5 process. Available data for a fourth batches are limited to 3 months long-term and accelerated data. Batch scales for the primary stability batches range from Additional supportive data (up to 36 or 48 months long-term) are provided for batches nmnufactured by EMS and (mo As communicated to ?le ?rm during the CMC pre-NDA meeting, data for tasimelteon batches manufactured by GM) are also considered as supportive only. (It) (4) (4) (4) The applicant proposes a retest date for both tasimelteon and for the drug substance. The retest date for (hm tasimelteon is supported by real time data. The adequacy of ?le data to support a om) retest date for the one drug substance is a review issue. Drug Product The proposed dosage form is an immediate release capsule containing 20 mg of tasimelteon and commonly used excipients. The unit composition is given in the applicant?s Table 3.2.P.1-1 below. Tasimelteon Capsules will be marketed in 30-c01n1t HDPE bottles. The applicant doe not propose distribution of physician samples. Table 3.2.P.l-l: Unit Formula for Tasimelteon 20-m2 Capsules Component Function Quantitative composition weight per capsule (mg) Tasimelteon drug substance Active 2000' ingredient 4} Lactose cellulose Colloidal silicon dioxide (?roscannellose sodium (4) Magneswm stearate (4) Size 1. dark blue opaque. hard gelatin capsules Gelatin capsule" (4) printed with 20 mg? in white' Total capsule weight for site 1 NA 376.00 Weight is adjusted for "n assay of drug substance. (?apsules used for stability and clinical batches were printed with (?but validation and commercial batches will have .20 mg" printed in white. Gelatin capsule consists of gelatin. titanium dioxide. Blue Red and Yellow #6 (5) (4) Tasimelteon Capsules willbe manufactured by a contract manufacturer, (W) The manufacturing process involves (hm) om "?""which are then packaged in 30-HDPE bottles with (hm-caps containing induction seals, M0 Reasonably detailed process narratives and ?ow (It) (4) diagram are provided. The proposed scale is Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 6 The proposed master batch record is not provided; this (or additional process details) my be requested if the reviewer determines that the information provided is insuf?cient. Executed batch records are provided for the registration stability/ clinical batches. The application includes limited information on phanmceutical development. Capsule ranging ??om 1 mg to 100 mg were used in clinical studies performed by EMS (1 111g, 10 mg and 50 mg) and Vanda (100 mg). With the exception of the 5.667 mg capsule, both companies clinical capsules am (I?m . The composition for the 20 mg Vanda clinical/conmiercial capsule is ?no to that of the 10 mg clinical capsule originally developed by EMS. A very brief summary of the original BMS clinical formulation and manufacturing process is included, supporting data are not provided. Formulation development performed by Vanda and M4) appears limited to adjustment of clinical capsule formulations (m4) Similarly the only signi?cant changes ?om the originalm BMS manufacturing process to the proposed commercial process are (4) (mo It is not clear that would be consistent with the requirement that ?The batch shall be formulated with the intent to provide not less than I 00 percent of the labeled or established amount of active ingredient. [21 It is recommended that this be determined dru?ing the review in consultation with the Of?ce of Compliance. The proposed speci?cation for Tasimelteon Tablets is included in Attachment 2. Test parameters and analytical procedures are straightforward and typical for a solid oral dosage form The I-IPLC method for assay and impurities appears to be essentially the same as for the diug substance. Speci?ed known and unspeci?ed impru?ities are controlled at the ICH quali?cation and identi?cation thresholds, respectively, based on the proposed 20 111g daily dose. The NDA primary stability package includes long-term data 60% R. H.) through 12 months and accelerated data 75% R. H.) through 6 months for three batches of Tasimelteon Tablets 20 mg. The primary stability batches were manufactured by commercial scale using commercial process drug substance batches manufactured by The post-approval commitment provides for placement of the ?rst three batches, and subsequent annual batches, on long-term stability. A 0W) expiration dating period is proposed based on the applicant?s statistical analyses (assay, impurities, disintegration, dissolution and M0 Based on a preliminary assessment of the provided statistical output for assay and impurities, extrapolation ?'om 12 to 24 months may not be allowable. (4) at (4) Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 7 Critical issues for review Drug Substance As noted above, the commercial manufacturer has limited experience with the process. GM) has only manufactured ?ve batches W4) of 0am) tasimelteon, with two of these requiring M0 to conform to speci?cation The tendency of the M0 drug substance to (we) The applicant?s attributes the lack of ?win stability samples to the (mo. If so, results ?'om studies performed (hm may not provide suf?cient assurance of quality. Drug Product The most critical issue regarding the drug product is whether the manufacturing process is robust enough mm of the active ingredient without compromising the quality of the resulting Additional issues Environmental Assessment: The ?rm has submitted a claim for categorical exclusion under 21 CFR 25.3 1(b) which states that the estimated concentration of the active moiety at the point of entry into the aquatic environment will be below one part per billion(1 ppb). EstablishmentEvaluation: A full list of facilities involved inthe nmnufacture, packaging and testing of tasimelteon and Tasimelteon Tablets is provided in the submission. All facilities have been submitted in EES. Labeling/Established Name: The active ingredient, tasimelteon, is not a salt. Therefore there are no issues of consistency between the established name ?tasimelteon capsules? and the labeled potency. Methods Validation: The drug substance is a new molecular entity; therefore, methods validation studies by the DPA St. Louis laboratory willbe requested Given the number of possible impurities resulting ?'om the process, it is recommended that the drug substance assay and related substances methods be validated. Comments for 74-Day Letter The following comments are suggested for inclusion in the 74-Day letter, pending any additions or revisions by the reviewer. With respect to the drug substance: Based on our initial evaluation of the information provided in the application, it is imclear whether you have adequate lmderstanding and control of the manufacturing process. We note that two of the ?ve batches of (I'm tasimelteon manufactured by 09(4) to Reference ID: 3334036 NDA 205677 Initial Quality Assessment Page 8 date have required in order to conform to eci?cation. Of these, batch Clarify whether ?Jis batch was tested for residual metals per tasimelteon (Table prior to release for You indicate that musimelteon is observed after long-term storage in- but not in es. Thus, we are concerned that results from studies performed using would not indicative of the e?ecm of the storage and shipping conditiom on drug substance . Provide any available data obtained from drug substance stored or shipped With resmct to the dLug product: The ro sed manufacturin rocess for Tasimelteon Ca sules rovides for the speci?cation for Review, Comments and Recommendation: The NDA is ?leable from a CMC perspective. The drug substance is a well-characterized s-ll molecule and the drug product is a simple immdiate release capsule. The application does not present approaches or use of in- process analytical technologies. Assignment of a CMC reviewerand a Biopharrmceutics reviewer is recommended. The submission has been evaluated by the New Drug Microbiology Sta?l Per the Micro Filing Review (Brian Riley, 06-Jun-2013) the microbiological controls are acceptable and further is not required. A Division-level regulatory brie?ng is appropriate for a new molecular entity and standard solid oral dosage form {See aggena?ed electronic signature gage} Martha R. CMC Lead, ONDQA {See appended electronic signature gage} Ramesh Sood, Branch Chief, ONDQA Reference ID: 3334036 CHEMICAL MANUFACTURING CONTROLS FILING CHECKLIST FOR A NEW NDA/BLA NDA Number: 205677 Applicant: Vanda Pharmaceuticals Supplement Number and Type: N/A Letter Date: 30-May-2013 Established/Proper Name: Tasimelteon Capsules Stamp Date: 31-May-2013 The following parameters are necessary in order to initiate a full review, i.e., complete enough to review but may have deficiencies. On initial overview of the NDA application for filing: 1. 2. 3. 4. 5. 6. 7. Parameter Is the CMC section organized adequately? Is the CMC section indexed and paginated (including all PDF files) adequately? Are all the pages in the CMC section legible? Has all information requested during the IND phase, and at the pre-NDA meetings been included? Parameter Is a single, comprehensive list of all involved facilities available in one location in the application? 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? This question is not applicable for synthesized API. 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) Reference ID: 3334036 Yes A. GENERAL No Comment X X X X B. FACILITIES* Yes No X 356h N/A X Comment NDA 205677 Filing Checklist, Page 2 Are drug product 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 8. X 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) Are additional manufacturing, packaging and control/testing laboratory 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 9. X 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) Is a statement provided that all facilities 10. are ready for GMP inspection at the time X of submission? * If any information regarding the facilities is omitted, this should be addressed ASAP with the applicant and can be a potential filing issue or a potential review issue. 11. C. ENVIRONMENTAL ASSESSMENT Parameter Yes No Comment Has an environmental assessment report X Categorical exclusion claimed. or categorical exclusion been provided? Reference ID: 3334036 NDA 205677 Filing Checklist, Page 3 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API) Parameter Yes No Comment Does the section contain a description of X the DS manufacturing process? Does the section contain identification and controls of critical steps and X intermediates of the DS? Does the section contain information X regarding the characterization of the DS? Does the section contain controls for the X DS? Has stability data and analysis been X provided for the drug substance? Does the application contain Quality by Design (QbD) information regarding the X DS? Does the application contain Process Analytical Technology (PAT) X information regarding the DS? Parameter Is there a description of manufacturing process and methods for DP production through finishing, including formulation, filling, labeling and packaging? Does the section contain identification and controls of critical steps and intermediates of the DP, including analytical procedures and method validation reports for assay and related substances if applicable? Is there a batch production record and a proposed master batch record? Has an investigational formulations section been provided? Is there adequate linkage between the investigational product and the proposed marketed product? Have any biowaivers been requested? Does the section contain description of to-be-marketed container/closure system and presentations)? Does the section contain controls of the final drug product? Has stability data and analysis been provided to support the requested expiration date? Does the application contain Quality by Design (QbD) information regarding the DP? Does the application contain Process Analytical Technology (PAT) information regarding the DP? Reference ID: 3334036 E. DRUG PRODUCT (DP) Yes No Comment X X Executed batch records are provided. The proposed master batch record is not provided. X X X X X X X NDA 205677 Filing Checklist, Page 4 29. 30. 31. F. METHODS VALIDATION (MV) Parameter Yes No Is there a methods validation package? X Parameter If appropriate, is a separate microbiological section included assuring sterility of the drug product? 33. 34. 35. 36. HOLDER ITEM REFERENCED (b) (4) I. Yes Parameter Has the draft package insert been provided? Have the immediate container and carton labels been provided? Parameter Is the product quality section of the application fileable? If the NDA is not fileable from the product quality perspective, state the reasons and provide filing comments to be sent to the Applicant. Are there any potential review issues to be forwarded to the Applicant for the 74-day letter? LOA DATE 11-Mar-2013 19-Mar-2013 04-Mar-2013 11-Mar-2013 COMMENTS Comment X J. FILING CONCLUSION Yes No Martha R. Heimann, Ph.D. CMC Lead, DNDQA-1, ONDQA {See appended electronic signature page} Reference ID: 3334036 LABELING No Comment X {See appended electronic signature page} Ramesh Sood, Ph.D. Branch Chief, DNDQA-1, ONDQA Comment N/A H. MASTER FILES (DMF/MAF) Parameter Yes No Is information for critical DMF references (i.e., for drug substance and X important packaging components for non-solid-oral drug products) complete? DMF (b) # (4) TYPE III III III III 32. G. MICROBIOLOGY Yes No Comment Comment X N/A X Refer to comments in Initial Quality Assessment above. --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MARTHA R HEIMANN 06/28/2013 RAMESH K SOOD 07/01/2013 Reference ID: 3334036 FDA CDER EES ESTABLISHMENT EVALUATION REQUEST SUMMARY REPORT Application: NDA 205677/000 Sponsor: VANDA PHARMS INC Org. Code: 120 2200 AVE NORTHWEST STE 3 'z 1 WASHINGTON, DC 20037 5.- Date: 31-MAY-2013 Brand Name: TASIMELTEON PDUFA Date: 31-JAN-2014 Estab. Name: Action Goal: Generic Name: TASIMELTEON District Goal: Product Number; Dosage Form; Ingredient; 001; 20MG FDA Contacts: R. KAMBHAMPATI Prod Qual Reviewer (HFD-830) 3017961382 T. BOUIE Product Quality PM 3017961649 C. MICHALOSKI Regulatory Project (HFD-120) 3017961123 M. HEIMANN Team Leader 3017961678 Overall Recommendation: ACCEPTABLE on 11-DEC-2013 by J. WILLIAMS 3017964196 PENDING on 15-Nov-2013 by PENDING on 18-OCT-2013 by PENDING on 25-JUN-2013 by PENDING on 21-JUN-2013 by Establishment: CFN: FEI: (5X7) DMF No: AADA: Responsibilities: DRUG SUBSTANCE MANUFACTURER Pro?le: NON-STERILE API BY CHEMICAL OAI Status: NONE Last Milestone: 0C RECOMMENDATION Milestone Date: 3 Decision: ACCEPTABLE Reason: DISTRICT RECOMMENDATION .rary 8, 2014 11:12 AM FDA Con?dential - Internal Distribution Only Page 1 of 2 Establishment: DMF No: Responsibilities: FDA CDER EES ESTABLISHMENT EVALUATION REQUEST SUMMARY REPORT (we) CFN: FEI: (we) AADA: FINISHED DOSAGE MANUFACTURER Profile: CAPSULES, PROMPT RELEASE OAI Status: NONE Last Milestone: OC RECOMMENDATION Milestone Date: Decision: ACCEPTABLE Reason: DISTRICT RECOMMENDATION Establishment: CFN: FEI: 09?" DMF No: AADA: Responsibilities: DRUG SUBSTANCE OTHER TESTER Pro?le: CONTROL TESTING LABORATORY OAI Status: NONE Last Milestone: OC RECOMMENDATION Milestone Date: 11-DEC-2013 Decision: ACCEPTABLE 1: DISTRICT RECOMMENDATION Establishment: CFN: FEI: (5X4) DMF No: AADA: Responsibilities: Profile: Last Milestone: Milestone Date: Decision: Reason: DRUG SUBSTANCE OTHER TESTER CONTROL TESTING LABORATORY OAI Status: NONE OC RECOMMENDATION 30-AUG-2013 ACCEPTABLE DISTRICT RECOMMENDATION ?ary a. 2014 11:12 AM FDA Con?dential - Internal Distribution Only Page 2 of 2