CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`MICROBIOLOGY REVIEW(S)
`
`
`
`
`
`
`
`

`

`Product Quality Microbiology Review
`10 January 2012
`
`NDA 202-236/N-000
`
`Drug Product Name
`Proprietary:
`Dymista (proposed)
`Non-proprietary: Azelastine Hydrochloride (AH) 0.1% and
`
`Fluticasone Proprionate (FP) 0.037%
`
`(AH-FP)
`
`Review Number: 1
`
`Dates of Submission(s) Covered by this Review
`Submit
`Received
`Review Request
`01-APR-2011
`01-APR-2011
`01-JUN-2011
`07-DEC-2011
`07-DEC-2011
`NA
`
`Assigned to Reviewer
`03-JUN-2011
`NA
`
`Applicant/Sponsor
`Name:
`Meda Pharmaceuticals, Inc.
`Address:
`265 Davidson Avenue, Suite 300
`Somerset, NJ 08873-4120
`
`Representative: Richard Fosko, RPH, MPH
`Telephone:
`732-564-2358
`
`Name of Reviewers: Steven Fong, Ph.D.
`
`Denise Miller, Microbiologist
`
`Conclusion: CMC-Microbiology Recommends APPROVE.
`
`Reference ID: 3070799
`
`

`

`NDA 202-236/N-000
`
`
`
`Microbiology Review #1
`
`Product Quality Microbiology Data Sheet
`1.
`TYPE OF SUBMISSION: Original NDA
`
`A.
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`2.
`
`3.
`
`
`
`
`
`
`
`4.
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`5.
`
`6.
`
`SUBMISSION PROVIDES FOR: New drug product: non-sterile nasal
`spray
`
`
`MANUFACTURING SITE:
`Cipla Ltd.
`Plot No. L139 to L146
`Verna Industrial Estate
`Verna, Salcette 403722
`Goa, INDIA
`Facility Establishment Identifier: 3004081307
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: Non-sterile,
` multi-dose nasal spray
`containing 0.1% AH and 0.037% FP.
`
`METHOD(S) OF STERILIZATION: N/A. Product is non-sterile.
`
`PHARMACOLOGICAL CATEGORY: Allergic rhinitis therapeutic.
`
`B.
`
`C.
`
`SUPPORTING/RELATED DOCUMENTS: None.
`
`REMARKS:
`1) The submission was submitted electronically in CTD format.
`
`2) On 31-AUG-2011 the following IR (Communication 8) was submitted to the
`Applicant:
`(1) Please amend the Microbial Quality section of the drug product Specification
`(Table 2 of Section 3.2.P.5.1) to include absence of Burkholderia cepacia and
`the method that will be used for B. cepacia detection. Your test method should
`be validated and a discussion of the test methods should be provided. Test
`methods validation should address multiple strains of the species and cells that
`are acclimated to the environments (e.g., warm or cold water) that may be
`tested.
`(2) Please provide the manufacturing controls that will be implemented to limit
`contamination of the drug product with B. cepacia. We recommend that
`potential sources are examined and sampled as process controls. These may
`include raw materials and the manufacturing environment. A risk assessment
`for B. cepacia in the raw materials is recommended to develop sampling
`procedures and acceptance criteria.
`An Amendment response, Supporting Document 14, was received 07-DEC-
`2011.
`
`
`
`Reference ID: 3070799
`
`Page 2 of 17
`
`(b) (4)
`
`(b) (4)
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`

`

`NDA 202-236/N-000
`
`
`
`Microbiology Review #1
`
`3) On 01-SEP-2011, Meda Pharmaceuticals sent an e-mail to RPM Philantha
`Bowen that contained questions regarding the 31-AUG-2011 microbiology
`quality IR. The questions are indicated below in italic font. Reviewer
`responses to the questions were provided in a 13-SEP-2011 communication to
`Meda Pharmaceuticals, and are indicated below the questions in regular font.
`(1) Regarding the request for multiple strains of B. cepacia, would three separate
`ATCC strains of the organism be appropriate? If the manufacturing site does
`not have an industrial isolate from their purified water system is it required
`that they still use cells that are acclimated to the environments (eg., warm or
`cold water).
`Microbiology Reviewer Response: For validation of the B. cepacia
`identification test, testing with three separate ATCC strains of the bacterium
`would be appropriate. If a B. cepacia isolate from the manufacturing site is
`not available, you are recommended to acclimate the ATCC strains to warm
`or cold water prior to conducting validation studies.
`
`(2) For process controls such as the manufacturing environment, is it acceptable
`to monitor the production surfaces for Total Aerobic Microbial Count
`(TAMC) and Total Yeasts and Molds Count (TYMC). Would the TAMC
`monitoring be adequate to show contamination control? Would the same be
`acceptable for air monitoring (TAMC and TYMC would be tested in the
`production areas).
`
`Agency Microbiology Reviewer Response: Monitoring of the air and
`production surfaces for TAMC and TYMC would be adequate to demonstrate
`contamination control. Testing for the specific presence of B. cepacia will not
`be necessary.
`(3) Is the following approach acceptable? The raw material risk assessment
`would include those materials (including purified water) which have the
`potential for microbiological contamination. This would include obtaining
`water activity data for dry materials, historical data
` and
`adding a B. cepacia screen to the purified water. For raw materials is USP
`<61> and <62> testing is appropriate or would a separate B. cepacia screen
`be required?
`Agency Microbiology Reviewer Response: The approach appears
`reasonable. The addition of a B. cepacia screen for purified water, and the
`performance of a risk assessment of the raw materials used for formulation, is
`appropriate and recommended.
`
`4) On 17-NOV-2011 the following second IR was submitted to the Applicant:
`Your proposed commercial product stability testing protocol should be amended to
`include a microbial limits Burkholderia cepacia detection assay and acceptance
`criterion.
`The response was included in the 07-DEC-2011 Amendment (Supporting
`Document 14).
`
`
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`Reference ID: 3070799
`
`Page 3 of 17
`
`(b) (4)
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`

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`NDA 202-236/N-000
`
`
`
`Microbiology Review #1
`
`5) On 30-NOV-2011 the quality microbiology review of this application was
`transferred to Denise Miller. At this time, the review was substantially complete
`and was waiting for the response to the information request dated 31-AUG-2011.
`Denise Miller reviewed the response.
`
`filename: N202236N000R1.doc
`
`
`
`Reference ID: 3070799
`
`Page 4 of 17
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`

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`NDA 202-236/N—000
`
`Microbiology Review #1
`
`Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability — Recommended for
`approval from a microbiology quality standpoint.
`
`B.
`
`Recommendations on Phase 4 Commitments and/or
`
`Agreements, if Approvable — N/A
`
`11.
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`Summary of Microbiology Assessments
`
`A.
`
`B.
`
`C.
`
`Brief Description of the Manufacturing Processes that relate to
`Product Quali Microbiology — Following formulation, the non—
`sterile,
`0" bulk product is filled in 6 g or 23 g amounts,
`respectively, into
`(m4) Type I amber glass bottles.
`The bottles are fitted with a
`(mo spray pump closure that
`allows for metered intranasal delivery.
`
`Brief Description of Microbiology Deficiencies — None.
`
`Assessment of Risk Due to NIicrobiology Deficiencies — N/A
`
`III.
`
`Administrative
`
`A.
`
`Reviewer's Signature
`
`B.
`
`Endorsement Block
`
`C.
`
`CC Block—N/A
`
`Steven Fong, Ph.D.
`Microbiology Reviewer
`
`Stephen E. Langille, Ph.D.
`Senior Microbiology Reviewer
`
`12 Pages have been Withheld in Full as b4 (CCIITS) immediately
`following this page.
`
`Reference ID: 3070799
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`Page 5 of 17
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`DENISE A MILLER
`01/12/2012
`
`STEPHEN E LANGILLE
`01/12/2012
`
`Reference ID: 3070799
`
`