CENTER FOR DRUG EVALUATION AND RESEARCH APPLI CA I 0N NUMBER: 2056410rig15000 CHEMISTRY DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Silver Spring, MD 20993 NDA 205-641 CR01 Addendum 01 Date NDA Applicant Drug Reviewer 23-Apr-2014 205-641 Merck Sharp & Dohmn Corp. Asmanex HFA Xiaobin Shen, Ph.D. NDA 205-641 was recommended for approval in chemistry review 01 signed off on 18-Mar2014. At the end of the review the Agency listed two comments to be communicated to the applicant; the applicant provided their responses to these comments on 22-Apr-2014 in Amendment 0010. This review evaluates the applicant responses. The 1st Agency comment was ‒ Update your post-approval long term ongoing stability study protocol to specify the storage orientation (valve up, down, or horizontal). The applicant response is ‒ The Sec.3.2.P.8.2 Post-Approval Stability Protocol and Stability Commitment is updated to specify the valve down orientation for the stability study. Evaluation: Adequate. The 2nd Agency comment was ‒ As required under 21 CFR 314.81(b)(1)(ii), commit to immediately discuss with the Agency any aberrations of the drug product from its approved specifications and to withdraw the affected lots from the market as warranted. The applicant response is ‒ Merck Sharp & Dohme Corp. (Merck) maintains suitable procedures within the Merck Manufacturing Division that ensures compliance with the requirements of 21 CFR 314.81 (b)(1)(ii) for Asmanex® HFA. Consistent with these Quality procedures, Merck will discuss aberrations of drug product from approved specifications with FDA in a timely manner and withdraw affected batches from the market as warranted. Evaluation: Adequate. Both comments are satisfactorily addressed. Reference ID: 3494309 Page 2 Xiaobin Shen, Ph.D. Chemistry Reviewer Prasad Peri, Ph.D. Branch VIII Chief, ONDQA Reference ID: 3494309 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------XIAOBIN SHEN 04/23/2014 The responses are adequate. The NDA remains recommended for approval from CMC perspective. CRAIG M BERTHA 04/23/2014 Signing for Dr. P. Peri Reference ID: 3494309 CHENIISTRY REVIEW NDA 205-641 Asmanex HFA (Mometasone uroate) Merck Sharp Dohme Corp. Xiaobin Shen, for Division of Pulmonary, Allergy and Rheumatology Drug Products Reference ID: 3470706 CHENIISTRY REVIEW Table of Contents Table of Contents 2 Chemistry Review Data Sheet 3 The Executive Summary 7 1. Recommendations 7 A. Recommendation and Conclusion 011 Approvability 7 B. Recommendation 011 Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk Management Steps. if Approvable 7 II. Slunmary of Chemistry Assessments 7 A. Description of the Drug Substance and Drug Product 7 B. Description of How the Drug Product is Intended to be Used 9 C. Basis for Approvability or Not-Approval Recommendation 9 HI. Administrative 9 A. Reviewer?s Signature 9 B. Endorsement Block 9 C. CC Block 9 Chemistry Assessment 10 I. Review Of ommon Technical Document-Quality (Ctd?Q) Module 3.2: Body Of Data 10 DRUG SUBSTANCE [Mometasone Furoate] 10 DRUG PRODUCT [Mometasone Furoate. Metered Dose Inhaler] 12 REGIONAL INFORMATION 48 H. Review Of ommon Technical Docmnent-Quality (C td-Q) Module 1 48 A. Labeling Package Insert 48 B. Enviromnental Assessment Or Claim Of Categorical Exclusion 53 Reference ID: 3470706 CHENIISTRY REVIEW Chemistry Review Data Sheet Chemistry Review Data Sheet 1. NDA 205-641 2. REVIEW 1 3. REVIEW DATE: 13-Mar?2014 4. REVIEWER: Xiaobin Shen, 5. PREVIOUS DOCUMENTS: Previous Docrunents Document Date NA NA 6. BEING REVIEWED: Submission(s) Reviewed Document Date Original 27-Jun-2013 Other amendments older than the last listed do not have MC related information for review. . NAME ADDRESS OF APPLICANT: Name: Merck Sharp Dohme Corp. Address: One Merck Drive, PO. Box 1000, Whitehouse, NJ 08889 Scott Hambaugh Representative 351 N. Sunneytown Pike (Agent): PO. Box 1000, UG2C-26 North Wales, PA 19454-2505 Telephone: 267-305-5867 Fax: 732-594-4980 Email: Scott.hambaugh@merck.com 8. DRUG PRODUCT TYPE: Page 3 of 56 Reference ID: 3470706 CHENIISTRY REVIEW Chemistry Review Data Sheet a) Proprietary Name: Asmanex HFA b) Non-Proprietary Name (U SAN): Mometasone Furoate c) Code Name/# (ONDC only): (1) Chem. Type/Submission Priority (ONDC only): 0 Chem. Type: 3 0 Submission Priority: 9. LEGAL BASIS FOR SUBMISSION: NDA 505(b)(l) 10. PHARMACOL. CATEGORY: Corticosteroid 11. DOSAGE FORM: Metered Dose Inhaler 12. 100 and 200 per actuation 13. ROUTE OF ADMINISTRATION: Inhalation by the oral route 14. DISPENSED: 15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM): product Form Completed Not a SPOTS product 16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT: Chemical name: 9,2 1 -dichloro-1 1 (Beta), 1 7-dihydroxy-16 1 ,4-diene- 3 ,20-dione 1 7-(2-furoate) United States Adopted Name (USAN): Mometasone furoate ompendial name: Mometasone furoate Chemical structure: Molecular formula: C27H30C1206 Molecular weight: 521.44 g/mol Page 4 of 56 Reference ID: 3470706 -A.n Em . CHENIISTRY REVIEW . Chemistry Review Data Sheet 17. SUPPORTING DOCUMENTS: A. DMFs: DATE TYPE HOLDER STATUS2 REVIEW COMMENTS COMPLETED *See note 4 4 below. 4 *See note below. 4 *See note below. *See note 3 4 below. *See note 3 4 below. 3 21-Feb-2014 *See note 3 4 below. 9. [He DMFs Eve new amengents smce Earl ere Is no 5 ety an ty concern expected based on the reviews conducted at time 1 Action codes for DMF Table: 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) approval. This table will be updated in a review addendum once the DMF amendments are reviewed. Page 5 of 56 Reference ID: 3470706 CHENIISTRY REVIEW hemistiy Review Data Sheet B. Other Documents: DOCUMENT APPLICATION NUMBER DESCRIPTION MF/formoterol fumarate NDA 22518 inhalation aerosol (Dulera?) for asthma MF inhalation powder NDA 21067 (Asmanex? Twisthaler? for prophylaxis for asthma MF/formoterol fumarate IND 70283 . . mhalation aerosol IND 52214 MF inhalation aerosol IND 46216 MF inhalation aerosol 112669 MF inhalation aerosol 18. STATUS: ONDC: CMC RELATED RECOMMENDATION DATE REVIEWER REVIEWS EES Acceptable 06-AUG-2013 Pharm/Tox Not needed Biophaim Not needed Methods Validation Not needed EA Not needed Microbiology Not needed Page 6 of 56 Reference ID: 3470706 CHENIISTRY REVIEW Executive Suimnaiy Section The Chemistry Review for NDA 205-641 The Executive Summary 1. Recommendations A. Recommendation and Conclusion on Approvability From the chemistry, manufacturing and controls standpoint, the NDA is recommended for approval. B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable NA. II. Summary of Chemistry Assessments This NDA has (mm The differences between this Asmanex and the Dulera products are 1. Dulera? is a combination product that contains two actives, namely, mometasone fuorate and formoterol fumarate actives; while Asmanex? only contains a single active mometasone fuorate, which is at the same as the Dulera?. 2. The Dulera? metered dose inhalers have a green mouthpiece cover; while the Asmanex? metered dose inhalers have a pink mouthpiece cover; both products use the same blue actuator. Essentially, when manufacturing the Asmanex? products, the applicant has excluded the formoterol fumarate active, which is mm by weight, from the Dulera? products and replaced it with . The colorant of metered dose inhaler mouthpiece cover has also been changed from green to pink. The submitted NDA therefore referenced to the already approved NDA 22-518 for support of the common contents between both products. onespondingly, the focuses of this review are on the information 1mique to this NDA, what is common and ah'eady deemed acceptable in the Dulera? NDA commercially available will not be further evaluated. A. Description of the Drug Substance and Drug Product Page 7 of 56 Reference ID: 3470706 CHENIISTRY REVIEW Executive Summary Section Mometasone Fru?oate drug substance is the same as used in the Asmanex? Twisthaler? and Dulera? drug products, all information is referenced to those two approved NDAs (21-067 and 22-518) that are currently marketed. The drug products are manufactru?ed as 100 mc and 200 per actuation pressurized metered dose inhalers designed to deliver a minimum of 120 actuations. Each dose is achieved with two single actuations of the product. The drug product formulation contains (m4) ethanol (mm oleic acid, both are USP grade and have additional quality controls required for inhalation use docrunented in the supporting NDA 22-518, and HFA 227 as excipients. The HFA 227 also ?mctions as propellant. The product formulation is packaged and sealed in its container closure system that is also an integral part of the drug product. The container closure system quanti?es and delivers the active when the user actuates the product. Speci?cally, the container closure system consists of a 16 mL aluminum canister mmclosed with a valve. A press and breathe actuator with the mouthpiece cap is provided with the pressru?ized canister to deliver a dose to the patient. The (m4) actuator incorporates an integrated displacement driven dose counter. All excipients and container closru?e system used (mm the color of the cap cover is pink. The pink actuator cover is supported by that is deemed adequate. (4) The drug product speci?cations include appearance, identi?cation, assay, related substances, dose content 1miformity, aerodynamic particle size distribution, ethanol content, water content, degradation products of ethanol, leachables, microbial limits, foreign particulate, microscopic examination, ?ll weight, valve delivery, number of actuations per container, leak rate and spray pattern. All acceptance limits are the same as those of the corresponding quality attributes for the Dulera? products and supported by the actual release and stability results. This is expected because the excluded second active formoterol fumurate is less than (m4) of the Dulera? formulation. Almost all release and real time stability results met the proposed and fully justi?ed drug product speci?cations. Low rate occurrence of out of speci?cation dose content uniformity results, at a maximum of (mm for individual and (mm for mean data per product strength, have been observed from the stability results available for up to 24 months when stored at long term /60% RH) conditions. Such occrurences appear to be random and most likely associated with the commonly seen large variations of products. The occurrences are acceptably justi?ed and its rate is similar to that of Dulera?. As expected, the stability results exhibit similar trends as those of Dulera?. Overall, the provided stability data support the applicant proposed 36 month product expirv in consideration of the referenced support of 36 n?arrth stability data from the Page 8 of 56 Reference ID: 3470706 CHENIISTRY REVIEW Executive Summary Section B. Description of How the Drug Product is Intended to be Used The diug product is a standard press and breathe metered dose inhaler which is labeled to deliver a minimum of 120 actuations. It is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. It should be administered twice daily (morning and evening) via oral inhalation; Each dose is achieved with 2 actuations. C. Basis for Approvability or Not-Approval Recommendation The NDA submission provided acceptable information on the chemistry, manufacturing, and controls of the Asmanex? The product is recommended for approval based on the following: The drug substance and product speci?cations provided adequate controls; 0 The drug product excipients are of grade and have additional quality controls to make them suitable for inhalation use; 0 The drug product container closure systems are acceptable for pharmaceutical use. 0 Both drug substance and drug product are stable in the studied stability period and support the currently claimed 36 months of diug product expiry. Administrative A. Reviewer?s Signature Review is digitally signed off in DARRTS. B. Endorsement Block Chemist Name/Date: Xiaobin Shen, l3-Mar-2014. Acting CMC Lead Name/Date: Craig M. Bertha, l3-Mar-2014. Project Manager Name/Date: Youbang Liu, 13-Mar-2014 C. CC Block 47 Page(s) have been Withheld in Full as b4 TS) immediately following this page Page 9 of 56 Reference ID: 3470706 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------XIAOBIN SHEN 03/14/2014 The NDA is recommended for approval from CMC perspective. Please send the two comments at end of the review to the applicant. CRAIG M BERTHA 03/18/2014 I concur Reference ID: 3470706 Asmanex® HFA (Mometasone Furoate) Inhalation Aerosol NDA 205641 Summary of the Basis for the Recommended Action from Chemistry, Manufacturing, and Controls Applicant: Merck Sharp & Dohme Corp. One Merck Drive P.O. Box 1000 Whitehouse, NJ 08889 Indication: Asmanex® is a corticosteroid drug product indicated for the prophylactic maintenance treatment of asthma in patients 12 years and older (not for acute bronchospasm) Presentation: There are two strengths of the inhalation aerosol drug product: 100 and 200 mcg of mometasone furoate (MF) per actuation delivered from the mouthpiece. The drug product formulation is a suspension of MF in HFA-227 (1,1,1,2,3,3,3heptafluoropropane) and ethanol, with oleic acid as a surfactant. The inhalation aerosol also includes a numerical dose counter, and is designed to deliver 120 actuations. EER Status: Acceptable. Consults: EA – categorical exclusion provided Statistics – N/A Methods Validation – Deemed not necessary to be forwarded to Agency laboratory. Microbiology – N/A Pharmacology/toxicology – N/A Original Submission: 27-JUN-2013 Re-submissions: N/A Post-Approval CMC Agreements: None beyond the typical stability commitment (see comments for applicant in CMC review #1). Drug Substance: The drug substance is mometasone furoate, a glucocorticoid, and information has been provided by the applicant by cross-reference to their approved NDAs 22518 (Dulera Inhalation Aerosol) and 21067 (Asmanex Inhalation Powder), both for the oral inhalation route of administration. Reference ID: 3472208 N205641 Summary Basis of Recommended Action CMC p. 2 Mometasone Furoate Conclusion: Drug substance is acceptable. Drug Product: The drug product is a suspension-based inhalation aerosol, which contains (m4) mometasone furoate (MP), mu) on?) ethanol. oleic acid, with the remainder HFA-227 propellant hepta?uoropropane). There are two of the product included in the application, 100 and 200 MF/actuation (mm (4) that there is no formoterol fumarate suspended in the formulation, the applicant has not presented additional pharmaceutical development studies. This is not lmreasonable as the MF monotherapy product was deemed to be suitably comparable in terms of dose delivery characteristics to be used in the supportive clinical studies for Dulera? (see p. 172 of CMC review #1 for N22518 dated 22-JAN-2010). The label recommends twice daily dosage of Asmanex? at 100 and 200 with a starting dosage based on prior therapy. The current proposed expiration dating period of 36 months is found to be acceptable based on evaluation of all data provided. Conclusion: Drug product is satisfactory. Overall Conclusion: From a CMC perspective, the application is recommended for approval. Craig M. Bertha, Acting CMC Lead, Branch HIV DNDQA Reference ID: 3472208 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CRAIG M BERTHA 03/18/2014 Reference ID: 3472208 NEW DRUG APPLICATION ONDOA REVIEW Initial Quality Assessment (IQA) and Filing Review for Pre-Marketing Applications APPLICATION INFORMATION 1. NEW DRUG APPLICATION NUMBER: N205641 Asmanex? HFA is the trademark proposed by the applicant for mometasone furoate (MF) formulated as an inhalation aerosol for the treatment of asthma. The applicant claims that the two of the Asmanex? HF A inhalation aerosol mm Therefore, it is recommended that the reviewer familiarize him or herself with the approved Dulera? Inhalation Aerosol combination and combination drug product of DA 22518, and associated CMC reviews, as it is likely that much of the material and data supporting and control strategy for the current DA is analogous or similar to what was approved for Dulera?. For example, (W) . Additionally, the Asmanex? HF A drug product uses the same container closure system as the Dulera? drug product except that the mouthpiece cap color differs. 2. Drug Name: Asmanex? HFA1 (mometasone furoate) Inhalation Aerosol 1 Typically applicants are discouraged from using as part of the proprietary name if there had been no previously approved chlorofluorocarbon inhalation aerosol version. However, it is noted that having the HFA present in this particular case might be considered beneficial to help distinguishes this drug product from the approved Asmanex? Twisthaler? Inhalation Powder drug product. Page 1 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA #: 205641 Received Date: 27-JUN-2013 The chemistry classification code is type 3 – New Dosage Form. There are two strengths of the drug product, with 100 and 200 mcg of MF per actuation delivered from the mouthpiece. The drug product formulation is a suspension of MF in HFA-227 (1,1,1,2,3,3,3heptafluoropropane) and ethanol, with oleic acid as a surfactant. 3. RECEIVED DATE: 27-JUN-2013 (Applicant: Merck Sharp & Dohme Corp.) 4. RELATED REVIEW DOCUMENTS: a. Drug Master Files listed on 356h form: DMF # (b) (4) LOA DATE COMMENTS 18-APR-2013 17-JUL-2012 Last reviewed 22DEC-2009 Verify LOA in file; not reviewed for (b) (4) specified 17-JUL-2012 Verify LOA in file 3 12-JUL-2012 3 29-APR-2013 3 29-APR-2013 3 29-APR-2013 Not reviewed for (b) (4) specified Verify LOA in file; Refer to review of 02-NOV-2009 for Dulera® Refer to review of 06-JAN-2010 supporting Dulera® Refer to review of TYPE HOLDER ITEM REFERENCED (b) (4) 4 Page 2 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA #: 205641 Received Date: 27-JUN-2013 (b) (4) 22-OCT-2009 supporting Dulera® b. Recommended Consults CONSULT Biometrics Clin Pharm EES YES NO X COMMENTS: (list date of request if already sent) Request evaluation of stability data if trends in parameters will limit expiry (e.g., water content, ethanol content, leachables, degradants). X X Pharm/Tox X Methods Validation X EA X New Drug Micro X CDRH X Other X Submitted to OC by ONDQA PM on 18 & 22JUL-2013 Compare controls (tests/acceptance criteria) for drug product impurities and leachables to that applied for the approved Dulera® application. If comparable, then there would be no need to request the pharmacology/toxicology team evaluate these controls. Left to reviewer discretion if any drug product methods are questionable, but MF is not an NME so it is not mandatory that any methods be assessed by the Agency laboratory. Applicant claims environmental introduction concentration allows exclusion as per 21 CFR 25.31(b); reviewer can evaluate if any data are needed to support claim. Inhalation Aerosol drug products are not sterile. Drug product specification is consistent with recommendations of USP <1111> for oral inhalation drug products. The microbiology team has been notified of the application and will determine if any microbiology review is needed. (b) (4) N22518 (Dulera® Inhalation Aerosol) according to the applicant. N/A Page 3 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA #: 205641 Received Date: 27-JUN-2013 c. Other Applications or Submissions to note (if any): DOCUMENT NAME DATE APPLICATION NUMBER DESCRIPTION NDA 22518 MF/formoterol fumarate inhalation aerosol (b) (4) (Dulera®) for asthma NDA 21067 IND 70283 IND IND pre-IND 52214 46216 112669 MF inhalation powder (Asmanex® Twisthaler®) for propylaxis for asthma MF/formoterol fumarate inhalation aerosol MF inhalation aerosol MF inhalation powder MF inhalation aerosol Page 4 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA 205641 Received Date: d. Previous Communications with the Applicant to note (see module 1.6.3 for complete detail): DOCUMENT APPLICATION NAME DATE NUMBER DESCRIPTION Written O9-SEP-2011 pre-IN 112669 Agency responds to CMC, responses clinical, and clinical pharmacology questions Written 14-SEP-2011 pre-IN 112669 Clarification regarding responses above written response OVERALL PRODUCT QUALITY CONCLUSIONS AND RECOMMENDATIONS Is the Product Quality Section of the application fileable from a CMC perspective? Yes No MC Filing Issues 1. Are there potential CMC review issues to be forward to the Applicant with the 74 day letter? Yes No Is the Product Quality Section of the application fileable from a biopharmaceutics perspective? Yes No Biophannaceutics Filing Issues To be separately assessed by the biopharmaceutics team Are there potential biopharmaceutics review issues to be forward to the Applicant with the 74 day letter? Yes No See above Page 5 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications DA 205641 Received Date: Does the submission contain any of the following elements? Yes omments Botanical Products Combination Products Nanotechnolo PET bD Elements SPOTS Is a team review recommended? Yes No Suggested expertise for team CMC Summary: Critical Issues and Complexities (This section is formatted to expand as far as needed by author.) Background: The drug substance is MF, which is a glucocorticosteroid to be used for the treatment of asthma. The crurent drug product (m4) This inhalation aerosol drug product includes a dose cormter. All MC information related to the substance, the glucocorticoid mometasone fru?oate is referenced to the Asmanex? Twisthaler? Inhalation Powder N21067, although a copy of the drug substance speci?cation from that application is included in 8.4. 1. The speci?cation from N21067 is appropriate for the crurent application as the formulation is suspension-based. There is no obvious reason, based on this preliminary review, for the reviewer to evaluate any aspects related to the MIF drug substance covered by N21067. Note that the Dulera? Inhalation Aerosol also uses the same diug substance. The diug product is a suspension-based inhalation aerosol, which contains (m4) mometasone furoate (MP), (m4) (m4) ethanol, (m4) oleic acid, with the remainder HFA-227 propellant (1 There are two of the drug product included in the application, 100 and 200 MF/actuation. Page 6 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre?Marking Applications DA 205641 Received Date: The ethanol and oleic acid are listed as compendial grade The reviewer should refer to our draft guidance regarding additional considerations for controls for these two excipients when used as part of an inhalation aerosol formulation (see section 01112). the applicant has not presented additional pharmaceutical development studies. This is not unreasonable as the MF monotherapy product was deemed to be suitably comparable in terms of dose delivery characteristics to be used in the supportive clinical studies for Dulera? (see p. 172 of MC review #1 for N22518 dated 22-JAN-2010). As addressed in the responses to the ?lm?s questions in the 112669 package dated 10-AUG-2011, not only has the applicant provided comparative release and stability data for drug product batches (DOM ?'om 2005-2012) prepared at the planned commercial site on with the commercial process (see P.5.4 and R83), but they have also provided comparative release data for the original formulation (100 and 200 me prepared at in 1997 to the to-be-marketed product (see P.5.4.3.1). Many of the clinical trials were done in 1997 using the original formulation, so the reviewer should also evaluate the comparative data in P.5.4 for the old (1997) versus the newer (2005 and on) MP MDI and confer with the clinical team on the potential importance of any signi?cant differences. See the listing of relevant drug product batches in tables 8 and 1 below. Start of Applicant Material Table 8 "Original" Asmanex and new Niometasone Furoate Batches used In Performance (?omparison Manufacturing Drug Product Strength Date of Site of Process Product Batch Number (mcg/actuation) Manufacture Manufacture Overview . (4) (4) (41 38101-039 100 Original 38101-043 100 Asmanex 38101-040 300 38101-043 200 (361044 100 (36.1045 200 New MF . CIMAOJQ 100 (331E096 200 I 7 200 Page 7 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre?Marking Applications DA #2 205641 Received Date: The batches presented in Table 1 are representative of the commercial drug products and were manufactured at the commercial site. Table 1 Batch Information for Mometasone Furoate Drug Products Batch 31212323111? Billing?? l'se 0f Batch 100 GGJOJJ Clinical! Stability 100 Stability 200 ClinicalI'Stability 200 631E096 Stability 200 GNB217 Stability End of Applicant Material Also addressed in the correspondence was the issue of drug product characterization studies. Due to the similarity of the drug product to Dulera?, the studies are truncated as agreed, with only the dose proportionality studies to be repeated (see P.5.4.2 for data). The correspondence also addressed what stability data were agreed upon to be included in the application. The applicant has provided the agreed upon stability data (see table 1 reproduced below). Start of Applicant Material Table 1 Stability Batches 100 per actuation 200 per actuation Drug product GMAO49 Batch Number Storage RH 35?C760?o RH RH 25?C?60?o RH RH Conditions 40007500 RH arc-7500 RH RH 40?C?75?'o RH RH Storage Valve Down Valve Down Valve Down \?alve Down Valve Down Orientation Valve Up Valve L'p Valve Up Valve [7p Valve Horizontal Horizontal Horizontal? (4) Manufacturing Date Batch Size mm {units} Months of Stability Data 24 13 24 12 6 Included in this Submission End of Applicant Material Page 8 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications DA 205641 Received Date: Description of Facility Related Risks or Complexities foreign sites, large number of sites involved, etc.) See EES. for complete list of facilities related to this application. Three sites have been entered into the EES request (18 22-IUL-2013). The ding substance manufacturer is a Merck site located in Singapore whereas the drug product manufactm'er is a 3M site in England. (hm) Thus, there are a relatively small number of sites involved in the production of the ding product, but they are foreign sites. Biopharmaceutics Filing Review: Summary, Critical Issues and Complexities (This section can expand as far as needed by author. Note: A separate filing review will be provided by the biopharmaceutics team. Page 9 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA 205641 Received Date: FILING REVIEW CHECKLIST The following parameters are necessary in order to initiate a full review. complete enough to review but may have de?ciencies. Orr initial overview of the NDA application for ?ling: organized adequately? A. GENERAL Parameter Yes No Comment Is the CMC sectrorr Is the CMC section indexed phase. and at the pre-NDA meetings been included? and pagirrated (including all PDF ?les) adequately? Are all the pages in the All pages examined for CMC section legible? IQA were Has all infomratiorr A . . . The adequacy of the provrded requested durmg the IND data will be determined during review. B. Parameter Yes No Comment Is a single. comprehensive list of all involved facilities available in one location in the application? El El See module 1.1.2 of Sequence 0000 (attaclnnent to Form 35611) and P.3.1 For a manually-derived API only. are the facilities responsible for critical intermediate or crude API manufacturing. or performing steps. speci?ed in the application? If not. has a justi?cation been provided for this omission? This question is not applicable for API. (4) Reference ID: 3345217 Page 10 0f 17 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA #: 205641 Received Date: 27-JUN-2013 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 7 • FEI number for facility (if previously registered with FDA) • Full name and title, telephone, fax number and email for on-site contact person. • Is the manufacturing responsibility and function identified for each facility?, and • DMF number (if applicable) X Are drug product manufacturing sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including street, city, state, country 8 • FEI number for facility (if previously registered with FDA) • Full name and title, telephone, fax number and email for on-site contact person. • Is the manufacturing responsibility and function identified for each facility?, and • DMF number (if applicable) X Page 11 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA 205641 Recei ved Date: list: country FDA) person. and Are additional manufacturing. packaging and control/testing laboratory sites are identi?ed 011 FDA Form 35611 or associated continuation sheet. For each site. does the application 0 Name of facility. 0 Full address of facility including street. city. state. 0 FBI munber for facility (if previously registered with 0 Full name and title. telephone. fax munber and email for on-site contact 0 Is the manufactm'ing responsibility and flulction identified for each facility?. 0 DMF mnnber (if applicable) See question 5 above. Is a statement provided that all facilities are ready for GMP inspection at the time of submission? If any inf01mation regarding the facilities is omitted. this should be addressed ASAP with the applicant and can be a potential ?ling issue or a potential review issue. C. ENVIRONMENTAL ASSESNIENT categorical exclusion been Parameter Yes No Comment It is left to the reviewer to decide whether . . or not supportive infmmation or data is Has an envnonmental . . assessment re 0 rt or needed for the request for categorical 11 exclusion 1u1der 21 FR Applicant also claims that they know of no . r) p10v1ded. extraordinary circumstances regarding the EA. D. MASTER FILES I I Parameter I Yes I No I Comment Page 12 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications Received Date: NDA 205641 12. Is information for critical DMF references for drug substance and important packaging components for non-solid- oral drug products) complete? See table on cover page. Parameter Yes . DRUG PHARMACEUTICAL INGREDIENT II Comment 13. Does the section contain a description of the DS manufacturing process? El El El Yes. by reference to approved NDA 21067. 14. Does the section contain identi?cation and controls of critical steps and intermediates of the DS (in process parameters? See comment for 13 above. Does the section contain information 011 impurities? See comment for 13 above. 16. Does the section contain information regarding the characterization of the See comment for 13 above. 17. Does the section contain controls for the See comment for 13 above: the NDA contains the speci?cation sheet for the drug substance. 18. Has stability data and analysis been provided for the drug substance? See comment for 13 above. 19. Does the application contain Quality by Design information regarding the See comment for 13 above. 20. Does the application contain Process Analytical Technology (PAT) information regarding the See comment for 13 above. 21. Does the section contain container and closru?e information? See for 13 above. Reference ID: 3345217 Page 13 of 17 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA 205641 Received Date: F. DRUG PRODUCT (DP) Reference ID: 3345217 Parameter Yes No Comment Does the section contain . reference to a roved Dulera? 22' (1113.11? CODUOIS 0f '3 agplication exc1p1ents? Does the section contain 23. information 011 composition? Reviewer is advised to compare this Is there a description of section to that approved for Dulera? as the manufacturing process and methods for DP production 24' through fmishing. including fonnulation. ?lling. labeling this description should be evaluated for and packaging? completeness as no actual master production record is provided. Does the section contain identi?cation and controls 9f (:11th3.1 steps and Refer to P.3.4 for control of critical steps: intermediates Of the there are no intermediate roducts 25. including analytical . . 1 d1 p. procedures and method assoc1ate Wit manufacture validation 1ep01ts f01 assay and related substances if applicable? Although an executed batch record is provided for one of the 200 111cg strength (representative commercial) batches. 110 Is there a batch production master production record is provided: see 26. record and a proposed for 24 above. Note the master batch record? application is submitted 1mder 505(b)(1). not so the inclusion of the actual master production record is not necessarily required. Has an investigational formulations section been provided? Is there adequate No. 27. linkage between the investigational product and the proposed marketed product? Have any biowaivers been The biopharmaceutics team will address 28. re ., . . quested. any biowalver requests. Eeieciithgofgtgi?inam By reference to the approved Dulera? 29. . NDA 22518 and assoc1ated DMFs marketed contamer/closure and (W4) system and presentations? Page 14 of 17 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications Received Date: NDA 205641 Reference ID: 3345217 Does the section contain 30. controls of the ?nal drug product? Data are provided. and plotted data are discussed relative to the proposed expiration dating period. however. 110 Has stability data and statistical analysis has been included in the 31 analysis been provided to application. If any important stability support the requested trends are noted that would appear to be expiration date? limiting in tenrrs of the proposed expiry. it is reconrmended that the reviewer ask the biometrics team to analyze the stability data for those parameters. Unless related information are Does the application contain contained in the current N21067 or DMFs 32 Quality by Design associated with the application. Review of information regarding the DMFs should only be done if new information has been submitted that has not previously been evaluated. Does the application contain Process Analytical 33. Technology (PAT) See comment for question 32 above. information regarding the G. METHODS VALIDATION (MV) I Parameter Yes No Comment 15 there a methods Some information is formd in the section 34. validation package? of the or by reference to NDA . 21067 for the MF substance H. MICROBIOLOGY Parameter Yes No Comment If appropriate. is a separate The microbiology team has been informed 3 5 microbiological section El of the submission of this application and included discussing sterility will make a determination of any review of the drug product? necessary. as per the pilot. I. LABELING Parameter Yes No Comment Has the draft package insert 36' been provided? Have the immediate 37. container and carton labels been provided? Page 15 Of 17 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA #: 205641 Received Date: 27-JUN-2013 Does section contain 38. tradename and established name? X Page 16 of 17 Reference ID: 3345217 ONDQA Initial Quality Assessment (IQA) and Filing Review For Pre-Marking Applications NDA 205641 Received Date: J. FILING CONCLUSION I Parameter Yes No Comment IS THE PRODUCT QUALITY SECTION OF 39' THE APPLICATION If the NDA is not ?leable from the product quality perspective. state the Describe ?ling issues here or 011 additional 40' reasons and provide ?ling sheets to be sent to the Applicant. Are there any potential 41 review issues to be Describe potentialtreview issues here or on forwarded to the Applicant addltional sheets for the 74-day letter? REVIEW AND APPROVAL This document will be signed in DARRTS by the following: Craig M. Beitha, Acting CMC Lead Prasad S. Peri. P11.D.. Branch Chief {See appended e/een?onic signature page} Page 17 of 17 Reference ID: 3345217 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CRAIG M BERTHA 07/23/2013 PRASAD PERI 07/24/2013 I concur Reference ID: 3345217