CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`APPLICATION NUMBER:
`ANDA 203760
`
`Name:
`
`Albuterol Sulfate Inhalation Aerosol 0.09mg
`base/actuation
`
`Sponsor:
`
`Perrigo Pharmaceutical Company
`
`Approval Date: February 24, 2020
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`APPLICATION NUMBER:
`
`ANDA203760Orig1s000
`
`CONTENTS
`
`
`Reviews / Information Included in this Review
`
`
`Approval Letter
`Tentative Approval Letter
`Labeling
`Labeling Review(s)
`Medical Review(s)
`Chemistry Review(s)
`Pharm/Tox Review
`Bioequivalence Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Other Review(s)
`Administrative & Correspondence Documents
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`APPLICATION NUMBER:
`
`ANDA 203760
`
`
`BIOEQUIVALENCE REVIEW(s)
`
`
`

`

`DIVISION OF BIO EQUIV ALEN CE REVIEW
`
`FOR PRESSURIZED METERED DOSE INHALATION PRODUCTS
`203760
`
`ANDA No.
`
`Drug Product Name
`Sh·ength(s)
`
`Applicant Name
`
`Applicant Address
`
`Albuterol Sulfate Inhalation Aerosol
`0.09 mg Base/Inhalation
`
`Perrigo Phamiaceutical Company
`515 Eastern Ave
`Allegan. MI, USA 49010
`
`US Contact Name and US
`Mailing Address
`
`US Contact Telephone
`Number
`US Contact Fax Numbe1·
`
`Original Submission Date(s)
`
`Submission Date(s) of
`Amendment(s) Under Review
`
`Matthew Popowski, Senior Regulatory Affairs Project Manager
`3940 Quebec Ave North
`Minneapolis, MN, USA 55427
`
`763-732-0481
`
`763-732-0509
`
`-
`
`12/16/2011
`03/09/2012 Re-submission (SD2)
`
`05/18/2012 Fonnulation Tablet (SD6)
`
`07/03/2013 Major amendment to support the addition of an
`
`integrated dose counter to the metered dose inhaler (SDIO)
`
`04/24/2015 Post-CR meeting request (SD20)
`
`07/01/2015 Response to complete response letter dated 04/13/2015
`
`(SD22)
`10/05/2015 Post-CR meeting request (SD24)
`04/ 13/2017 Major amendment (SD29)
`10/23/201 7 Meeting Request (SD3 l)
`12/29/2017 Major amendment (SD34)
`04/26/2018 Response to IR request (SD37)
`08/31/2018: Multiple Categories (SD 3 8)
`11/30/2018: Multiple Categol'ies (SD44)
`
`Ptimary Assesso1·
`
`Secondary Assessor
`Tertiary Assessor·
`
`Zhen Zhang, Ph.D.
`Vipra Kundoor, Ph.D.
`
`Qing Liu, Ph.D.
`
`Study Number(s)
`Study Type(s)
`Sh·ength(s)
`
`Clinical Site
`
`Clinical Site Addt·ess
`
`Analytical Site
`Analytical Site Address
`
`Study Number(s)
`Study Type(s)
`Sti·ength(s)
`
`In Vitro Test Site
`
`10825302
`Fasting
`2 x 90 mcg actuations (total dose = 180 mcg)
`
`Novum Phannaceutical Research Services
`
`Wilcrest Green Office Park, 3320 Walnut Bend Lane, Houston, TX
`77042-4712
`
`(bff(
`
`I TTP-CBJ-M00132
`TTP-CBJ-MOOSO
`In vitro Bioequivalence Study
`
`I TTP-CBJ-0282
`
`90 mcg/ actuation
`
`(bff4
`
`

`

`(DJ(4
`
`In Vitro Test Site Add1·ess
`
`- -
`
`Study Number(s)
`
`Study Type(s)
`
`Stl'ength(s)
`
`Clinical Site
`
`Clinical Site Address
`
`PRG-723
`Pharmacodynamic Bioequivalence Study
`
`90 mcg/ actuation
`fil!tl
`University ofFlorida
`
`Asthma Research Lab
`
`fil!f.1.
`Roy J and Lucille A Carver College of Medicine
`Department of Pediatrics, Allergy/Pulmonary
`~
`Allergy & Asthma Diagnostic Treatment Center
`fil!U
`California Allergy & Astluna Medical Group
`~
`Clinical Research Atlanta
`~
`Spattanburg Medical Research
`Site 7
`f AARA Research Center
`fil!tl
`1600 SW Archer Road
`Gainesville, FL 32610-0486
`fil!f.1.
`The University oflowa
`200 Hawkins Drive
`Iowa City, Iowa 52242-1083
`fil!!.l
`2300 Centerville Road
`Tallahassee, FL 32308
`fil!!..i
`11645 Wilshire Blvd, Suite 1155
`Los Angeles, CA 90025
`~
`175 Country Club Drive,
`Suite IOOA
`Stockbridge, GA 30281
`~
`485 Simuel Road
`Spa1tanblll'g, SC 29303
`.fil!tl
`9900 N Central Expy, Suite 555
`Dallas, TX 75231
`
`OSIS Status
`
`Backlog1 Yea1· 1 and Year 2
`ANDAs
`D Pending
`181 Complete
`
`Post October 11 2014 ANDAs
`0 To Be Determined by OSIS
`D Pending For Cause
`Inspection
`D Complete
`
`Formulation
`
`181 Adequate D Inadequate
`
`

`

`Will Response to CR Result in
`a Reformulation?
`
`D Possibly ONo 181 N/A
`
`Deficiency Classi.fica tion
`
`Overall Review Result
`
`Revised/New Draft Guidance
`Generated as Part of Current
`Review
`
`Bioequivalence study
`Tracking/Supporting
`Document#
`
`D Major
`D Minor
`181 N/A (Review is Adequate)
`181 Adequate D Inadequate
`
`DYES 181 NO
`
`Study/Test Type
`
`1, 2, 6
`
`Fasting BE Study
`
`1,2,6,29,34,37,38, 44
`
`Pharmacodynamic BE
`Study
`
`0.09 mg
`Base/Inhalation
`
`1, 2, 6, 29
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 34, 37
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 29, 34
`
`In vitro BE study #
`TTP-CBJ-M0050
`
`0.09 mg
`Base/Inhalation
`
`In vitro BE study #
`TTP-CBJ-M0282:
`Single Actuation
`Content through
`Container Life
`In vitro BE study #
`TTP-CBJ-M0282:
`Priming and
`Repriming
`In vitro BE study #
`TTP-CBJ-M0282:
`Aerodynamic Particle
`Size Distribution by
`Cascade Impaction
`
`In vitro BE study #
`TTP-CBJ-M0282:
`Spray Pattern
`
`In vit1·0 BE study #
`TTP-CBJ-M0282:
`Plume Geometry
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`Sb·ength
`(e.g., xx
`µg/inhalation)
`
`0.09 mg
`Ba.se/Inhalation
`
`Review Result
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`

`

`
`
`
`
`1
`
`Addendum to the Bioequivalence Amendment Assessment Dated 1/29/2019
`
`
`
`EXECUTIVE SUMMARY
`
`This addendum is to update the cover page of the amendment assessment dated
`1/29/20191. The updates include: 1) 11/16/2011 was updated to 12/16/2011 in the
`Original Submission Date(s); 2) 03/09/2012 Re-submission (SD2) and 05/18/2012
`Formulation Tablet (SD6) were added to Submission Date(s) of Amendment(s) Under
`Review.
`
`The 12/16/2011, 3/9/2012 and 5/18/2012 submissions were assessed and documented in
`
`the assessment of 08/04/2014.2
`
`
`The application remains adequate. No letter will be communicated to the applicant from
`
`this addendum.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1 GDRP, ANDA 203760; A203760N000DB-Review01-Amend11302018.docx (Completed 1/29/2019);
`
`
`http://panorama.fda.gov/task/view?ID=5c0680e6002d64bd3a10d877129483fb
`
` 2 DARRTS, ANDA 203760; Primary Review (REV-BIOEQ-21) dated 08/04/2014.
`
`
`
`
`
`

`

`
`
`
`2 COMPLETED ASSIGNMENT FOR 203760 ID: 38036
`
`
`
`
`
`
` Reviewer: Zhang, Zhen
`
`
` Verifier:
`,
`
` Division: Division of Bioequivalence
`
` Description: Albuterol Sulfate Inhalation Aerosol, 0.09 mg
`
`Base/Inhalation - Addendum
`
`
`
`Date
`
` Completed:
`
` Date Verified:
`
`
`
`
`
`
`
`
`
`
`
` Items:
` ID Letter Date
`
`
`Productivity
`
`Category
`
`38036 11/30/2018 BIO
`38036 11/30/2018 Parallel
`
`
`
`
`
`
`
`
`
`
`
`
`
` Sub Category
`
`
`
` Score Subtotal
`
`
`
` Addendum [1]
`
`Addendum (for clarification or
`
`Error Correction [0]
`
`
`0
`0
`
`0
`0
`
`Total:
`
`0
`
`
`
`

`

`DIVISION OF BIO EQUIV ALEN CE REVIEW
`
`FOR PRESSURIZED METERED DOSE INHALATION PRODUCTS
`
`203760
`
`ANDA No.
`
`Drug Product Name
`Strength(s)
`
`Applicant Name
`
`Applicant Address
`
`US Contact Name and US
`Mailing Add1·ess
`
`US Contact Telephone
`Number
`US Contact Fax Number
`
`Original Submission Date(s)
`
`Submission Date(s) of
`Amendment(s) Under Review
`
`Albuterol Sulfate Inhalation Aerosol
`0.09 mg Base/Inhalation
`
`Peffigo Pharmaceutical Company
`
`515 Eastern Ave
`Allegan, MI, USA 49010
`
`Matthew Popowski, Senior Regulatory Affairs Project Manager
`3940 Quebec Ave Notth
`Minneapolis, MN, USA 55427
`
`763-732-0481
`
`763-732-0509
`
`11/16/2011
`07/03/2013 Major amendment to support the addition ofan integrated
`dose counter to the metered dose inhaler (SDlO)
`04/24/2015 Post-CR meeting request (SD20)
`07/01/2015 Response to complete response lett.er dated 04/13/2015
`(SD22)
`10/05/2015 Post-CR meeting request (SD24)
`04/13/2017 Major amendment (SD29)
`10/23/2017 Meeting Request (SD3 l)
`12/29/2017 Major amendment (SD34)
`04/26/2018 Response to IR request (SD37)
`08/31/2018: Multiple Categories (SD 38)
`11/30/2018: Mutiple Categoties (SD44)
`
`Ptimary Assessor
`Secondary Assesso1·
`Tertiary Assesso1·
`
`Zhen Zhang, Ph.D.
`Vipra Kundoor, Ph.D.
`
`Qing Liu, Ph.D.
`
`Study Number(s)
`
`Study Type(s)
`
`Strength(s)
`
`Clinical Site
`
`Clinical Site Add1·ess
`
`Analytical Site
`Analytical Site Address
`
`Study Number(s)
`Study Type(s)
`
`Strength(s)
`In Vitro Test Site
`In Vitro Test Site Add1·ess
`
`10825302
`
`Fasting
`
`2 x 90 mcg actuations (total dose = 180 mcg)
`
`
`NovlJlll Phannaceutical Research Services
`
`
`Wilcrest Green Office Park, 3320 Walnut Bend Lane, Houston, TX
`
`77042-4712
`
`lbl~
`
`ITP-CBJ-M0050
`
`I TTP-CBJ-M00132
`
`I TTP-CBJ-0282
`
`~vitro Bioequivalence Study
`90 mcg/ actuation
`
`-
`
`lbT~
`
`

`

`coJT4]
`
`Study Number(s)
`Study Type(s)
`
`Strength(s)
`
`Clinical Site
`
`Clinical Site Address
`
`PRG-723
`Pharmacodynamic Bioequivalence Study
`90 mcg/ actuation
`fil!t!
`University of Florida
`Asthma Research Lab
`fil!tl
`Roy J and Lucille A Carver College ofMedicine
`Depa1iment of Pediatrics, Allergy/Pulmona1y
`fil.!!.1
`Allergy & Asthma Diagnostic Treatment Center
`.fil!t.i
`Califomia Allergy & Asthma Medical Group
`~
`Clinical Research Atlanta
`fil!!-2
`Spruianbw·g Medical Research
`Site 7
`f AARA Research Center
`1.s ite 1
`1600 SW Archer Road
`Gainesville, FL 32610-0486
`.filttl
`The University oflowa
`200 Hawkins Drive
`Iowa City, Iowa 52242- 1083
`fil.!!.1
`2300 Centerville Road
`Tallahassee, FL 32308
`.fil!t.i
`11645 Wilshire Blvd, Suite 1155
`Los Angeles. CA 90025
`~
`17 5 Country Club Drive,
`Suite lOOA
`Stockbridge, GA 30281
`fil!!-2
`485 Simuel Road
`Spruianbmg, SC 29303
`Site 7
`f 9900 N Central Expy, Suite 555
`I Dallas, TX 75231
`
`OSIS Status
`
`Formulation
`
`Will Response to CR Result in
`a Reformulation?
`
`Backlog, Year 1 and Year 2
`AND As
`D Pending
`181 Complete
`181 Adequate D Inadequate
`
`D Possibly D No 181 NIA
`
`Post Octobe1· l , 2014 ANDAs
`D To Be Determined by OSIS
`D Pending For Cause Inspection
`D Complete
`
`

`

`Deficiency Classification
`
`Overall Review Result
`
`Revised/New Draft Guidance
`Gene1·ated as Part of Cm-rent
`Review
`
`Bioequivalence study
`Tmcking/Supporting
`Document#
`
`D Major
`
`D Minor
`
`181 NIA (Review is Adequate)
`
`181 Adequate 0 Inadequate
`
`DYES 181 NO
`
`Study/Test Type
`
`1, 2, 6
`
`Fasting BE Study
`
`1,2,6, 29,34,37,38, 44
`
`Pharmacodynamic BE
`Study
`
`0.09 mg
`Base/Inhalation
`
`1, 2, 6, 29
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 34, 37
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 29, 34
`
`1, 2, 6, 29, 34
`
`In vitro BE study #
`
`TTP-CBJ-M0050
`
`
`0.09 mg
`Base/Inhalation
`
`In vitro BE study #
`TTP-CBJ-M0282:
`Single Actuation
`Content through
`Container Life
`
`In vitm BE study #
`TTP-CBJ-M0282:
`Priming and
`Reptiming
`
`In vitro BE study #
`TTP-CBJ-M0282:
`Aerodynamic Pa11icle
`Size Disttibution by
`Cascade Impaction
`
`In vitro BE study #
`TTP-CBJ-M0282:
`S1nay Pattern
`
`In vitro BE study #
`
`TTP-CBJ-M0282:
`
`Plume Geometry
`
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`0.09 mg
`Base/Inhalation
`
`Strength
`(e.g., xx
`µg/inhalation)
`
`0.09 mg
`Base/Inhalation
`
`Review Result
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`181 Adequate
`0 Inadequate
`0 Not Applicable
`181 Adequate
`0 Inadequate
`0 Not Applicable
`
`

`

`
`
`
`1 EXECUTIVE SUMMARY
`
`This is a review of the amendment dated 11/30/2018.
`
`
`In the original submission and subsequent amendments, the applicant submitted the
`results of the studies listed in the table below comparing the test product (Perrigo
`
`
`Pharmaceutical Company’s Albuterol Sulfate Inhalation Aerosol, 0.09 mg
`
`Base/Inhalation) to the corresponding reference product (Teva Global’s ProAir® HFA
`(albuterol sulfate) Inhalation Aerosol, 0.09 mg Base/Inhalation). All the studies are
`
`
`adequate except the pharmacodynamic (PD) study # PRG-723 due to deficiency related
`to the Office of Study Integrity and Surveillance (OSIS)’s inspection1, 2, 3, 4, 5, 6.
`
`
`
`
`
`
`
`
`
`
` Test Batch
`
`#
`
`Reference
`
`
`Batch #
`
`Dose
`
`counter?
`
`
` Relevant to BE
`
` determination?
`
`
`
` 08MM-050
`
`
`
` AEA13B
`
`
`
` 08MM-050
`
`
`
` AEA13B
`
`
` No for both T
`
` and R
`
` No for both T
`
` and R
`
` 08MM-050, AEA13B, No for both T Yes
`08MM-034, AEA12C,
`and R
`
`
`AEA14A
`
` 08MM-039
`
`
`
`
` Yes
`
`
`
` Yes
`
`
`
`
`
`Review Results
`for the relevant
`
`BE studies
`
` Adequate
`
`
`
` Inadequate
`
`
`
` Adequate
`
`Fasting Study #
`
`10825302
`PD Study #
`PRG-723
`
` In vitro
`bioequivalence
`(BE) study #
`TTP-CBJ-
`
` M0050
`In vitro BE
`study # TTP-
`
` CBJ-0282
`
`
` 15MM-023, DAC23A, Yes for both
`16MM-002, DAC34A, T and R; T
`
`
`
`
`DAC36A
`has optimized
`
` 16MM-003
`
`actuator
`
`
`
`
`
`
` Yes
`
`
`
` Adequate
`
`
`In the current amendment dated 11/30/2018, the applicant provided the response to OSIS
`
` related BE deficiency. Per the Division of Bioequivalence I (DBI)’s consult request,
` OSIS evaluated the applicant’s response and considered the data in the study report for
`
`
`study PRG-723 are reliable to support a regulatory decision7. The assessor re-evaluated
`the data of the PD study # PRG-723 and found it adequate.
`
`
`
`The application is adequate.
`
`
`
` 1 DARRTS, ANDA 203760; KUNDOOR, VIPRA R 08/04/2014 REV-BIOEQ-21(Primary Review)
`
`2 GDRP, ANDA 203760; A203760N000DB_NA07012015_GDRP version.doc (Date Uploaded
`
`9/11/2015); http://panorama.fda.gov/task/view?ID=559a876700fe4b13ce9f1ec18609f222
`
`3 GDRP, ANDA-203760; A203760N000DB_NA04132017 (Completed 09/08/2017);
`
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f88147efa5
`4 GDRP, ANDA-203760; A203760N000DPM-MeetingMinutes03.doc (Completed 12/14/2017);
`
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f8817ec1af
` 5 GDRP, ANDA 203760; A203760N000DB-Review01-AMEND12292017.docx (Completed 05/17/2018);
`
`
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f881ae8679
`
` 6 GDRP, ANDA 203760; A203760N000DB-Review01-Amend08312018.docx (Completed 10/26/2018);
`
`
`http://panorama.fda.gov/task/view?ID=5b8fc23200f01deb2a746fc266654760
`
`
` 7 GDRP, ANDA 203760; OSIS memo 2019-01-8.pdf (Completed 01/08/2019);
`
`
` http://panorama.fda.gov/task/view?ID=5c12a35e00d018462807b37e0cb7cd3d
`
`
`
`
`
`

`

`
`
`
`2 REVIEW OF THE APPLICANT’S RESPONSE TO BIOEQUIVALENCE
`
`DEFICIENCY
`
`
`
`2.1 Evaluation of the impact of revised Product-Specific Guidance (PSG) for
`Albuterol Sulfate Inhalation Aerosol on the BE studies of the current
`application
`
`
`
`
`
` Assessor’s Comments
`
`The original assessments of the pharmacokinetic (PK) study # 10825302, in vitro BE
`studies # TTP-CBJ-M0050 and pharmacodynamic (PD) study # PRG-723 were
`
`conducted based on the PSG for Albuterol Sulfate Inhalation Aerosol dated Jun 20138.
`The PSG was then revised in Dec 20169. The evaluation of the impact of the revised PSG
`
`dated Dec 2016 is as follows:
`
`
`
` Recommendations Difference between the PSGs dated Jun
`
`2013 and Dec 201610
` The PSG dated Dec 2016 removed the
`
` following recommendation:
` Baseline PC20 or PD20 on each study day
`
`should be within a two-fold dilution (i.e.,
`within 50-200 %) of the value measured on
`
` the qualifying day.
`
`
`
`
`
` PD study
`
`
`
`
`
` The PD study # PRG-723 in the current
`
`
` application did not measure baseline PC20
` challenge on each study day, which is in
`
`
`
`line with the current PSG dated Dec 2016.
`
`
`This was also discussed in the review of
`controlled correspondence (CC) # 4271511.
`Therefore, the revised PSG dated Dec 2016
`
`
`
`
`
`
`
`
`
` has no impact on the PD study # PRG-723.
`No impact
`
`
`
` PK study
` In vitro BE studies
`
`
`
`
`Other minor edits to be consistent with other
`
`PSG for MDI products
`
` Remain the same
` The PSG dated Dec 2016 changed the term
`
`
` from “actuator tip” to “actuator mouthpiece”
`
` for plume geometry study.
`
`
`
`
`
`No impact
`
` Both in vitro BE study # TTP-CBJ-M005012
` and in vitro BE study # TTP-CBJ-028213
`
`
`measured plume geometry at a single delay
`
`
`
`
`time while the fully developed plume is still
`
`
`in contact with the ‘actuator mouthpiece’.
`
`Therefore, the revised PSG dated Dec 2016
`
`
`
`
`
`
`
`has no impact on in vitro BE studies
`
`
`
`
`Conclusion: The revised PSG for Albuterol Albuterol Sulfate Inhalation Aerosol dated
`
` Dec 2016 has no impact on the current application.
`
`
` 8 DARRTS, ANDA 203760; KUNDOOR, VIPRA R 08/04/2014 REV-BIOEQ-21(Primary Review)
`
`
`9
`https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM3469
`
`85.pdf
`
` 10 http://panorama.fda.gov/task/view?ID=54ee35f40008767878f9a2eaafab4564
`
`
`
` 11 http://panorama.fda.gov/task/view?ID=546669ea0017fdd5cca5e468b8b066ca
` 12 GlobalSubmit Review; ANDA 203760; Module 5.3.1.2 Test Methods (Page 5 of 52); Submitted
`
`03/09/2012; \\cdsesub1\evsprod\anda203760\0001\m5\53-clin-stud-rep\531-rep-biopharm-stud\5312-
`
`compar-ba-be-stud-rep\in-vitro-bio-study\methods.pdf
` 13 GlobalSubmit Review; ANDA 203760; Module 5.3.1.3 In-Vitro BE Study Report TTP-CBJ-M0282
`
`(Page 21 of 407); Submitted 04/13/2017; \\cdsesub1\evsprod\anda203760\0028\m5\53-clin-stud-rep\531-
`
`rep-biopharm-stud\5313-in-vitro-in-vivo-corr-stud-rep\characterization-study\invitro-be-m0282.pdf
`
`
`
`
`
`
`
`

`

`2.2 BE Deficiency
`
`Deficiency Related to the Pharmacodynamic Study (PRG-723)
`
` The Office of Study Integrity and Surveillance (OSIS) evaluated your response to the
`
`
`
` bioequivalence deficiency, amendment dated August 31, 2018, and has the following
`comments.
`
`related to the Master Randomization
`Please provide the audit trails from
`
`(b) (4)
`
` Code (MRC) and scratch-off labels. The audit trails should include all activity related to
`the MRCs and scratch-off labels prior to the enrollment of the first study subject and until
`the date of the last FDA inspection (January 9, 2015).
`
`2.3 Applicant’s Response
`
` As requested, Perrigo submits the audit trails of the Master Randomization Code (MRC)
`
`and the audit trails from the production of the clinical labeling, inclusive of the scratch-
`off kit labels, downloaded by
`(b) (4) and supplied to us. The
`audit trails show all activity related to the MRCs and scratch-off labels from prior to
`enrollment of the first study subject through 2018. The documents demonstrate that:
`
`x
`
`x
`
`(b) (4) used two MRCs to print two batches of clinical labeling for
`Perrigo’s study, as described in Perrigo’s ANDA.
`
`x The two MRCs used to print Perrigo’s clinical labels match the MRCs in
`
`Perrigo’s ANDA.
`
`(b) (4) printed labels for Perrigo’s study only in January 2010 (for
`MRC #1) and April 2010 (for MRC #2).
`x MRC #1 and MRC #2 were never modified.
`x No activity occurred for the MRCs between April 2010 and August 2018.
`x No activity occurred related to label printing between April 2010 and October
`2015.
`
`In the sections below, for ease of understanding, Perrigo describes the organization of
`the audit trail documents and the specific data supporting the above conclusions.
`
`i. Audit Trails for Master Randomization Codes
`
`(b) (4)
`
`Assignment Set #1
`
`

`

`Assignment Set #1 was created on December 29, 2009 with Transaction #1 and
`includes Transactions #1 and #2. It was never used in the Perrigo study. As
`
`previously described in Perrigo’s response to CRL#4 (Affidavit from
`(b) (4)
` (b) (4) generated Assignment Set #1 as a
`
` in Sequence 0037),
`preliminary MRC with 10 treatment sequences. Prior to study enrollment,
`however, Perrigo reduced the number of treatment sequences from 10 to 5.
`
`The transactions in the audit trail for Assignment Set #1 show the following:
`
` x Transaction #1 (December 29, 2009) - Creation of this preliminary MRC with
`10 treatment sequences
`x Transaction #2 (January 14, 2010) - Quarantine of Assignment Set #1, noting
`
`that it was retained as an “unused entity” and therefore not a viable MRC
`used in the Perrigo study
`
`Assignment Set #2
`
`Assignment Set #2 was created on January 14, 2010 with Transaction #3 and
`includes Transaction #3, #4, #8 and #9.1 Assignment Set #2 contains 5 treatment
`sequences and corresponds to MRC #1 for subjects 001-100 in the Perrigo study.
`
`The transactions in the audit trail for Assignment Set #2 show the following:
`x Transaction #3 (January 14, 2010) – Creation of MRC #1 with 5 treatment
`
`sequences
`x Transaction #4 (January 18, 2010) - Approval of MRC #1 prior to the
`
`production of clinical study materials commencing on January 21, 2010
`x Transactions #8 and #9 (August 2, 2018) - Query of MRC #1 at Perrigo’s
`
`request to retrieve information to respond to CRL #4.
`
`Assignment Set #3
`
`Assignment Set #3 was created on April 12, 2010 with Transaction #5 and
`includes Transaction #5, #6, #7, and #10. Assignment Set #3 contains 5 treatment
`sequences and corresponds to MRC #2 for subjects 101-210 in the Perrigo study.
`
`The transactions in the audit trail for Assignment Set #3 show the following:
`x Transaction #5 (April 12, 2010) – Creation of MRC #2 with 5 treatment
`
`
`sequences
`x Transaction #6 (April 12, 2010) – Modification of number of subjects in MRC
`
`#2 from 265 to 210
`x Transaction #7 (April 21, 2010) - Approval of MRC #2 prior to the production
`
`of clinical study materials commencing on April 22, 2010
`x Transaction #10 (August 2, 2018) - Query of MRC #2 at Perrigo’s request to
`
`retrieve information to respond to CRL #4
`
`The MRCs provided in the audit trails correspond to the MRCs in Perrigo’s
`ANDA. The
`(b) (4) audit trails demonstrate that the MRCs for Perrigo’s
`
`

`

`study remained the same from their initial generation in January and April 2010
`(shown in Transaction 3 and Transaction 5), through the FDA inspection on
`January 9, 2015, and indeed through 2018 (shown in Transaction 9 and
`Transaction 10). The last substantive transaction was the approval of MRC #2 in
`April 2010 (Transaction 7). The audit trail then shows no activity until
`Transactions 8, 9 and 10, which were queries of the MRCs in August 2018 to
`retrieve information for the response to CRL #4.
`
`ii. Audit Trails for Scratch-Off Labels
`
`(b) (4) system also provides a comprehensive audit trail of the
`The
`production of scratch-off labels, canister labels and actuator labels printed from
`the Perrigo Model in a document titled “Model Log Report.” Page 1 of the Model
`Log Report identifies the model as PRR PRG-723 (the Perrigo Model). In total,
`there are 197 ‘Transactions’ in the Model Log Report. The breakdown of
`Transactions is as follows:
`
`The final 3 Transactions of the Model Log Report audit trail record the following:
`x Transaction #195 (April 29, 2010), last clinical supply produced at the end of
`the production run (sample reprint)
`x Transaction #196, (October 2, 2015), query at Perrigo’s request to retrieve
`
`information to respond to CRL #2.
`x Transaction #197, (August 2, 2018), query at Perrigo’s request to retrieve
`information to respond to CRL #4.
`
`The audit trail shows there was no access to the scratch-off labels or any clinical
`supplies between the period of April 29, 2010 and January 9, 2015. After the
`printing of the labels in 2010 for the study, the only access to the
`(b) (4)
`system occurred on October 2, 2015 and August 2, 2018 after the date of the last
`FDA inspection at Perrigo’s request to retrieve information to respond to CRL#2
`and CRL#4 respectively.
`
`

`

`Perrigo is confident the audit trails provided in this Bioequivalence response establish
`without question the integrity of Pharmacodynamic study PRG-723 and fully addresses
`the request of the Office of Study Integrity and Surveillance.
`
`2.4 Assessor’s Comment
`
`Per the Division of Bioequivalence I (DBI)’s consult request, the Office of Study
`
`
`Integrity and Surveillance (OSIS) evaluated the applicant’s response as follows14:
`
`
`In the documentation provided in Perrigo’s complete response amendment dated
`August 31, 2018, I was previously unable to verify the sequence of treatments
`actually administered to subjects in study PRG723. Using the audit trails
`provided in the current response amendment, I was able to confirm that the
`sequence of treatments in the original randomization schedule and the treatment
`assignments in each kit are consistent with the sequence of treatments (i.e.,
`DECAB, CDBEA, BCADE, EADBC, and ABECD) in the study report for study
`PRG-723 supporting ANDA 203760.
`
`OSIS’s Recommendations:
`
`Based on the audit trails provided in the complete response amendment dated
`November 30, 2018, the data in the study report for study PRG-723 are reliable
`to support a regulatory decision.
`
`
`
`Therefore, all PD study related deficiencies have been addressed except for the data
`
`reliability from the California Allergy & Asthma Medical Group. The assessor copies the
`deficiency issued on 09/21/2015, applicant’s response on 04/13/2017 and BE assessor’s
`comment on 09/08/2017 below for the reference15:
`
`BE Deficiency
`
`Investigational records were not retained. Specifically, three randomized subjects'
`
`and ten screen-failed subjects' bioequivalence study Source Records, Informed
`Consent Forms and Case Report Form Files were missing and could not be
`located during the inspection. The following subjects’ entire study records were
`missing:
`
`Screening Number / Randomization Number
`(b) (6)
`
`
`
`
` 14 GDRP, ANDA 203760; OSIS memo 2019-01-8.pdf (Completed 01/08/2019);
`
`http://panorama.fda.gov/task/view?ID=5c12a35e00d018462807b37e0cb7cd3d
`
`15 GDRP, ANDA-203760; A203760N000DB_NA04132017 (Completed 09/08/2017);
`
`
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f88147efa5
`
`
`

`

`(b) (6)
`
`Applicant’s Response
`
`Perrigo acknowledges the above comment. The attached statistical report
`(Attachment F, provided in section 5.3.4.1) demonstrates that, when the 3
`randomized subjects referenced above, as well as the entire clinical site’s data,
`are removed from the study analysis, the 90% CI is still contained entirely
`between 67-150%.
`
`Assessor’s Comment
`
`Since the PD study is not acceptable per the evaluation in Section 4.5, the
`recalculation is not performed at this time by the reviewer.
`
` The original BE assessment already deemed the PD study met the BE criteria of 67% -
`
`
`
`
`
` 150% when all data were included in the dose-scale analysis. Here, the BE assessor re-
`
`
` evaluated the PD study data by 1) excluding 3 affected subjects
`and
`(b) (6)
` 2) excluding all the data from the California Allergy & Asthma Medical Group (Site 4).
`
`
`The results are shown below:
`
`Data
`All17
`Excluding 3
`subjects
`Excluding all
`subjects from
`Site 4
`
`Applicant’s Results16
`Assessor’s Results
`N F (T/R)
`90% CI
`N F (T/R)
`90% CI
`93
`1.17
`102.68% - 132.85% 93
`1.16
`102.3% - 133.0%
`90
`1.16
`101.83% - 132.71% 90
`1.16
`102.8% - 133.2%
`
`66
`
`1.12
`
`98.33% - 125.46%
`
`66
`
`1.14
`
`100.4% - 128.4%
`
`The assessor’s results are similar to the applicant’s results for all three datasets above.
`
`The minor difference could be caused by that the assessor bootstrapped the data 10,000
`times whereas the applicant only bootstrapped the data 2,000 times16. Nevertheless, both
`the assessor and applicant’s results meet the BE criteria of 67.00% - 150.00%.
`
`
`
`
`
` 16 GlobalSubmit Review; ANDA 203760; Module 5.3.4.1 Attachment F –Dose Scale Model Report;
`
`Submitted 04/13/2017; \\cdsesub1\evsprod\anda203760\0028\m5\53-clin-stud-rep\534-rep-human-pd-
`stud\5341-healthy-subj-pd-stud-rep\study-prg-723\model-rpt-attach-f.pdf
`
`
`
` 17 DARRTS, ANDA 203760; KUNDOOR, VIPRA R 08/04/2014 REV-BIOEQ-21(Primary Review)
`
`
`
`
`

`

`
`
`
`The PD study # PRG723 is adequate.
`
`
`2.5 R Output
`
`
`
`
` Study
`
`
`
` Dataset
`
`R Code
`
`
`
` R Output
`
` PD Study
`
`# PRG723
`
`
`
`exclude 3 subjects
`
`exclude site 4
`
`
`
`
`
`
`
`R Code
`
`R code
`
`
`
`
`
`Output
`
`Output
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`BIOEQUIVALENCE COMMENTS TO BE PROVIDED TO THE APPLICANT
`
`
`
`203760
` ANDA:
`
` Perrigo Pharmaceutical Company
` APPLICANT:
`
`
` DRUG PRODUCT: Albuterol Sulfate Inhalation Aerosol, 0.09 mg Base/Inhalation
`
` The Division of Bioequivalence I (DBI) has completed its review and has no further
`questions at this time.
`
` The bioequivalence comments provided in this communication are comprehensive as of
`
`
` issuance. However, these comments are subject to revision if chemistry, manufacturing
`and controls, microbiology, labeling, or other scientific, regulatory or inspectional issues
`or concerns arise in the future. Please be advised that these concerns may result in the
` need for additional bioequivalence information and/or studies, or may result in a
`
`
`conclusion that the proposed formulation is not approvable.
`
`
`
`
`
`Sincerely yours,
`
`
`
`{See appended electronic signature page}
`
`
`
`Bing V. Li, Ph.D.
`
`Director, Division of Bioequivalence I
`
`Office of Bioequivalence
`
`Office of Generic Drugs
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`

`

`
`
`
`3 COMPLETED ASSIGNMENT FOR 203760 ID: 37658
`
`
`
`
` Reviewer: Zhang, Zhen
`
`
` Verifier:
`,
`
` Division: Division of Bioequivalence
`
` Description: Albuterol Sulfate Inhalation Aerosol, 0.09 mg
`
`
` Base/Inhalation (SD44)
`
`
`
`
` Items:
` ID Letter Date Productivity
`
`
`Category
`
`37658 11/30/2018 BIO
`
`37658 11/30/2018 BIO
`
`
`
`
`
` 37658 11/30/2018 Parallel
`
`
`
` 37658 11/30/2018 Parallel
`
`
`
` 37658 11/30/2018 Parallel
`
`
`
`
`
` Sub Category
`
` ANDA Amendment [1]
`
`Consult Review (For Consults to
`
`Other Office) [1]
`Minor Amendment (Original or
`
` Supplement) [1]
`Review of the Consult Response
`
`
` and Formal Consult to DB [1]
`
` Pre-Screening [0.25]
`
`Date
` Completed:
`
` Date Verified:
`
`
`
`
`
`
`
`
`
`
`
` Score Subtotal
`
`
`
`1
`1
`
`1
`
`1
`
`1
`1
`
`1
`
`1
`
`0.25
`0.25
`Total: 4.25
`
`
`
`

`

`DIVISION OF BIOEQUIV ALEN CE REVIEW
`
`FOR PRESSURIZED MEIERED DOSE INHALATION PRODUCTS
`
`
`ANDA No.
`
`Drug Promct Name
`
`
`Strength(s)
`
`
`AwUcant Name
`
`
`.Awlicant AM·ess
`
`
`IB Contact Name and US
`Mailing AM·ess
`
`IB Contact Telepione
`Number
`
`203760
`Albuterol Sulfate h1halation Aerosol
`
`0.09 mg Base/fuhalation
`
`Penigo Phanmceutical Co~any
`
`515 F.astem Ave
`Allegan, Ml, USA 49010
`
`Matthew Popowski, Senior Regulatory Affairs Project Manager
`3940 Quebec Ave North
`Minneapolis, MN, USA 55427
`
`I
`
`!bH&I
`
`IB Contact Fax Number
`
`763-732-0509
`
`Original Submission Date(s)
`
`11/ 16/2011
`
`Submission Date(s) of
`Amendment(s) Under Re'iew
`
`07/03/2013 Major am~ndm!nt to support the addition of an integrated
`dose counter to the rretered dose inhaler (SDlO)
`04/24/2015 Post-CR m!eting request (SD20)
`07/01/2015 Response to co~lete response letter dated 04/13/2015
`(SD22)
`10/05/2015 Post-CR meeting request (SD24)
`04/13/2017 Major ammdn~nt (SD29)
`10/23/2017 Meeting Request(SD31)
`12129/2017 Major arrendm!nt (SD34)
`04/26/2018 Response to IR request (SD37)
`08/31/2018:Multipe Categories (SD 38)
`
`Primary Re'ielWr
`Secondary Re'ielWr
`
`Tertiary Re'ielWr
`
`Zhen Zhang, Ph.D.
`Vipra Kundoor, Ph.D.
`
`Qing Liu, Ph.D.
`
`Study Number(s)
`
`Study Type(s)
`
`
`Strength(s)
`
`
`Clinical Site
`
`
`Clinical Site Address
`
`
`Analytical Site
`
`Analytical Site Address
`
`
`Study Number(s)
`
`
`Study Type(s)
`
`Strength(s)
`
`In Vitro Test Site
`
`
`In Vitro Tes t Site AM·ess
`
`10825302
`Fasting
`2 x 90 m;g actuations (total dose = 180 m:g)
`
`Novum Phanmceutical Research Se1vices
`Wilcrest G-een Office Park, 3320 Walnut Bend lane, Houston,TX
`77042-4712
`
`TIP-CBJ-MOOSO
`
`I TIP-CBJ-M>0132
`In 'itro Bioe<plivalence Study
`90 m:g/ actuation
`
`I TIP-CBJ-0282
`
`!bT~
`
`(1))\.4
`
`

`

`S tudy Number(s)
`
`S tudy Type(s)
`s n·ength(s)
`
`Clinical Site
`
`Clinical Site Address
`
`PRG-723
`Pharmacodynamic. Bioequh'alence Study
`
`90 m::g/ actuation
`
`Site 1
`University ofFlorida
`Asthma Research lab
`Site 2
`Roy J and Lucille A Carver College of Medicine
`Department of Pediatrics , Allergy/Puhmnaiy
`Site 3
`Allergy & Asthtm Diagnostic Treatment Center
`Site.4
`California Allergy & Asthtm Medical Guup
`fil!U
`Clinical Research Atlanta
`Site 6
`Spartanburg Medical Research
`fil!tl
`AARA Research Center
`Site 1
`1600 SW Archer Road
`Giinesville, FL 32610-0486
`Site 2
`TI1e University oflowa
`200 Hawkins Drive
`Iowa City, Iowa 52242-1083
`Site3
`2300 Centerville Road
`Tallahassee, FL 32308
`Site 4
`11645 Wilshire Blvd, Suite 1155
`Los An