CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`»
`
`22-350
`
`CHEMISTRY REVIEWg S!
`
`

`

`Onglyza
`(saxagliptin) tablets
`NDA 22-350
`
`Summary Basis for Recommended Action
`
`From Chemistry, Manufacturing, and Controls
`
`Applicant:
`
`Bristol-Myers Squibb Company
`PO. Box 4000
`
`Princeton, NJ 08543-4000
`
`Indication:
`
`Saxagliptin is an orally active reversible dipeptidyl peptidase—IV (DPP—IV)
`inhibitor proposed for the treatment of type 2 diabetes.
`
`Presentation: Onglyza (saxagliptin) tablets are film coated tablets containing 2.5 mg or
`5 mg, .2.»-
`. Both strengths will be available in 30 count (95 ml)
`
`and 500 count (200 m1) white opaque
`bottles with
`desiccant. The 5 mg tablets will be additionally available in aluminum/
`aluminum blisters.
`
`M4)
`
`EER Status: Acceptable, 26-FEB-09
`
`Consults:
`
`Methods Validation — Revalidation by Agency was not requested
`EA — Categorical exclusion granted under 21 CFR §25.3l(C)
`
`Original Submission: 30-JUN-08
`
`Post-Approval Agreements: None
`
`. Background for CMC Section of Application
`
`The CMC portion of this NDA was submitted as part of the ONDQA CMC Pilot
`Program to explore science and risk based approaches to assuring product quality.
`A Comprehensive Quality Overall Summary was provided in Module 2 and an
`expanded pharmaceutical development section was submitted in Module 3,
`Section P2. The applicant applied several Quality by Design (QbD) principles in
`the pharmaceutical development and manufacturing approaches.
`
`Drug Substance:
`
`monohydrate form.
`The drug substance for Onglyza is saxagliptin in
`The formal chemical name is (lS,3S,5S)-2-[(2S)—2—Amino-2-(3-hydroxytricyclo
`[3.3.1 .l3,7]dec-1-yl)acetyl]-2-azabicyclo[3. l .0]hexane—3-carbonitrile,
`monohydrate. The molecular structure is provided as follows:
`
`M4)
`
`
`
`

`

`0 H20
`
`CN
`
`The molecular formula is: C13H25N302 - H20 with a calculated molecular weight
`of 333.43. Saxagliptin has been chemically and structurally characterized using:
`
`-
`
`C.
`C
`
`,,
`
`a
`‘
`
`.3
`D
`
`M4)
`
`"
`
`m4)
`"
`
`”(4}
`
`Saxagliptin drug substance will be manufactured at the BMS facility in Swords,
`Ireland using a -—-—~
`commercial process from / starting materials.
`
`The NDA contained expanded information for the synthesis and process
`development of saxagliptin, using Quality by Design approaches. The approach
`included identification the critical quality attributes of the drug substance,
`identification of critical and “key” process parameters, and the implementation of
`process controls for producing drug substance of the desired quality. Several
`statistically designed experiments (DOES) were utilized in the drug substance
`process development. The application included a design space for drug substance,
`allowing for increased flexibility for manufacturing. Drug substance quality is
`assured through manufacturing process controls combined with conventional end-
`product testing, including appearance, color, identification, and assay and
`impurities/degradants by
`High Performance Liquid
`Chromatography /-HPLC).
`
`.
`
`Based on the 32-month primary stability data for saxagliptin drug substance from
`Process C and the 12-month primary stability data for saxagliptin drug substance
`from Process D, stored at 5°C (i3°C), a If” , period for the drug
`substance is granted with the following label statements:
`
`K
`
`._
`
`.
`
`9 11(4)
`
`Conclusion: Drug substance is satisfactory
`
`

`

`Drug product
`
`Onglyza (saxagliptin) tablets is an immediate release tablet, with the following
`description:
`
`0
`
`0
`
`2.5 mg tablet, containing 2.79 mg saxagliptin hydrochloride (anhydrous):
`round, biconvex yellow tablet printed with “2.5” on one side and “4214”
`on the other side, with a tablet weight of 236mg
`5 mg tablet, containing 5.58 mg saxagliptin hydrochloride (anhydrous):
`round, biconvex pink tablet printed with “5’ on one side and “4215” on the
`other side, with a tablet weight of 239 mg
`
`Based on tablet dimension measurements, saxagliptin film coated tablets, 2.5 mg,
`and saxagliptin film coated tablets, 5 mg, are expected to have an average
`thickness of 4.2 mm and average diameter of 8.2 mm.
`
`11(4)
`
`The saxagliptin film coated tablets contain the following excipients: lactose
`monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium
`
`state,
`‘
`yellow (2.5 mg), \— pink (5 mg tablet),
`
`,
`No novel excipients are used in the
`manufacture of saxagliptin film coated tablets. The drug loading for both
`strengths is relatively low at less than /
`
`M4)
`
`The drug product is manufactured by a —/‘ coating process in a
`
`
`
`M4)
`
`W)
`
`The enhanced pharmaceutical development provided in the application included
`use of risk assessment and DoEs to evaluate the criticality of process parameters
`and support development of the control strategy and design space. In addition,
`experimental data was leveraged to develop a mechanistic model of the coating
`operation used to predict process performance. Drug product quality is assured
`through manufacturing process controls combined with conventional end-product
`
`

`

`testing, including identification, dissolution, water content, uniformity of dosage
`units, and assay and impurities/degradants by \HPLC.
`
`MM.
`
`Saxagliptin film coated tablets will be packaged and marketed as 30 and 90 count
`in 95 mL and 500 count in 200 mL white, opaque, ’ I’M
`. bottles, with a two piece child resistant closure having an aluminum foil
`induction seal. Each bottle contains a cotton coil and one 2g pouch containing
`silica gel (desiccant) and activated carbon. 5 mg saxagliptin film coated tablets
`will also be packaged and marketed in aluminum/aluminum (alu/alu) blisters.
`
`N4)
`
`Based on provided stability data, the 2.5 mg strength saxagliptin tablets are
`granted a 36 month stability period for 30 and 90 count bottles containing
`desiccant. The 5 mg strength saxagliptin tablets are granted a 36 month stability
`period for 30, 90 and 500 count bottles containing desiccant, and 36 month
`stability period when stored in aluminum/aluminum blisters. Both the 2.5 mg and
`5 mg strengths contain the following labeling statement: “Store at 25°C (77°F);
`excursions permitted to 15°~30°C (59°-86°F) [see USP Controlled Room
`Temperature].
`
`Conclusion: Drug product is satisfactory.
`
`Additional Items:
`
`All associated Drug Master Files are acceptable or the pertinent information has
`been adequately provided in the application.
`
`The analytical methods used in the testing procedures (release, stability and in-
`process) are well known and widely used by the biopharmaceutical
`industry;
`revalidation by Agency laboratories will not be requested.
`
`The application includes design space for both drug product and drug substance.
`
`A comparability protocol for extensive changes that could be made with reduced
`reporting requirements was originally submitted in the application but was later
`withdrawn. The applicant expressed interest in submitting a revised version of the
`comparability protocol as a supplement at a later date following additional
`discussion and clarification from the Agency.
`
`Overall Conclusion: From a CMC perspective, the application is recommended for
`approval.
`.
`
`Christine M. V. Moore, Ph.D.
`Acting Director, DPA I/ONDQA
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Christine Moore
`4/17/2009 10:47:05 AM
`CHEMIST
`
`

`

`Overall Summary of Quality
`
`NDA 22-350
`
`Onglyza (saxagliptin) IR tablets
`
`Bristol—Myers Squibb (BMS)
`
`ONDQA CMC Pilot Program Application
`
`CMC Quality Review Team
`
`Sharmista Chatterjee, Ph.D.
`
`John C. Hill, Ph.D.
`
`Prafull K. Shiromani, Ph.D.
`
`Suong T. Tran, Ph.D.
`
`

`

`I. Overview
`
`This Overall Summary of Quality is intended to provide a synopsis of the review teams’
`thoughts, deliberations and decisions associated with the CMC review of NDA 22-350,
`. Onglyza (saxagliptin) IR tablets. The intent is to capture the teams’ thoughts to facilitate
`future CMC supplement review and ONDQA discussions about regulatory submissions
`containing Quality by Design (QbD) information. This application was submitted as part
`of ONDQAs’ CMC Pilot Program, published in the Federal Register (Vol. 70, No.134,
`July 14, 2005).
`
`Initial evaluation of this NDA and the decision as to its fileability was conducted by the
`PAL assigned to this project, Su Tran. This Initial Qiality Assessment (IQA) review is
`filed in DFS/DARRTSI.
`
`In this initial assessment, several critical CMC deficiencies were identified and
`communicated to the applicant in the filing memo. The timely responses to these
`deficiencies provided critical CMC information to facilitate the full CMC evaluation of
`this NDA.
`
`The team review process for this specificpilot program application consisted of several
`independent reviews from each of the team members. These reviews were filedwithin
`the regulatory review timelines mandated under the Good Review Management
`Principles guidance. Each of these reviews focus on specific aspects of the CMC review,
`specific to the area of expertise of the individual reviewer. These reviews have been
`entered into DFS/DARRT82’3’4:
`
`Each of these reviews resulted in several CMC deficiencies which were communicated to
`the applicant. The evaluations of the responses to these deficiencies have also been
`entered into DFS/DARRTSS’6’7.
`
`The current document summarizes the pertinent issues discussed in the six individual
`reviews filed in DFS/DARRTS.
`
`II. Description of the Drug Product(s) and Drug Substance(s)
`
`' Initial Quality Assessment: Su Tran (chem.IQA/filing,27-AUG-2008)
`2 Drug substance CMC/QbD review: Prafull Shiromani (CMC Review 1, 28-OCT-2008)
`3 Drug product CMC/QbD review: Sharmista Chatterjee (Drug Product QbD Review, 24-NOV-2008)
`4 Overall CMC review: John Hill (CMC Review #1 for NDA 22-350, 08-DEC-2008)
`5 Drug substance CMC/QbD review: Prafull Shiromani (CMC Review 2, 23-MAR-2009)
`6 Drug product CMC/QbD review: Sharmista Chatterjee (Drug Product QbD Review, 23-MAR-2009)
`7 Overall CMC review: John Hill (Review, 23-MAR—2009)
`
`

`

`Drug Product
`
`‘ /'-—"‘ will be
`Saxagliptin film-coated tablets, 2.5 mg and 5 mg i’
`manufactured at the BMS facility in Mount Vernon, Indiana. Saxagliptin film
`coated tablets, 2.5 mg and 5 mg strength- \——— , have been
`developed for commercializationThe active in the drug product is the
`hydrochloride salt form of the drug substance. The structure for this salt form is
`provided as follows.
`
`11(4)
`
`H N+
`
`N
`
`- CI-
`
`CN
`
`Molecular Formula: C18H25N3Oz * HCl
`
`Molecular Weight: 351.87
`
`Since subjecting saxagliptin to common pharmaceutical operations such as
`
`M4)
`
`31(4)
`
`11(4)
`
`

`

`”(4)
`
`M4)
`
`M4)
`
`Based on tablet dimension measurements, saxagliptin film coated tablets, 2.5 mg,
`and saxagliptin film coated tablets, 5 mg, are expected to have an average
`thickness of 4.2 mm and average diameter of 8.2 mm.
`
`The saxagliptin film coated tablets contain the following excipients: lactose
`monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium
`state,
`.——————-
`yellow (2.5 mg),/’ pink (5 mg tablet),
`.
`_____. No novel excipients are used in the
`manufacture of saxagliptin 1 m coated tablets. Due to the M
`system, traditional excipient compatibility studies were not performed for the
`saxagliptin drug substance, it was addressed through saxagliptin stability studies.
`
`The two strengths will be differentiated by color and printing on the tablets.
`
`-
`
`o
`
`2.5 mg tablet, containing 2.79 mg saxagliptin hydrochloride (anhydrous):
`Round, bi-convex yellow tablet printed with “2.5” and “4214”
`5 mg tablet, containing 5.58 mg saxagliptin hydrochloride (anhydrous):
`Round, bi-convex pink tablet printed with “5’ and “4215”
`
`Saxagliptin film coated tablets will be packaged and marketed as 30 and 90 count
`in 95 mL and 500 count in 200 mL white, opaque,
`---——-"""—'—"“
`”T 7": bottles, with a two piece child resistant closure having an aluminum foil
`induction seal. Each bottle contains a cotton coil and one 2g pouch containing
`silica gel (desiccant) and activated carbon. 5 mg saxagliptin film coated tablets
`will also be packaged and marketed in aluminum/aluminum (alu/Alu) blisters.
`
`The quality of the drug product is assessed by visual and ’~ High
`Performance Liquid Chromatography (’-HPLC) methods and assured by
`Quality by Design (QbD) principles.
`
`Saxagliptin is a highly potent, selective, reversible, and competitive dipeptidyl
`.peptidase—4 (DPP4) inhibitor. DPP4 is the enzyme primarily responsible for the
`inactivation of the incretin hormones glucagon-like peptide-l (GLP-1) and
`glucose-dependent insulinotropic polypeptide (GIP). Incretin hormones are
`gastrointestinal hormones that increase insulin secretion in response to enteral
`stimulation. These hormones contribute to the control of postprandial glucose
`excursions in a glucose dependent manner, mitigating the risk of hypoglycemia.
`In addition to enhancing postprandial insulin release, GLP-l also reduces
`glucagon release from the pancreatic (Jr-cells, thereby reducing hepatic glucose
`production. This effect is also glucose-dependent, such that when plasma glucose
`is normal or low, the counter-regulatory response of glucagon release is not
`impaired.
`
`Saxagliptin is intended to improve glycemic control for patients with T2DM:
`- as monotherapy as an adjunct to diet and exercise;
`
`

`

`- in combination with metformin, a thiazolidinedione (TZD), or a
`sulfonylurea (SU)when the single agent alone, with diet and exercise does
`not provide adequate glycemic control; and
`‘
`- as initial combination with metformin, as an adjunct to diet and exercise,
`when treatment with dual saxagliptin and metformin therapy is
`appropriate.
`
`The proposed usual clinical dose is 5 mg once daily. The recommended dose is
`2.5 mg once daily in subjects with moderate or severe renal impairment, and end-
`stage renal disease requiring hemodialysis.
`
`Drug substance
`
`Saxagliptin drug substance will be manufactured at the BMS facility in Swords,
`Ireland using a /-— step commercial process fronV‘ starting materials. The
`A” , is used in the manufacture of
`saxagliptin tablets.
`
`M4)
`
`The Drug substance is saxagliptin. The formal chemical name is (lS,3S,5.S’)—2-
`[(23)-2-Amino—2-(3-hydr0xytricyclo [3 .3 . l . 1 3,7]dec-1 —y1)acetyl]-2-
`azabicyclo[3.l .0]hexane-3-carbonitrile, monohydrate. The molecular structure is
`provided as follows:
`
`no
`
`HzN
`
`I H20
`
`N
`
`CN
`
`The molecular formula is: C13H25N302 - H20 with a calculated molecular weight
`of 333.43.
`
`Sanapliptin has been chemically and structurally characterized using: P‘ ‘
`
`
`
`Saxagliptin drug substance is manufactured using a' / step commercial process
`from /starting materials. The lm is used in the
`manufacture of saxagliptin tablets.
`
`I1(4)
`
`

`

`Based on the 32-month primary stability data for saxagliptin drug substance from
`Process C and the lZ-month primary stability data for saxagliptin drug substance
`from Process D stored at 5°C (13°C), a ’ [period for the drug
`substance is granted with the following label statements:
`
`\
`
`III. Background
`
`The Quality section of the NDA was submitted as part of the FDA’s CMC Pilot Program.
`On June 9, 2006 EMS requested acceptance into the Agency’s CMC pilot program. BMS
`met with the Agency on August 14, 2006, to outline the saxagliptin QbD program and
`was accepted into the program on September 5, 2006. In the meeting minutes, FDA
`indicated BMS should submit a comprehensive Quality Overall Summary (QOS) and an
`expanded Pharmaceutical Development Section. BMS met with the Agency on April 26,
`2007 to further discuss BMS’s progress in the saxagliptin QbD development program.
`FDA agreed to BMS’s proposed NDA content, which would include a comprehensive
`QOS and an expanded Section 3.2.P.2 “Pharmaceutical Development.”
`
`The FDA provided the following in response dated November 18, 2005 to a CMC-
`specific End of Phase II Briefing Document, submitted August 22, 2005 (IND
`63,634,Serial No. 0085):
`
`would be acceptable
`o The starting materials
`provided appropriate technical information as outlined in the Agency’s reply is
`provided.
`0 Acceptance of the drug substance long term stability protocol.
`0 The Agency suggested the utilization of protocols to address changes to vendors,
`manufacturing processes, impurity profiles and acceptance specifications for
`starting materials, as well as changes to the manufacturing process and acceptance
`specifications for bulk drug substance.
`0 Acceptance of the proposed dissolution methodology which utilizes USP
`Apparatus II at 50 RPM in 0.1 N HCl.
`0 The Agency recommended modifying the drug product long term stability
`protocol for bottles, and accepted the proposed bracketing for blisters. The agency
`recommended modifying the proposed matrix to include testing each lot at the
`final time point.
`
`BMS submitted additional information on April 12, 2007 (IND 63,634 Serial No. 0189)
`on the proposed starting materials, along with information about the proposed
`commercial drug substance manufacturing process and our proposal to utilize data from
`both Process C and Process D to determine the drug substance re-test period. Also, BMS
`requested comments on a proposed change to the dissolution method approved during
`
`

`

`review of the End of Phase II briefing document. The Agency’s response received via
`electronic mail on May 3, 2007 and May 11, 2007 indicated the following:
`
`0 The proposal to base the retest period on long-term stability data obtained on both
`Process C and D was acceptable
`0 The proposed modification to the dissolution method was acceptable
`0 The Agency had no objection to the information provided on starting materials.
`0 The Agency requested BMS address the possibility of low levels of the
`"_'—_’
`
`in the drug substance.
`0 Discuss in the NDA observations regarding the behavior of saxagliptin tablets
`during dissolution testing.
`
`M4)
`
`12(4)
`
`BMS submitted Pre-NDA CMC questions to the Agency on December 27, 2007 (IND
`63,634 Serial No. 0238). A response to these questions was received via electronic mail
`on February 15, 2008. The FDA had no comments on BMS’ plan to submit 18- and 24-
`month LTSS data during the NDA review provided it was submitted no later than 6
`months after submission of the NDA. In addition, the Agency indicated that it would not
`be able to review a Post-Approval Management Plan as outlined by EMS, but that BMS
`had the option of submitting one or more comparability protocols permissible under the
`current draft guidance. As a result of these responses, BMS submitted a Comparability
`Protocol as part of the saxagliptin NDA.
`
`BMS submitted the NDA on June 30, 2008. Some of the issues identified in the Initial
`Quality Assessment1 were:
`
`0 Lack of characterization information on saxagliptin hydrochloride, the active
`ingredient form in the drug product
`
`0 Different dosage strengths having! .———-——-—————-——-——.W
`
`0 Lack of information ( 7AMr‘~——-“"—'——.
`
`0
`
`' 6"” not being proposed as a Critical Quality Attribute in the drug product
`manufacture ‘ ”m
`0 Use of2M
`
`Understanding and Design Space” studies
`0 Lack of Dissolution in the drug product specification
`
`h(4)
`
`l1(4)
`
`These and other issues identified in the IQA were addressed in subsequent reviewsz’z’4
`and adequately resolved.
`
`IV. Assessment of Implementation of Quality by Design
`
`As part of the pilot program, BMS was expected to include in this NDA an expanded
`Pharmaceutical Development section and critical CMC information that appropriately
`demonstrate product knowledge and process understanding of the drug substance and
`drug product using QbD principles and science-based approaches. In addition, a more
`
`

`

`comprehensive Quality Overall Summary (cQOS) summarizing all critical CMC
`elements, along with an evaluation and assessment of those elements was expected.
`
`These sections have been included in NDA 22-350. As part of the pilot program, the
`expanded pharmaceutical sections for both the drug substance and drug product have
`been independently assessed as part of ONDQA’s team review philosophy. Several
`deficiency letters have been communicated to EMS and their responses have been
`received and evaluated.
`
`The six reviews filed in DFS for this application 2’3’4’5’6’7 reflect the teams’ evaluation of
`the overall quality of the CMC data provided. Each review reflects the strengths and
`expertise of the individual team members. While these evaluations have been filed
`independently, significant team discussions about the adequacy of the CMC data
`submitted have provided a unifying focus to the review process. The result is an in-depth
`evaluation of the overall QbD data (both drug substance and drug product) which BMS
`has provided in support of this application and the applicability of these data to aspects of
`the general chemistry and stability of saxagliptin.
`
`After thorough evaluation of the quality data presented in this NDA, it is clear that BMS
`has demonstrated an understanding and implementation of aspects of QbD. The review
`process has also. identified areas in which BMS would benefit from further exploration,
`development and refinement of their design space.
`
`In general, the positive aspects of this QbD application have been identified as:
`
`0 The depth of specific information describing the control of the starting materials
`‘ ‘M—fl md
`
`the manufacturing of the drug substance (DS). This information includes
`- acceptable rationale for proven acceptable ranges (PARS) of reaction parameters
`and determination of the criticality of these parametersLPagM'g- ”- "2").
`
`o The implementation of suitable in-process PAT controls, e.g. 'a
`W (above
`reference: page 10).
`
`o The implementation ofQbD during dexielopment ofthe DS manufacturing
`process, facilitating the identification 0 critical and key process parameters.
`Critical Quality Attributes have also been identified (above reference: pages 45, 46, 52).
`
`0 The establishment of proven acceptable ranges (PARS) and normal operating
`ranges (NORs) to ensure consistent quality and yield of the DS. It is noteworthy
`that the NORs for the manufacture of the drug substance are within the
`experimental range studied in the DOE for the drug substance. All the
`experiments performed in this DOE produced high—quality drug substance thus,
`substantiating these NORs, i.e. the Design Space (above reference: pages 54,57).
`
`

`

`Rationale for selection of formulation variables e.g. coating thickness, choice of
`coating material, ratio of drug substance to p, in the coating suspension, pH
`of coating suspension3.
`
`M4)
`
`Presentation of scientific rationale for designating various drug product (DP)
`quality attributes as critical3.
`
`Implementation of a scientific, top down risk assessment methodology as per ICH
`Q9, e.g. use of '/"" diagrams, to determine operations that were critical to
`drug product quality. Once the critical operation was identified, risk assessment
`methodology was again used to determine the critical sub steps. The critical sub
`steps were then examined in detail using a combination of risk assessment and
`DOE based experimentation3.
`
`M4)
`
`Following a step by step rationale approach to determine DP manufacturing
`design space for critical variables at pilot scale based on DOE data and then scale
`to commercial scale3.
`‘
`
`approach to leverage understanding gained from
`Use of w————/‘
`experimentation related to DP manufacturing and use it to limit future trial and
`error type experiments.
`
`Presenting a rationale approach to use the
`a new operating range within/outside the design space3.
`
`
`
`model to select
`
`Points where BMS would benefit from further exploration and development include:
`
`Provide alclear thesis/rationale for why they decided to submit the additional
`QbD, DoE and expanded manufacturing data in the application and what their
`expectations were (what regulatory actions or relief were they seeking)
`
`The mathematical model and associated statistical analyses for the DOE
`associated with the manufacture of sazxagliptin were not presented/explained
`adequatelym the original submissionz. Preferably, these data should be presented
`in a systematic manner, with a few appropriate concise tables, e. g i) Independent
`(X) and Dependent (Y) variables for the particular DOE; ii) Experimental range-
`statistical and corresponding physical units of Xs; iii) Yates Algorithm - the value
`of Xs for each experimental batch - with the whole set of experimental batches
`manufactured in a random order so as minimize experimental error; iv) Table of
`Y- values for each batch with mean and SD; v). Mathematical model/equation
`generated by the computer from the input raw Ys' data in the form: A
`" 7"
`
`Correlation coefficients (R2)— to determine the fit ofeach
`g
`Y to the computer generated model; vii) Optimum Formulation- through
`computer search techniques (feasibility and grid searches); viii) Validation
`
`l1(4)
`
`11(4)
`
`

`

`experiment and it's data to confirm predictive power of the predictor equation; xi)
`Determination of critical Ys, i.e. Model Reduction/Refinement, by Principal
`Component Analysis or comparison of each regression coefficient with the
`standard error; x) Contour and Response Surface Plots, (in all fairness, this
`deficiency is not restricted to this BMS NDA, but to a few recent NDAs with
`QbD elements; this should be resolved, eventually, as the QbD paradigm
`becomes the norm in drug product development).
`
`Provide data justifying criticality analysis of excipients, i.e. to show if any
`variation in excipient properties would impact CQA of finished product. For
`example no data was presented to show if lot to lot variation in amounts
`.—--—-
`
`would have an impact on quality of drug
`product. This information was provided as a response to an information request
`letter6, response to comment #4, pg 6.
`
`Lumping several variables to assess probability (P), severity (S) and risk (R)
`while performing risk assessment for DP manufacturing process variables.
`Individual effects are thus masked. Upon communicating this deficiency to the
`sponsor, they a eed to follow the suggested approach for future submissions6’
`response to comment
`, pg 13)
`
`Lack of assurance of the controls in place to ensure content uniformity of finished
`drug product, especially for movements outside the target operating conditions
`within the design space, at commercial scale6’ “m”, P31).
`
`Some gaps identified in not evaluating interaction of design spaces. For example,
`sponsor did not evaluate interaction of PAR of nozzle parameter with variation in
`equipment design. They agreed to add appropriate manufacturing controls in the
`batch record in terms of nozzle dimensionsé’ “’5me ‘° ”men‘s” and 8’ pg 13’ 18).
`
`Lack of data presented in the original submission to show how proven acceptable
`ranges for critical coating process variables were scaled from pilot to commercial
`scale, for example no scale up correlations were resented. This was provided
`later in response to an information request letter ”65pm” t° °°mme“t#l4’ Pg 25).
`
`Minimal information was provided in the original submission about the in-process
`assay that is performed after at least ’——_——_~.‘—"
`u
`. Note, this in process step is performed only at
`commercial scale,A
`Similar in process step was not deemed necessary at pilot scale. Adequate
`information was provided about this assay in response to IR letters6’ ”pm” t° °°mm°m
`#16, 17,18 pg 28, 32-34)
`
`M4)
`
`It is opined that if this was well understood and controlled at all scales, such an in
`process step would not have been required at commercial scale. Having said that,
`
`10
`
`

`

`the in process step would give additional assurance that the final product would
`meet the criterion for assay.
`
`Lack of assurance in the original submission about procedures for handling
`movements within design space at commercial scale. In addition, some critical
`manufacturing procedures and controls including the design space table were not
`included in the P3 section. These omissions were corrected subsequentlsy via
`.
`1
`amendments to the NDA, 1n response to IR letters6’ ”Spmsm cmmems #3’ 4 ’
`6’ H’ 5 pg
`13-16, 19, 26-28)
`
`Insufficient information presented in the original submission for the DOE’s that
`were used for formulation and manufacturing process development (e.g. statistical
`analysis of the DOE data). These omissions were corrected subsequently via
`I‘CSponS6 to IR letters6’ response to comments #6, 21 pg 8, 36 respectively).
`
`I1(4)
`
`2
`
`1
`
`f
`
`11(4)
`
`< 5
`
`V. Notes for future inspections and Supplement Reviews
`
`1.) The applicant executed a statistically designed set of experiments (DOE) to test and
`verify the ranges proposed for key and critical process parameters of the/
`/
`1 process. The primary
`
`/purpose ofthe DOE was to confirm that the critical impurity/
`
`l_ was
`
`adequately controlled. Indeed, all/
`
`lexperiments, covering the extreme values of
`
`ll
`
`W“
`
`

`

`the parameters studied, produced drug substance with ~—- below the
`,7 reporting limit of the HPLC method. None of the main effects were
`significant, as determined by appropriate statistical tests, and hence, it was assumed
`that the associated f were insignificant. The applicant found that
`the quality of the drug substance1n each of these experiments was indistinguishable
`from the quality of the drug substance produced at commercial manufacturing scale.
`Based on the DOE results and the alignment between the DOE and commercial
`manufacturing batch quality, BMS believes that the design space proposed for the
`drug substance manufacture has been substantiated, to which this reviewer concurs.
`Accordingly, movement within the design5space requires no agency notification
`during routine commercial manufacturings.
`
`2.) One interesting feature in the developmental report for the saxaglintin drug nrodnct
`
`\
`
`\
`
`/
`
`\
`
`K
`
`\/"
`
`.
`
`b”)
`
`h(4)
`
`3.) A lingering concern is the issue of demonstration of adequate tablet content
`uniformity when moving outside the target operating condition but within the design
`space for active coating of tablets ’—"—" 1‘0 be noted that this is a
`relatively low dose drug (<2.5%) and USP<905> is currently followed to demonstrate
`content uniformity. The concern is based in part on the fact that it is noted that there
`is an increase in /" when moving outside the target operating condition (refer
`table 13. 1'1n amendment # 17 to the NDA dated January 21, 2009 )3. It1s
`recommended to evaluate the sponsor’s quality system to ensure that it includes
`appropriate sampling to assure content uniformity when moving outside the target
`operating condition but within the design space at commercial scale.
`
`bkfi
`
`4.) If the opportunity arises, participation by an ONDQA reviewer in any inspection to
`support a Prior Approval Supplement dealing with modification of the approved
`
`12
`
`

`

`design space is recommended. Onsite inspection by the reviewer would be beneficial
`to the investigator to understand the various approaches to QbD.
`
`5.) In the NDA application, BMS did not include dissolution as a regulatory requirement
`for final drug product release or stability. In order to attain approval of their
`application, BMS has agreed to include a regulatory test for dissolution for release
`and stability. The Agency indicated that we were open to discussions about
`alternative tests for dissolution/bioavailability in the future.7. The upshot of this
`action is that there will be further interactions/meetings with the applicant to explore
`alternative method(s) to evaluate dissolution. Such discussions will require
`participation by ONDQAs’ Biopharrn review staff.
`
`6.) The stability data for the saxagliptin 2.5 mg coated tablet packaged1n blisters
`—'—‘
`demonstrate that this packagingis not as robust as the Alu/Alu blister or
`the /bottle configuration. The stability data demonstrate that thereis a humidity
`and temperature affect on overall impurity profile; elevations1n either lead to the
`drug product failing to pass the proposed stability specification4. In the 74 day filing
`letter (12-SEP-2008), BMS was asked to Clarify whether the 2.5 mg tablets will be
`packaged in blisters because this packaging is not in the proposed labeling even
`though this packaging is listed for this dosage strength in the Container Closure and
`Stability sections of the NDA. In their response dated 15-OCT—2008, EMS states that
`they plan to launch the 2.5 mg tablets1n bottles. Subsequently, blister packs might be
`added for hospital unit doses and physician samples.7 Potentially, there will be a
`CMC supplementin the future requesting review and _127-“
`
`.7
`In such a case, the impact of the proposed blister
`material (moisture permeability, etc.) will be an important review consideration
`
`”(4)
`
`M4)
`
`l3
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`John C. Hill
`4/3/2009 10:24:03 AM
`CHEMIST
`
`Suong Tran
`4/3/2009 10:32: