CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`MICROBIOLOGY REVIEW(S)
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`Product Quality Microbiology Review
`
`28 SEP 2010
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`200-678
`
`
`NDA:
`
`Drug Product Name
`Proprietary:
` (proposed)
`
`Non-proprietary: Saxagliptin/metformin HCl extended-release
`
`Assigned to Reviewer
`17 FEB 2010
`N/A
`N/A
`
`
`Review Number:
`
`
`Dates of Submission(s) Covered by this Review
`Submit
`Received
`Review Request
`29 DEC 2009
`29 DEC 2009
`2 FEB 2010
`23 APR 2010
`23 APR 2010
`N/A
`24 SEP 2010
`24 SEP 2010
`N/A
`
`1
`
`
`Applicant/Sponsor
`Name:
`Bristol-Myers Squibb Co.
`
`
`Address:
`P.O. Box 4000
`
`
`
`
` Princeton, NJ 08543-4000
`Representative:
`Pamela J. Smith, M.D.
`Telephone:
`
`609-252-5228
`
`
`Name of Reviewer:
`
`Conclusion:
`
`
`
`
`Jessica G. Cole
`
`Recommend approval.
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`(b) (4)
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`

`

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`Microbiology Review #1
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`NDA 200-678
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`
`A.
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`Product Quality Microbiology Data Sheet
`1.
`TYPE OF SUBMISSION: Original NDA
`
`2.
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`SUBMISSION PROVIDES FOR: New fixed-dose combination product.
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`MANUFACTURING SITE: Bristol-Myers Squibb
`
`
`
`
` 4601 Highway 62 East
`
`
`
`
` Mount Vernon, IN 47620 USA
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY:
`• Oral tablet
`• 5/500 mg, 5/1000 mg, 2.5/1000 mg saxagliptin/metformin HCL-
`XR
`
`METHOD(S) OF STERILIZATION:
`
` oral tablet.
`
`PHARMACOLOGICAL CATEGORY: Indicated for Type 2 diabetes
`treatment.
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`3.
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`
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`4.
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`5.
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`6.
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`B.
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` A
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`SUPPORTING/RELATED DOCUMENTS: None.
`
`REMARKS:
`C.
`The following microbiology information request was included in the 74-day letter to the applicant.
`Reviewer Comment
`Please provide the following information:
`1. The
` in the finished drug product.
`2. The microbial limits test validation studies or a summary of these studies.
`3. The microbial limits testing protocols 5450A, 249965, 249966, and 249967.
`4. A justification for only performing microbial limits testing
` during routine
`production.
`
` response was received 23 April 2010 and the information was incorporated into the relevant sections of
`this review.
`
` A
`
` second comment was sent to the sponsor through the project manager on 7/7/10:
`Reviewer Comment
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`
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`
`. The product specification should
`state that the product will meet the requirements of USP<1111>, if tested. These process controls, tests and
`acceptance criteria should be identified in the batch release criteria, and include, for example:
`
`
`• Microbial limits data for critical raw materials,
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`Page 2 of 10
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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`NDA 200-678
`
`
`•
`
`Microbiology Review #1
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`
`) that may affect product quality
`
`
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`• Microbiological environmental monitoring data for critical processing steps that can be related to
`the batch, and
`In-process control parameters
`microbiology.
`
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`In addition, microbial limits testing should be performed at the initial time point (at a minimum) on
`stability samples.
`
` A
`
` response was received on 24 September and the response was incorporated into the relevant sections of
`this review.
`
`filename: N200678R1.doc
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`Page 3 of 10
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`(b) (4)
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`Microbiology Review #1
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`NDA 200-678
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`Executive Summary
`
`
`Recommendations
`
`A.
`
`Recommendation on Approvability – Recommended for
`approval on the basis of product quality microbiology.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable – Not applicable.
`
`
`Summary of Microbiology Assessments
`
`I.
`
`II.
`
`
`
`B.
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`A.
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`
`B.
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`C.
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`Brief Description of the Manufacturing Processes that relate to
`Product Quality Microbiology – The drug product is a
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`tablet manufactured
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`
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`Brief Description of Microbiology Deficiencies – Not applicable.
`
`Assessment of Risk Due to Microbiology Deficiencies – Not
`applicable.
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`Reviewer's Signature _____________________________
`
`
`
`
`Jessica G. Cole, Ph.D.
`
`Endorsement Block _____________________________
`
`
`
`
`Stephen Langille, Ph.D.
`
`
`
` Senior Microbiology Reviewer
`
`
`CC Block
`N/A
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`Page 4 of 10
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`III. Administrative
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`A.
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`B.
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`C.
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`(b) (4)
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`(b) (4)
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`6 Page(s) have been Withheld in
`Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JESSICA COLE
`09/29/2010
`
`STEPHEN E LANGILLE
`09/29/2010
`
`Reference ID: 2842556
`
`

`

`PRODUCT QUALITY MICROBIOLOGY FILING CHECKLIST
`NDA Number: 200678
`Applicant: Bristol-Myers
`Letter Date: 12/29/2009
`Squibb
`NDA Type: Standard
`
`Stamp Date: 12/29/2009
`
`Comments
`
`
`
`
`
`Protocols for microbial
`limits testing not
`provided.
`
`
`Not applicable
`
`.
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`
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`No information is
`provided on the
`verification studies for
`microbial limits testing.
`
`Not applicable.
`
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`
` X
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` X
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` X
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` X
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` X
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` X
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` X
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`1
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`Drug Name:
`Saxagliptin/Metformin XR
`
`The following are necessary to initiate a review of the NDA application:
`Content Parameter
`Yes No
`
`
`Is the product quality microbiology information described
`in the NDA and organized in a manner to allow substantive
`review to begin? Is it legible, indexed, and/or paginated
`adequately?
`
`2 Has the applicant submitted an overall description of the
`manufacturing processes and microbiological controls used
`in the manufacture of the drug product?
`3 Has the applicant submitted protocols and results of
`validation studies concerning microbiological control
`processes used in the manufacture of the drug product?
`4 Are any study reports or published articles in a foreign
`language? If yes, has the translated version been included
`in the submission for review?
`5 Has the applicant submitted preservative effectiveness
`studies (if applicable) and container-closure integrity
`studies?
`6 Has the applicant submitted microbiological specifications
`for the drug product and a description of the test methods?
`7 Has the applicant submitted the results of analytical method
`verification studies?
`
`8 Has the applicant submitted all special/critical studies/data
`requested during pre-submission meetings and/or
`discussions?
`Is this NDA fileable? If not, then describe why.
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`9
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`Additional Comments: Please provide the protocols (5450A, 249965, 249966, and 249967) and
`the validation studies for the microbial limits tests.
`
`
`
`
`Jessica G. Cole, Ph.D.
`
`
`Bryan S. Riley, Ph.D. Senior Review Microbiologist
`
`X
`
`
`
`
`
` 2/3/2010
`
`Date
`
`
`
`Date
`
`(b) (4)
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`

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`Application
`Type/Number
`--------------------
`NDA-200678
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`BRISTOL MYERS
`SQUIBB
`
`------------------------------------------
` (saxagliptin +
`metformin XR) Tablets
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JESSICA COLE
`02/03/2010
`
`BRYAN S RILEY
`02/03/2010
`I concur.
`
`(b) (4)
`
`