`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206073Orig1s000
`
`MICROBIOLOGY / VIROLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`Y’silVICA-s.
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`
`DEPARTNIENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`08 August 2014
`
`TO:
`
`NDA 206073
`
`FROM:
`
`Erika Pfeiler, PhD.
`
`Microbiologist
`CDER/OPS/NDMS
`
`THROUGH:
`
`Stephen Langille, Ph.D.
`Senior Review Microbiologist
`CDER/OPS/NDMS
`
`cc:
`
`Callie Cappel—Lynch
`CDER/OND/ODEII/DMEP
`
`SUBJECT:
`
`Product Quality Microbiology assessment of Microbial Limits for
`Empagliflozin and Linagliptin tablets [Submission Date: 29 January
`2014]
`
`The NDA for Empagliflozin and Linagliptin tablets presents a waiver for microbial limits
`testing for product release, and the applicant provides a suitable rationale for the exclusion of
`this testing. Therefore, this submission is recommended for approval from the standpoint of
`product quality microbiology.
`
`The product is a fihn-coated tablet with 10 mg/5 mg and 25 mg/5 mg (Empagliflozin/Linagliptin)
`presentations.
`
`The drug product is manufactured
`The applicant presents a rationale for waiving microbial limits testing for product
`release and stability. The rationale describes raw material controls, enviromnental monitoring
`procedures, equipment holding times,
`M“) holding times, and
`(um)
`holding times are in place to ensure microbiological quality.
`
`(hm)
`
`(may
`
`Reference ID: 36071 53
`
`

`

`MEMORANDUM
`
`(m4)
`
`Fmther, the applicant provides stability data to demonstrate a lack of microbial growth in the
`finished product. Microbial limits testing was performed for primary stability batches.
`Specifications for these studies are in agreement with those described in USP <1111>, and
`include a total aerobic microbial count ofNMT (hm) CFU/g, a total yeast and mold count of NMT
`(hm) CFU/g, and the absence ofEscherichia coli per gram. Testing was performed using methods
`described in USP <61>
`(m4) Microbiological testing
`m (4) was
`performed at initial, 6, 12, and 24 month timepoints under long-term storage conditions
`(25°C/60% RH) and at initial and 6 months under accelerated conditions (30°C/75% RH). All
`batches met microbiological acceptance criteria at each time point tested. Under long—term
`storage conditions,
`M“) in the tablets remained below mar
`(hm)
`under accelerated conditions to a maXimum of (m ), With no noted increase in microbial load.
`
`The drug product will be tested for microbial limits annually as part of the post-approval stability
`protocol.
`
`ADEQUATE
`
`Reviewer Comments — The applicant’s proposal to waive microbial limits testing for product
`release is acceptable.
`
`END
`
`Filing Letter Information Request
`1.
`You propose to perform skip lot testingfor the Microbial Limits testfor drug product release. Skip-lot
`testingfor drug products is not allowed by regulation (21 CFR 211.165 (a) and (b).) Ifa drugproduct
`release specification includes tests and acceptance criteriafor a given attribute, then the test rrrust be
`performed on every batch. However, microbial limits testing may be ornittedfi‘om the product release
`specification provided adequate upstream microbiological controls are established and documented. 1fyou
`wish to omit the microbial limits specification, more information on yourprocess is needed. Address the
`following points.
`a.
`Identrfl andjustrfv critical controlpoints in the manufacturing process that could aflect microbial
`
`load ofthe drug product.
`i.
`u.
`
`(lam)
`
`b.
`
`Describe microbiological monitoring and acceptance criteriafor the critical control points that
`
`you have identified. Verrfv the suitabilitv ofyour testing rrrethodsfor your drugproduct.
`
`Conformance to the acceptance criteria establishedfor each critical control point should be
`docurrrented in the batch record in accordance with 21 CFR 211.188.
`
`c.
`
`Describe activities taken when microbiological acceptance criteria are not met at control points.
`
`Ifyou choose to orrrit microbial lirrrits testingfor release, then remove the microbial limits tests and
`acceptance criteriafrom the drug product release specification. Alternatively, you may retain a microbial
`limits specification for product release, brrt testing rrrust be performed on every lot ofdrug product
`
`Reference ID: 36071 53
`
`

`

`M E M O R A N D U M
`
`2.
`
`produced. Please submit a revised drug product release specification for whichever microbial limits
`testing alternative that you select.
`Your release and stability specifications include microbial limits and the absence of Escherichia coli, but
`you do not describe testing methods. Describe these methods and state whether validation has been
`performed to ensure that these methods are adequate for use with the drug product.
`
`30 June 2014 Response
`The applicant provided a rationale for omitting microbial limits testing for product release. The applicant plans to
`submit revised release specifications at a later date.
`
`31 July 2014 Response
`The applicant provided a revised release specification, omitting microbial limits testing.
`
`Reference ID: 3607153
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ERIKA A PFEILER
`08/08/2014
`
`STEPHEN E LANGILLE
`08/08/2014
`
`Reference ID: 3607153
`
`

`

`PRODUCT QUALITY MICROBIOLOGY NON-STERILE
`DRUG PRODUCT FILING CHECKLIST
`
`NDA Number: 206073
`
`Drug Name:
`Empagliflozin/Linagliptin
`Glyxambi® (proposed)
`Dosage Form: Tablet
`
`Applicant: Boehringer
`Ingelheim Pharmaceuticals,
`Inc.
`
`Letter Date: 29 January 2014
`
`NDA Type: 505(b)(1)
`
`Stamp Date: 30 January 2014
`
`Reviewer: Erika Pfeiler, Ph.D.
`
`The following are necessary to initiate a review of the NDA application:
`Content Parameter
`Yes
`X
`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?
`Has the applicant submitted an overall description of the
`manufacturing processes and microbiological controls used
`in the manufacture of the drug product?
`Has the applicant submitted microbiological specifications
`for the drug product and a description of the test methods?
`Has the applicant submitted the results of analytical method
`verification studies?
`Has the applicant submitted preservative effectiveness
`studies (if applicable)?
`Is this NDA fileable? If not, then describe why.
`
`X
`
`X
`
`X
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`No
`
`Comments
`
`See Additional
`Comments.
`See Additional
`Comments.
`N/A
`
`X
`
`Additional Comments: The application contains microbial limits release specifications for the
`two presentations of drug product (25 mg empagliflozin/5 mg linagliptin, 10 mg empagliflozin/5
`mg linagliptin). The release specifications are in agreement with those listed in USP <1111> for
`dosage forms of this type; however, the application states that microbial limits testing will be
`performed as skip-lot testing with one production batch per year tested. Additionally, the
`application does not describe test methods for microbial limits testing. Information requests to
`resolve these issues will be sent to the applicant.
`
`Product Quality Microbiology Information Request
`1. You propose to perform skip lot testing for the Microbial Limits test for drug product
`release. Skip-lot testing for drug products is not allowed by regulation (21 CFR 211.165
`(a) and (b).) If a drug product release specification includes tests and acceptance criteria
`for a given attribute, then the test must be performed on every batch. However, microbial
`limits testing may be omitted from the product release specification provided adequate
`upstream microbiological controls are established and documented. If you wish to omit
`
`Reference ID: 3460194
`
`

`

`the microbial limits specification, more information on your process is needed. Address
`the following points.
`a.
`Identify and justify critical control points in the manufacturing process that could
`affect microbial load of the drug product.
`i.
`ii.
`b. Describe microbiological monitoring and acceptance criteria for the critical
`control points that you have identified. Verify the suitability of your testing
`methods for your drug product. Conformance to the acceptance criteria
`established for each critical control point should be documented in the batch
`record in accordance with 21 CFR 211.188.
`c. Describe activities taken when microbiological acceptance criteria are not met at
`control points.
`If you choose to omit microbial limits testing for release, then remove the microbial
`limits tests and acceptance criteria from the drug product release specification.
`Alternatively, you may retain a microbial limits specification for product release, but
`testing must be performed on every lot of drug product produced. Please submit a
`revised drug product release specification for whichever microbial limits testing
`alternative that you select.
`2. Your release and stability specifications include microbial limits and the absence of
`Escherichia coli, but you do not describe testing methods. Describe these methods and
`state whether validation has been performed to ensure that these methods are adequate for
`use with the drug product.
`
`Erika Pfeiler, Ph.D.
`Microbiologist
`
`John Metcalfe, Ph.D.
`Senior Review Microbiologist
`
`Date
`
`Date
`
`Reference ID: 3460194
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ERIKA A PFEILER
`02/25/2014
`
`JOHN W METCALFE
`02/25/2014
`I concur.
`
`Reference ID: 3460194
`
`