`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203794Orig1s000
`
`MICROBIOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`
`
`Product Quality Microbiology Review
`
`7 AUGUST 2012
`
`
`
`NDA: 203794/N-000
`
`Drug Product Name
`Proprietary: NUCYNTA
`Non-proprietary: Tapentadol Hydrochloride
`
`
`Review Number: 1
`
`
`Dates of Submission(s) Covered by this Review
`Submit
`Received
`Review Request
`15 December 2011
`15 December 2011
`6 January 2012
`7 May 2012
`7 May 2012
`N/A
`13 June 2012
`13 June 2012
`N/A
`
`
`
`
`Assigned to Reviewer
`13 January 2012
`N/A
`N/A
`
`
`
`
`Submission History (for amendments only): N/A
`
`Applicant/Sponsor
`Name: Janssen Pharmaceuticals, Inc.
`Address: 1125 Trenton-Harbourton Road, P.O. Box 200
`Titusville, NJ 08560-0200
`Representative: Peggy Ferrone
`Telephone: 908-704-5116
`
`
`Name of Reviewer: Bryan S. Riley, Ph.D.
`
`Conclusion: Recommend Approval
`
`
`
`
`Reference ID: 3170974
`
`

`

`NDA 203794 (NUCYNTA)
`
`Microbiology Review #1
`
`Product Quality Microbiology Data Sheet
`
`A.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`TYPE OF SUBMISSION: 505(b)(1)NDA
`
`SUBMISSION PROVIDES FOR: A new oral solution drug product
`
`MANUFACTURING SITE:
`
`"’"°
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: Non-sterile, aqueous solution for oral
`administration in a HDPE bottle, 100mL in a 120 mL bottle or 200 mL in
`
`a 235 mL bottle, 20 mg/mL.
`
`METHOD(S) OF STERILIZATION: N/A
`
`PHARMACOLOGICAL CATEGORY: Analgesic
`
`B.
`
`SUPPORTING/RELATED DOCUMENTS: N/A
`
`C.
`
`REMARKS: This was an eCTD submission. Information requests were sent to
`the applicant via email on 20 April 2012 and 6 June 2012. The text of the Product
`Quality Microbiology questions is provided below:
`
`20 April 2012 IR
`1. The drug product microbiological specifications should clearly identify the acceptance
`criteria both for enumeration and specific microorganisms. Merely stating that the drug
`product meets Current USP <1111> is not sufficient.
`
`2. Provide test methods and acceptance criteria to demonstrate the product is free of the
`objectionable microorganisms of the Burkholderia cepacia complex. We recommend that
`potential sources are examined and sampled as process controls, and these may
`include raw materials and the manufacturing environment. A risk assessment for this
`species in the product and raw materials is recommended to develop sampling
`procedures and acceptance criteria. Your test method should be validated and a
`discussion of those 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.
`
`3. Your proposal to perform skip lot testing for the Microbial Limits test is unacceptable
`because it does not comply with 21 CFR 211.165(a) and (b). Microbial limits testing
`should be performed on each lot of drug product at release. After obtaining sufficient
`data to demonstrate control of drug product bioburden, you may submit a prior approval
`supplement proposing to omit finished product microbial limits testing for batch release.
`
`Reference ID: 31 70974
`
`Page 2 of 8
`
`

`

`Microbiology Review #1
`
`
`
`NDA 203794 (NUCYNTA)
`
`
`After approval of omitting microbial limits testing at release, microbial limits testing
`should continue to be performed at the initial time point (at a minimum) on stability
`samples.
`
`6 June 2012 IR
`Your proposal to perform skip lot testing for the Microbial Limits test is unacceptable
`because it does not comply with 21 CFR 211.165(a) and (b). An attribute listed in the
`drug product specifications must be assessed for each lot of drug product at release by
`performing the appropriate test procedure. Therefore, the proposal to use skip lot testing
`for microbial limits should be withdrawn from your application.
`
`However, after obtaining sufficient manufacturing experience and acceptable microbial
`limits testing data to demonstrate control of drug product bioburden, you may submit a
`prior approval supplement proposing to omit finished product microbial limits testing for
`batch release. After approval of omitting microbial limits testing from the release
`specification, microbial limits testing should continue to be performed at the initial time
`point (at a minimum) on stability samples.
`
`
`The applicant responded with amendments dated 7 May 2012 and 13 June 2012.
`The review of the amendments is included in section 3.2.P.5.
`
`
`filename: N203794R1.doc
`
`
`
`
`
`Reference ID: 3170974
`
`
`
`Page 3 of 8
`
`
`
`

`

`
`
`
`Microbiology Review #1
`
`
`NDA 203794 (NUCYNTA)
`
`Executive Summary
`
`
`Recommendations
`
`A.
`
`I.
`
`II.
`
`
`Recommendation on Approvability – This submission is
`recommended for approval on the basis of product quality
`microbiology.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable – N/A
`
`
`Summary of Microbiology Assessments
`
`
`B.
`
`A.
`
`Brief Description of the Manufacturing Processes that relate to
`Product Quality Microbiology – The drug product is a non-sterile
`oral liquid. Although the drug product does not contain a specific
`preservative, it meets the acceptance criteria for USP Chapter
`<51>. The drug product is tested for microbial limits at release.
`
`Brief Description of Microbiology Deficiencies – N/A
`
`Assessment of Risk Due to Microbiology Deficiencies – N/A
`
`
`B.
`
`C.
`
`III. Administrative
`
`
`A.
`
`
`B.
`
`
`C.
`
`Reviewer's Signature _____________________________
`Bryan S. Riley, Ph.D.
`Senior Review Microbiologist, OPS/NDMS
`
`
`
`Endorsement Block ______________________________
`Stephen E. Langille, Ph.D.
`Senior Review Microbiologist, OPS/NDMS
`
`CC Block
`N/A
`
`
`
`
`
`Reference ID: 3170974
`
`
`
`Page 4 of 8
`
`
`
`4 Page(s) has 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/
`----------------------------------------------------
`
`BRYAN S RILEY
`08/07/2012
`
`STEPHEN E LANGILLE
`08/08/2012
`
`Reference ID: 3170974
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`5 June 2012
`
`Luz Rivera, Project Manager, (ONDQA)
`
`
`
`DARRTS
`
`Bryan S. Riley, Ph.D., Senior Review Microbiologist (OPS/NDMS)
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`THROUGH: Stephen E. Langille, Ph.D., Senior Review Microbiologist (OPS/NDMS)
`
`CC:
`
`SUBJECT: NDA 203794 - Product Quality Microbiology Information Request
`
`
`An information request addressing 3 product quality microbiology issues was sent to the
`applicant via email on 20 April 2012. The applicant responded by submitting an amendment to
`the NDA on 7 May 2012. Two of the three product quality microbiology issues were adequately
`addressed in the amendment.
`
`The third product quality microbiology issue in the 20 April IR was related to the use of skip-lot
`testing for microbial limits. The applicant was informed that skip-lot testing was not acceptable
`because it did not conform with 21 CFR 211.165(a) and (b). However, the applicant responded
`by restating the justification for skip-lot testing contained in their original submission. Therefore,
`the following information request should be sent to the applicant:
`
`
`
`
`
`
`Your proposal to perform skip lot testing for the Microbial Limits test is unacceptable
`because it does not comply with 21 CFR 211.165(a) and (b). An attribute listed in the
`drug product specifications must be assessed for each lot of drug product at release by
`performing the appropriate test procedure. Therefore, the proposal to use skip lot
`testing for microbial limits should be withdrawn from your application.
`
`However, after obtaining sufficient manufacturing experience and acceptable microbial
`limits testing data to demonstrate control of drug product bioburden, you may submit a
`prior approval supplement proposing to omit finished product microbial limits testing
`for batch release. After approval of omitting microbial limits testing from the release
`specification, microbial limits testing should continue to be performed at the initial time
`point (at a minimum) on stability samples.
`
`END
`1
`
`Reference ID: 3140893
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRYAN S RILEY
`06/05/2012
`
`STEPHEN E LANGILLE
`06/06/2012
`
`Reference ID: 3140893
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`18 April 2012
`
`Khushboo Sharma, Project Manager, (ONDQA)
`
`Bryan S. Riley, Ph.D., Senior Review Microbiologist (OPS/NDMS)
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`THROUGH: Stephen E. Langille, Ph.D., Senior Review Microbiologist (OPS/NDMS)
`
`CC:
`
`SUBJECT: NDA 203794 - Product Quality Microbiology Information Request
`
`
`
`The specifications for the drug product include the following section:
`
`
`
`
`DARRTS
`
`
`
`
`
`
`
`
`
`The submission also states (section 3.2.P.5.6 Justification of Specifications) that the applicant
`will test, at a minimum, the first 10 production batches of the drug product for microbiological
`purity and use the results to generate data for a risk assessment. Skip lot testing would not be
`implemented until the risk has been determined to be low.
`
`Reviewer Comment:
`
`The drug product microbiological specifications should clearly
`identify the acceptance criteria both for enumeration and
`specific microorganisms. Merely stating that they meet
`Current USP <1111> is not sufficient. The drug product
`microbiological specifications should also include a test for the
`1
`
`Reference ID: 3118936
`
`

`

`M E M O R A N D U M
`
`
`
`opportunistic pathogens in the Burkholderia cepacia complex.
`Additionally, skip lot testing is unacceptable because it does
`not comply with 21 CFR 211.165(a) and (b).
`
`
`
`
`Comments to be sent to the Applicant:
`
`
`
`
`
`
`
`
`1. The drug product microbiological specifications should clearly identify the acceptance
`criteria both for enumeration and specific microorganisms. Merely stating that the drug
`product meets Current USP <1111> is not sufficient.
`
`2. Provide test methods and acceptance criteria to demonstrate the product is free of the
`objectionable microorganisms of the Burkholderia cepacia complex. We recommend
`that potential sources are examined and sampled as process controls, and these may
`include raw materials and the manufacturing environment. A risk assessment for this
`species in the product and raw materials is recommended to develop sampling procedures
`and acceptance criteria. Your test method should be validated and a discussion of those
`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
`
`3. Your proposal to perform skip lot testing for the Microbial Limits test is unacceptable
`because it does not comply with 21 CFR 211.165(a) and (b). Microbial limits testing
`should be performed on each lot of drug product at release. After obtaining sufficient data
`to demonstrate control of drug product bioburden, you may submit a prior approval
`supplement proposing to omit finished product microbial limits testing for batch release.
`After approval of omitting microbial limits testing at release, microbial limits testing
`should continue to be performed at the initial time point (at a minimum) on stability
`samples.
`
`END
`
`2
`
`Reference ID: 3118936
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRYAN S RILEY
`04/19/2012
`
`STEPHEN E LANGILLE
`04/19/2012
`
`Reference ID: 3118936
`
`

`

`PRODUCT QUALITY MICROBIOLOGY FILING CHECKLIST
`NDA Number: 203794
`Applicant: Janssen
`Letter Date: 15 December 2011
`Pharmaceuticals, Inc.
`NDA Type: 505(b)(1)
`
`Stamp Date: 15 December 2011
`
`
`
`
`
`
`
` X
`
`
`
`
`
`X
`
`
`
`
`
` X
`
`
`
` X
`
`
`
` X
`
`
`
`
`
` X
`
`X
`
`
`
`
`
` X
`
`
`1
`
`Comments
`
`
`
`
`
`
`
`
`
`AME testing was
`provided in section
`P.2.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`26 January 2012
`Date
`
`Date
`
`Reference ID: 3077854
`
`Drug Name: NUCYNTA
`
`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.
`
`X
`
`
`
`9
`
`Additional Comments: The drug product is a non-sterile, aqueous, oral solution. The applicant is
`proposing skip-lot testing for microbial limits and is not testing for Burkholderia cepacia. An IR
`will be drafted to send to the applicant regarding skip-lot testing and B. cepacia.
`
`
`
`
`
`
`Bryan S. Riley, Ph.D.
`Senior Review Microbiologist
`
`
`John W. Metcalfe
`Senior Review Microbiologist
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRYAN S RILEY
`01/28/2012
`
`JOHN W METCALFE
`01/30/2012
`I concur.
`
`Reference ID: 3077854
`
`