Sterility BET Review Memo_Amendment, November 21, 2013 - Ruconest

CBER REGULATORY REVIEW                                                             21 November, 2013

To             Administrative File: STN 125495/0
                   
From         Dr. Hyesuk Kong
             Laboratory of Microbiology, In-vivo Testing & Standards (LMIVTS)

Through      Dr. James L. Kenney, Lab Chief 
             LMIVTS/ Division of Biological Standards and Quality Control (DBSQC)

             Dr. William M. McCormick, Director
             DBSQC/OCBQ/CBER/FDA

Subject     Amendment to Dr. Kongs Review Memo Dated 24 September, 2013; Review of Sterility and Bacterial Endotoxin Test Qualifications for Recombinant Human C1 Esterase Inhibitor (rhC1INH), Ruconest

Recommendation
 Based on the scope of the review memo dated 24 September, 2013 and this amendment to that memo, I recommend approval of this Biological License Application (BLA).

Conclusion   
 After a through review of this BLA and the response to CBERs Information Request (IR) (amendment 125495/0/5, 125495/0/8, 125495/0/9, 125495/0/13, 125495/0/16 and 125495/0/17) received on 27 June, 2 August, 7 August, 15 October, 31 October, and 13 November 2013, this reviewer finds the sterility and -----------(b)(4)--------- and ------(b)(4)------ bacterial endotoxin test (BET) were qualified in accordance with ---(b)(4)--- and ---(b)(4)---, respectively, by demonstrating the Ruconest matrix is suitable for these intended test methods.

Background  
 Background review information is covered in Dr. Kongs review memo dated 24 September, 2013.

Review
 Sterility
 Ruconest is currently tested for sterility at only -----(b)(4)----- Site.

Qualification - the ---------(b)(4)-------- sterility test   
 ---------------(b)(4)---------------- qualification studies were performed on samples from (b)(4) batches of lyophilized DP (--------------(b)(4)---------------) of Ruconest to demonstrate if its matrix is suitable for the ---(b)(4)--- sterility --------(b)(4)--------- method. Pharming Group NV reported these results in their re-validation report (VAL-R-03-292).

Pharming Group NV qualified their Ruconest product using the contents of (b)(4) vials of rhC1INH sample volume ((b)(4) final containers reconstituted with 14 mL). The test sample was filtered ---------------------------------------------------------------------(b)(4)-------------------------------------------------
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-------------------------------------------------------------. The test was performed and compliant with ---(b)(4)--- and the test results indicate there is no product inhibition on microorganism growth; thus indicating the Ruconest product matrix is suitable for testing via the  -------------(b)(4)--------------- sterility test method.

Endotoxin
 Pharming Group NV performs BET on their Ruconest product matrix using the -----------(b)(4)-------------------------- BET method at -----(b)(4)------ site and the -------(b)(4)-------- BET method at         ---(b)(4)--- site in accordance with ---(b)(4)---.

----------(b)(4)--------- Bacterial Endotoxin Test ((b)(4)-BET) Method Qualification performed at        ----(b)(4)---- site
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However, CBER performed licensing support bacterial endotoxin testing using a (b)(4)-BET method on their final container conformance lots (-----------------------------(b)(4)---------------------------------------- sample testing dilution. CBER experienced inhibition of these (b)(4)-BET results and requested information for the qualification report showing the lyophilized product matrix is suitable for testing using the (b)(4)-BET method to include the testing dilution chosen for release testing and (b)(4) results for all dilutions tested during the qualification process (amendment 125495/0/9).

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CBER retested the three conformance lots (----------------------------(b)(4)---------------------------- testing dilution (see CBER in-support BET test results memo dated 4 September, 2013) and determined the DP, when tested at a -----(b)(4)-----, meets the suitability requirements necessary to qualify its matrix for the intended test method. 

---------(b)(4)---------- Bacterial Endotoxin Test ((b)(4)-BET) Method Qualification performed at      -----(b)(4)----- site
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Based on this information, this reviewer finds Pharming Group NVs proposed BET release specification of ---(b)(4)--- acceptable.

Summary
 After a thorough review of the information submitted in this BLA, this reviewer finds Pharming Group NVs rhC1INH product matrix is suitable for testing using their sterility and bacterial endotoxin testing method; these tests were qualified and performed in accordance with -----------(b)(4)---------------, respectively. In addition, as reviewed in the review memo dated 24 September, 2013, the bioburden qualification tests on -------------------------(b)(4)--------------------------------- were performed in accordance with ----(b)(4)---- and these test results indicate the product matrix is suitable for their bioburden testing method. Therefore, this reviewer finds these methods acceptable for their intended purpose and recommends their approval.
