CENTER FOR DRUG EVALUATION AND
`RESEARCH
`'
`
`APPLICA TION NUMBER:
`
`21-995
`
`CHEMISTRY REVIEW! S!
`
`

`

`- ONDQA Division Director’s CMC Memorandum on NDA 21-995
`
`Date:
`From:
`
`To:
`
`October 15, 2006
`Chi-wan Chen, Acting Director, Division of Pre-Marketing Assessment I Office of
`New Drug Quality Assessment
`DA 21-995 File
`
`Applicant:
`Drug Name:
`Indication:
`
`Merck and Co., Inc.
`Januvia (Sitagliptin) tablets, 25, 50, 100 mg
`Type 2 diabetes mellitus
`
`The CMC portion of this NDA was submitted on December 16, 2005, under the ONDQA Pilot Program
`to explore science- and risk-based approaches to assuring product quality. An expanded pharmaceutical
`development section was submitted. Several quality-by-design (QbD) elements were presented with
`respect to product design and process understanding.
`
`-
`
`Drug Substance
`
`The following critical process parameters (CPPs) for the drug substance manufacturing process were
`identified: .9.“
`
`:
`
`,,,
`
`,
`
`,
`
`The major issues identified and resolved during the review are:
`
`'.—
`1. The applicant proposed no measurement of —— even though the
`has been shown to have an impact on drug product processing (e. g. ——
`“—-
`
`0 A batch made at I —_ . site was _-_— and
`incurred a' --E—-——'—
`. The applicant agreed to include
`-dl—-
`in their process description.
`0 While the applicant has demonstrated a higher than usual level of understanding of the
`——9"‘
`,the data provided does not provide sufficient assurance over the range
`of operation proposedin the application. A test was added to the specification sheet to ensure
`the desired
`“—-
`is obtained.
`
`2. No specific designation of critical quality attributes (CQAs) or design space was discussed in the
`process development section, and the process description for the commercial scale production
`was vague. The applicant revised the process description and provided a table capturing
`established design space and initial control space with a few identified CQAs. The revised
`version contains much more informatiOn than a typical process description and provides
`additiOnal value to reviewers for post—approval changes and for field inspectors.
`
`Drug Product
`
`The application included detailed studies on ——_—-—_1_—— __ i’rocess risks associated with
`“—-
`scale—up were proactively identified, which include —'-—»
`
`

`

`#—
`
`The
`
`process development studies were focused on defining a robust operating space that effectively
`minimized the inherent process risks. The applicant claimed that none of the process parameters were
`found to be critical. They defined a critical step or operation as “one that requires process conditions or
`parameters to be carefully controlled within a predetennined operating range” to assure quality. The
`applicant established a design space for
`.__.
`
`The applicant proposed a non-traditional approach to the drug product control strategy. Assay by M
`/
`are tested on
`"4 , in-process only, though the criteria
`are included in the specification. The remaining attributes in the drug product specification includes
`
`will be used for stability testing.
`
`The major issues identified and resolved during the review are:
`
`.vas conducted to assess the potential risks
`.4
`1. Although
`—_
`related to drug substance or excipient variability, the applicant proposed to monitor the
`
`. They did not investigate and understand the effects of material attributes on process or
`—-
`product performance and relied instead on th'
`_ ""
`-
`to ensure
`and on pharmacopeial standards for the excipients. And the applicant did not intend to monitor or
`control
`,
`_,—
`y during commercial production. .
`
`.ne applicant agreed to
`At our request and after the PAI of the drug product facility in
`1, against a set of quality
`control the variability in excipients, including p —/
`specifications as defined in their quality standard, and include key attributes for all excipients in
`their drug product design space and control space table.
`
`2. No specific designation of critical quality attributes (CQAs) or design space is discussed in the
`process development section. The applicant revised the process description and provided a table
`capturing established design space and initial control space with a few input variables, rather than
`product attributes, as CQAs. The applicant has identified which design spaces for the unit
`operations are dependent upon scale or equipment. The revised version contains much more
`information than a typical process description and provides additional value to reviewers for post-
`approval changes and for field inspectors.
`
`3.
`
`’was proposed, but no in-process control
`.2
`/ - was considered. The applicant addressed FDA’s concern by incorporating
`for
`additional controls to help prevent or minimize:
`~—
`—/
`These additional controls are:
`
`ssay is ~ Label claim (LC) for the mean of a
`4. The proposed acceptance criterion for \'
`pre-determined number of — tablets without an acceptance limit for the SD or a tolerance limit
`for the number of outliers allowed. The sample size is typically ',ablets for a '
`p
`tablet batch of the 100-mg strength sampled during the
`7
`'~ '
`The applicant has
`agreed to include an acceptance limit for the standard deviation (SD) of the individual
`_ assay
`concentrations to ensure that greater than L of the individual
`-’ .ablets assay values, when
`converted to %LC, are within
`v fLC.
`
`

`

`5. The proposed acceptance criterion for. ‘
`Typically “ ablets for a. 9
`
`
`.——‘r LC_
`;s
`.
`‘
`'
`___,
`tablet batch of the lOO-mg strength were sampled during
`
`0
`
`o
`
`The applicant has agreed to change the acceptance limits to ensure that the , f4
`.—’/
`‘
`——’
`
`The applicant also agreed to add a
`
`/'7' cest'
`
`' I
`
`/
`
`1//
`/
`
`The revised procedure and criteria are more scientifically sound and provide an increased level of
`quality assurance.
`
`6. The proposed “ ’
`Clinical Pharmacology ’
`The applicant agreed to replace
`dissolution to future stability testing.
`
`~—
`._ 7
`‘_
`
`’
`
`as found unacceptable by Office of
`
`vith dissolution for product release and to add
`
`7. The proposed established name did not correspond to the labeled strength. The applicant was
`advised of the FDA policy that the name and the strength should match. They agreed to drop
`“phosphate” from the established name at the next printing in January, 2007.
`'
`
`As a footnote, the applicant proposed a CMC regulatoryagreement outlining the regulatory mechanisms
`for managing changes related to process, equipment, scale, site, and design and control spaces for the
`drug substance and drug product post—approval. The agreement will not be approved at this time since
`FDA has not established a regulatory pathway to allow us to approve such an agreement.
`
`Recommendation
`
`The applicant has provided sufficient scientific information to demonstrate product knowledge and
`process understanding of the drug substance and product, and made necessary changes to their control
`strategy to increase the level of assurance in product quality. Other traditional aspects of the NDA,
`including demonstration of stability and establishment of retest period (36 months) and shelf life (30
`months), are satisfactory. The application is recommended for approval from the chemistry,
`manufacturing, and control standpoint.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Chi Wan Chen
`
`-
`
`10/16/2006 05:35:28 PM
`CHEMIST
`
`

`

`
`
`NDA 21-995
`
`JanuviaTM (sitagliptin phosphate) Tablets
`
`Merck And Co., Inc.
`
`Stephen Moore, PhD
`Christine Moore, Ph.D.
`
`Vibhakar Shah, Ph.D.
`
`ONDQA/ DPA I
`
`DMEP
`
`

`

` CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................5
`
`The Executive Summary .............................»............................................................9
`
`1. Recommendations ..............................................................‘........................................................ 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments ......................................................................................... 9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 1 1
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 11
`
`III. Administrative......................................................................................................................... 11
`
`A. Reviewer’s Signature ........................................................... . .......................................................... 12
`
`B. Endorsement Block ......................................................................................................................... 12
`
`C. CC Block ........................................................................................................................................ 12
`
`Chemistry Assessment\......................; ................................................................... 13
`
`I. Review of Common Technical Document—Quality (CTD—Q) Module 3.2: Body
`of Data ................................................................................................................................... 13
`
`S DRUG SUBSTANCE [sitagliptin phosphate] ......................................................................... 13
`
`8.1
`
`General Information................................L .......................................................................... 13
`
`82 Manufacture ....................................................................................................................... 16
`
`8.2.] Manufacturers .................................................................................................................... 16
`
`8.2.2 Description of Manufacturing Process and Process Controls ............................................ 17
`
`2.2.1
`
`2.2.2
`
`Process Flow Diagram .............I............................................................................., ............... 17
`
`Description of Process — General Description ....................................................................... 17
`
`8.2.3 Control of Materials .............................................................................................. . ............ 23
`
`

`

`
`
`8.2.4 Control of Critical Steps and Intermediates .......................................................................24
`
`8.2.5 Process Validation and/or Evaluation ................................................................................29
`
`8.2.6 Manufacturing Process Development ................................................................................ 30
`
`2.6.]
`
`2.6.2
`
`2.6.3
`
`Development of —— ......................................................................................... 30
`
`Process Optimization - _
`
`‘———————-
`
`................................................ 32
`
`Development of the Commercial Process ............................................................................. 40
`
`8.3
`
`8.4
`
`8.5
`
`8.6
`
`8.7
`
`Characterization .................................................................................................................41
`
`Control of Drug Substance .................................................................................................52
`
`Reference Standards orMaterials ....................................................... 64
`
`Container Closure System ............................................ 65
`
`Stability......................... ......................................................................................................65
`
`P DRUG PRODUCT [JanuviaTM( sitagliptin phosphate) Tablet] ............................................... 68
`
`P.1
`
`P2
`
`DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT .................................................68
`
`PHARMACEUTICAL DEVELOPMENT ...............................V......................................................70
`
`P23 Manufacturing Process Development ................................................................................... 82
`
`P24 CONTAINER CLOSURE SYSTEM ................................................................................ 98
`
`P25 Microbiological Attributes ...............................................................................
`
`................ 99
`
`P25 Compatibility ..................................................................................................................... 99
`
`P3 MANUFACTURE ........................................................................................ 100
`P.3.1 Manufacturer(s)......................
`...................................................... 100
`P.3.2 Batch Pormula..........................................7........................................................................ 100
`
`P.3.3 Description of Manufacturing Process and Process Controls ........ . ................................. 102
`
`3.3.] General DeScription .............................................................................'............................ 102
`
`P34 Controls of Critical Steps and Intermediates ...................................................................... 114
`
`P.3.5 Process Validation and/or Evaluation .............................................................................. 116
`
`R4
`
`CONTROL OF EXCIPIENTS ......................................................................................... 116
`
`

`

`
`
`P.5
`
`CONTROL OF DRUG PRODUCT .........................................................I.................................. 1 19
`
`R6
`
`REFERENCE STANDARDS OR MATERIALS .......................................................................... 193
`
`R7
`
`CONTAINER CLOSURE SYSTEM ......................................................................................... 193
`
`R8
`
`STABILITY ..................................................................................................................... 199
`
`3.2.A
`
`APPENDICES ..........................................................................,........................................... 2 38
`
`3.2.R
`
`REGIONAL INFORMATION ........................................................................................... 238
`
`II. Review Of Common Technical Document—Quality (CTD—Q) Module 1 .............................. 239
`
`A. Labeling & Package Insert .......................................................................................................... 239
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 242
`
`111. List of Deficiencies To be Communicated ............................................................................248
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet;E
`
`l. NDA 21—995
`
`2. REVIEW #:
`
`1
`
`3. REVIEW DATE: 16—OCT-2006
`
`4. REVIEWER:
`
`Stephen Moore, Ph.D., Christine Moore, Ph.D. and Vibakhar Shah, Ph.D.
`
`5. SPREVIOUS DOCUMENTS:§
`
`Previous Documents
`
`IND 65,495 (MK-0431)
`IND 70,934 (MK—0431A)
`
`6. ‘SUBMISSION(S) BEING REVIEWED:
`
`Submissiong 5) Reviewed
`Original
`Amendments
`
`Document Date
`
`Document Date
`l6-DEC—2006
`13-JUN—2006
`23-JUN—2006
`20—JUL-2006
`21-SEP-2006
`12-OCT-2006
`16—OCT—2006
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Merck and Co., Inc.
`
`Summeytown Pike, PO. Box 4
`BLA-20
`West Point, PA 19486
`USA
`
`Representative:
`
`Telephone:
`
`Steven A. Aurecchia, MD.
`Director Regulatory Affairs
`484-344-4662
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):§
`c) Code Name/# (ONDQA only):
`(1) Chem. Type/Submission Priority:
`_
`Chem. Type:
`Silbinission'PiiorityE:
`
`Januvia
`sitagliptin phosphate
`MK—043I
`
`Type 1 (New molecular entity)
`S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505(b)(1)
`
`1o. fPHARMACOL. CATEGORY?
`
`Hypoglycemic
`
`Page 5 of248
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`11. ngOSAGE FORM:
`
`Tablet
`
`12. gSTRENGTH/POTENCY:
`
`25, 50 and 100 mg
`
`13. §ROUTE OF ADMINISTRATION;
`
`Oral
`
`.
`
`14. Px/OTC DISPENSED:
`
`__x_Rx
`
`OTC
`
`15. ESPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEMllNoteQO]:
`SPOTS product — Form Completed
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT;
`
`Chemical name: 7-[(3R)-3—amino-1—oxo-4-(2,4,5-trifluorophenyl)butyl]—5,6,7,8—tetrahydro-3-(trifluoromethyl)—
`1,2,4-triazolo[4,3—‘a]pyrazine phosphate (1 :1) monohydrate.
`'
`
`Structural formula:
`
`F
`
`F
`
`—'—'
`
`' ‘:~-.
`. .2
`
`15*1
`‘1
`”- {IA-.9,
`”‘9'— TH f'fi“ "in
`I
`N
`
`x
`
`l"5FGq
`
`"gD
`
`(I!
`C: F 1
`
`Molecular formula: C16H15F§N5O-H3O4P-HZO
`
`Molecular weight: 523.32..
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`
`COME/IBM
`REVIEW
`
`
`
`
`COMPLETED
`13—JUL-2006
`
`DATE
`
`
`
`STATUS2
`
`Adequate
`
`HOLDER REEEEEIECED CODEI
`
`Colorcon
`
`___—.
`
`—
`
`”
`
`
`
`
`- ’
`
`N/A
`
`N/A
`
`Lyondell
`
`Page 6 of 248
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l — DMF Reviewed.
`’ Action codes for DMF Table:
`Other codes indicate why the DMF‘was not reviewed, as follows:
`2 ~Type I DMF
`3 ~ Reviewed previously and no revision since last review
`4 — Sufficient information in application
`'
`5 — Authority to reference not granted
`6 — DMF not available
`7 — Other (explain under "Comments")
`2 Adequate7 Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed
`
`B. Other Documents:
`
`DOCUMENT
`
`
`
`
`APPLICATION NUMBER
`DESCRIPTION
`
`
`
`18. STATUS:
`
`Page 7 of 248
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED REVIEWS
`RECOMMENDATION
`DATE .
`REVIEWER
`
`Biometrics
`N/A
`
`
`EES
`Acceptable
`’
`lZ-OCT—2006
`
`Phami/Tox
`N/A
`
`
`Biopharm N/A
`
`LNC N/A
`Methods Validation Pending
`
`
`OPDRA N/A
`EA
`Microbiologx N/A
`
`
`
`
`
`N/A
`
`OGD:
`CONSULTS/ CMC
`
`RELATED REVIEWS
`RECOMMENDATION
`DATE
`REVIEWER
`
`Microbiology
`EES
`
`Methods Validation
`
`
`Labeling_
`_
`
`Bioequivalence
`
`EA
`Radio harmaceutical
`
`
`Page 8 of 248
`
`

`

`
`
` ‘CMC REVIEW — NDA 21995 — Januvia® Table
`
`
`
`The Chemistry Review for NBA 21-995
`
`The Executive Summafl-
`
`]. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This application can be approved with respect to chemistry, manufacturing and controls (CMC).
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`The following statements regarding CMC should be included in the action letter:
`
`1. As indicated in our Information Request (IR) letter dated 07—SEP-2006 and teleconference on
`October 13, 2006, your proposed CMC Regulatory Agreement submitted as part of the CMC Pilot
`Program is under review. Your proposal outlines the regulatory mechanisms for managing
`changes related to process design and control spaces post-approval. While a mutually accepted
`CMC Agreement is not a condition for the approval of this application, it will have implications
`for post—approval changes. Therefore, you are reminded that, until the CMC Agreement is
`approved, the existing regulations and guidances should be followed, as appropriate for the post—
`approval CMC changes.
`
`2. We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified,
`
`II. Summary of Chemistry Assessments '
`
`A. EDesc'ription of the Drug Product(s) and Drug Substance(s)§
`
`Drug Product:
`
`The drug product consists of film coated tablets of 25, 50 and 100 mg strengths packaged in bottles. The active
`ingredient is stigaliptin phosphate in the form of a monohydrate. The strengths, however, are expressed as
`sitagliptin free base. The tablets contain as inactive ingredients microcrystalline cellulose, anhydrous dibasic
`calcium phosphate, croscarrnellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film
`coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide,
`red iron oxide, and yellow iron oxide. The tablet strengths are weight multiples. The tablets have been formulated
`for immediate release (IR). Information on a 200 mg tablet is also provided, however, this tablet does not appear in
`the labeling and is not intended to be marketed.
`
`The applicant indicates that a Quality byDesign (QbD) approach was used to develop a robust formulation and drug
`product manufacturing process. ~—‘—__—_—_—
`
`.
`. w'
`,
`N The excipients were selected to
`provide a chemically and physically stable formulation with optimized performance.
`
`The tablets are manufactured using —— followed by —“
`— The same blend is used for all tablet strengths. Tablet core weights and ~ tablet core
`assays are performed in—process, although the weights and assay measurements are not paired on the same tablet
`cores. Tablets are then film coated for appearance and taste masking in a —
`
`The application includes detailed studies on —— and identification of a ——
`i The applicant indicates that the drug product manufacturing process exhibits no Critical Process Parameters
`
`Page 9 of248
`
`

`

`
`
`,cMc REVIEW — NDA 21995 — Januvia® Tabl
`
`
`
`(CPPs). Failure Modes Effects Analysis (FEMA) was conducted to assess the potential risks related to drug
`substance or excipient variability.
`
`The applicant proposes a "streamlined" approach to quality testing of the drug product. The testing includes
`
`W T
`
`he stabilitv of the drug substance was studied under
`, -,_,\U__———— will be monitored in the
`
`both accelerated and long term conditions.
`stability protocol.
`
`The applicant proposes outlines for the regulatory mechanisms for managing changes related to process design and
`control spaces for the drug product post-approval. An agreementhas not yet been reached regarding these items.
`
`Drug Substance:
`
`The drug substance is sitagliptin phosphate in the form of a monohydrate. The drug substance is a chiral compound
`with a single asymmetric carbon. Its chemical name is 7—[(3R)—3-amino-1—oxo-4L(2,4,5-trifluorophenyl)butyl]—
`5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3—a]pyrazine phosphate (1:1) monohydrate. The drug
`substance in a BCS Class III (high solubility, low permeability) [borderline Class 1 (high solubility, high
`permeability) compound.
`
`The drug substance is chemically;
`
`
`
`The applicant indicates that the drug substance process development included process optimization using Quality by
`Design (QbD) concepts, employing both design of experiments and first principles of chemical engineering unit
`operations. The applicant further indicates that the experiments provided in-depth understanding of the process and
`an increased assurance that the process will consistently provide final drug substance with the appropriate crystal
`morphology, particle size and degree of hydration.
`
`Critical process parameters (CPPs) for the drug substance manufacturing process were identified as ( l) the
`
`.\
`,
`impurities may form in
`Potentlal impurities in the drug substance are descnbed. The . _—"
`the drug substance due to the presence 'of the corresponding -‘r
`impurities in the "
`The maximum level of -— r in drug substance lots used in safety studies was
`
`‘"
`
`The applicant proposes a "streamlined'f approach to quality testing of the drug substance. The testing includes,
`"
`
`-W,.
`and I ——_~—-_..
`_' will be tested in—process only, however the criteria are retained
`inthe specification. Based on development, the drug substance specification will not include testing for _'
`-’ , however, these are controlled in—process. Also based on development, no testing is performed for
`_—————-———— .'. The stability of the drug substance was studied under long term,
`accelerated and stress conditions. The ——-§
`
`The applicant proposes outlines for the regulatory mechanisms for managing changes related to process design and
`control spaces for the drug substance post—approval. An agreement has not yet been reached regarding these items.
`
`Page 10 of248
`
`

`

`
`
`' B. §])escription of How the Drug Product is intended to be Used?
`
`Januvia (sitagliptin phosphate) is an orally active, highly potent, selective competitive reversible inhibitor of
`dipeptidyl peptidase 4 (DPP-4) l and a member of a new therapeutic class of drugs intended to treat type 2 diabetes
`mellitus (T2DM).
`‘
`
`Each film—coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate, which is
`equivalent to 25, 50, or 100 mg, respectively, of free base. Tablets contain the following inactive ingredients:
`microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscannellose sodium, magnesium stearate, and
`sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol,
`polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
`
`The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with
`metforrnin or a peroxisome proliferator—activated receptor gamma (PPARy) agonist (e.g., thiazolidinedione).
`
`Tablets JANUVlA are supplied in bottles and blister packages. Storage is at 20—25°C (68-77°F) [see USP
`Controlled Room Temperature]. The expiration dating period is 30 months.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The applicant has satisfactorily addressed all outstanding CMC deficiencies in the chemistry
`amendments filed to this NDA. All manufacturing facilities have been given an acceptable CGMP
`compliance status.
`
`III. Administrative
`
`This NDA was submitted electronically as a 505(b)(l) application. A Quality Overall Summary is included in the
`application. The CMC information in this NDA was accepted for review under the CMC pilot program (FR Vol. 70,
`No. 134, pp. 40719-40720, July 14, 2005). This program proposes innovative approaches to ensuring product
`quality.
`
`The CMC section of this application was reviewed by a team approach. The review team members selected for the
`quality assessment and their individual responsibilities are listed below:
`
`
`
`Review Team
`Assessment Responsibility
`
`
`Stephen Moore, PhD.
`Team Liaison/Lead
`
`Drug substance section excluding its manufacturing_p_rocess
`Vibhakar Shah,.Ph.D. Drug product section excluding its manufacturing process
`
`
`
`
`
`lDPP—4 inhibitors enhance the levels of active incretin hormones. These hormones, including glucagon—like peptide-l (GLP-l) and glucose-
`dependent insulinotropic peptide (GIP), are released by the intestine in response to a meal. and are part of an endogenous system involved in
`maintaining glucose homeostasis. When blood glucose concentrations are elevated, GLP—l and 01? increase insulin synthesis and release from
`pancreatic beta cells. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-l lowers glucagon secretion from pancreatic
`alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production. However, when‘
`blood glucose concentrations are low, stimulation ofinsulin release and suppression of glucagon secretion by the incretin hormones are not
`observed. The activity of GLP-1 and GlP is limited by the DPP4 enzyme. which rapidly hydrolyzes the incretin hormones to produce inactive
`products. MK-043l prevents this hydrolysis. thereby increasing plasma concentrations of the active forms of GLP-l and 01?. By enhancing
`active incretin levels, the drug increases insulin secretion and decreases glucagon levels. In patients with TZDM and hyperglycemia, these
`changes in insulin and glucagon levels lead to lower fasting and postprandial glucose concentrations.
`
`Page 11 ol‘248
`
`

`

`
`
`CMC REVIEW — NDA 21995 — Januvia® Tibial.
`
`Christine Moore, Ph.D.
`Manufacturing processes including their development both for
`the drug substance and the drug product
`
`
`A. EReviewer’s Signature
`
`See appended electronic signature page.
`
`B. EEndorsement Bloclé
`
`Stephen Moore, PhD./ONDQA/Pharmaceutica] Assessment Lead
`Christine Moore, Ph.D./ONDQA/Branch Chief
`Vibakhar Shah, Ph.D.lONDQA/Reviewer
`Chi-Wan Chen, Ph.D./ONDQA/Deputy Director
`
`C. CC Block
`
`Lina Aljuburi, M.S., Regulatory Project Manager
`
`Page 12 of248
`
`

`

` 3437 Page(s) Withheld
`
`(/ § 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`.
`
`V
`
`§552(b)(5) Draft Labeling
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Stephen Moore
`10/16/2006 05:03:17 PM
`CHEMIST
`
`'
`
`Stephen Moore for Vibhakar Shah, Chemist
`
`Christine Moore
`
`10/16/2006 05:08:22 PM
`CHEMIST
`
`Chi Wan Chen
`
`10/16/2006 05:14:39 PM
`CHEMIST
`
`

`

`INITIAL QUALITY ASSESSMENT
`Office of New Drug Quality Assessment
`Division of Metabolism and Endocrinology Products
`NDA 21-995
`
`Applicant: Merck and Co., Inc.
`Stamp Date: 16-DEC-2005
`PDUFA Date: 16—OCT—2006
`
`Pharmacological Category: Hypoglycemia
`Proposed Proprietary Name: Januvia Tablets
`Established Name: (sitagliptin phosphate tablets) -
`Dosage Form and Strength: 25, 50 and 100 mg tablets
`Route of Administration: oral
`
`Indication(s): Treatment of Type 2 diabetes
`
`PAL: Stephen Moore, Branch II/DPA I/ONDQA
`
`.
`Fileability recommendation: Acceptable for filing
`Review Team Recommendation: The CMC review team was pre-selected by ONDQA office
`and primary reviews started immediately: Stephen Moore (drug substance characterization),
`' Christine Moore (drug substance development and process) and Vibhakar Shah (drug product).
`
`Time goals:
`Initial Quality Assessment in DFS: JAN-2006
`Chemistry filing memo in DFS: 14—FEB-2006
`Filing decision “Day 45”: Filed 14—FEB-2006 (no CMC filing issues stated at internal
`filing meeting 06—FEB-2006)
`'
`Filing review issues “Day 74”: N o CMC filing review issues. Filing letter issued by clinical
`division 27-FEB—2006
`
`.
`
`Chemistry Review (DR/IR) letter: l7—MAY-2006
`Mid—cycle meeting “Month 5”: 17—MAY-2006
`Final Chemistry Review “Month 8” in DF S: 16-AUG—2006
`PDUFA: 16—OCT—2006
`
`
`
`Biopharm/ClinPharm Not applicable
`
`
`REVIEWS
`
`ODS/DMETS
`Methods Validation
`
`Not Applicable
`
`To be assessed by Primary Reviewer(s)
`EER sent to Office of Compliance on 24—JAN-2006
`Labeling consult request will be sent as part of DMEP’s request.
`Validation may be requested of FDA labs after test methods are
`finalized.
`
` CON SULTS/ CMC
`COMMENT
`
`RELATED
`
`
`
`
`
`
`
`
`Microbiology
`Pharm/Tox
`
`
`
`Not Applicable
`Not Applicable
`
`
`
`SUMMARY:
`
`
`
`
`
`

`

`Submission type: This NDA was submitted electronically as a 505(b)(l) application with full clinical
`trials information. The active ingredient, sitigliptin phosphate, is classified as a new chemical entity
`(NCE). A Quality Overall Summary is included in the application. The CMC information in this
`NDA was accepted for review under the Quality by Design (QbD) pilot program (FR V01. 70, No. 134,
`pp. 40719—40720, July 14, 2005). This program proposes innovative approaches to ensuring product
`quality.
`
`Clinical indicationg s l: Januvia (sitagliptin phosphate) is proposed as an orally active, highly potent,
`selective competitive reversible inhibitor of dipeptidyl peptidase 4 (DPP-4) and a member of a new
`therapeutic class of drugs intended to treat type 2 diabetes mellitus (T2DM). DPP-4 inhibitors
`enhance the levels of active incretin hormones. These hormones, including glucagon—like peptide—1
`(GLP-1) and glucose-dependent insulinotropic peptide (GIP), are released by the intestine in response
`to a meal, and are part of an endogenous system involved in maintaining glucose homeostasis. When
`blood glucose concentrations are elevated, GLP—1 and GIP increase insulin synthesis and release from
`pancreatic beta cells. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-l
`lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along
`with higher insulin levels, lead to reduced hepatic glucose production. However, when blood glucose
`concentrations are low, stimulation of insulin release and suppression of glucagon secretion by the
`incretin hormones are not observed. The activity of GLP-1 and GIP is limited by the DPP—4 enzyme,
`which rapidly hydrolyzes the incretin hormones to produce inactive products. MK-043l prevents this
`hydrolysis, thereby increasing plasm