Bioburden Review Memo, September 24, 2013 - Ruconest

MEMORANDUM

24 September, 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 (acting)
 LMIVTS/ Division of Biological Standards and Quality Control (DBSQC)

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

Subject BLA, Review of Bioburden Test Method Qualifications for Recombinant Human C1 Esterase Inhibitor (rhC1INH), Ruconest

Conclusion 
 After a through review of this Biological License Application (BLA) and the response to CBERs Information Request (IR) (amendment 125495/0/5, 125495/0/8, and 125495/0/9) received on 27 June, 2 August, and 7 August, 2013, this reviewer finds the bioburden test was qualified in accordance with (b)(4) by demonstrating the Ruconest -------------------------------------------------(b)(4)----------------------------- are suitable for their intended bioburden assays. The bacterial endotoxin test (BET) and sterility method qualifications reviews have not completed at this time as an IR was submitted Pharming Group NV, these reviews will be completed and added as an amendment to this review memo after the IR responses are received by CBER. Thus, I recommend approval of the bioburden test method for testing the -----------------------------------(b)(4)-------------------------------------------. In addition, BET and sterility review memo will be also completed within weeks after receiving Pharming Group NVs submission.

Background 
 On 15 April 2013, Pharming Group NV (Leiden, The Netherlands) submitted this BLA for Ruconest under the referenced US Investigation New Drug Application (IND) #11785. Ruconest is indicated treatment for acute attacks of hereditary angioedema (HAE) in adult and adolescent patients. Ruconest is supplied as a lyophilized powder in each vial containing 2100 IU and once reconstituted with 14 mL water for injection for intravenous injection it contains 150 IU of rhC1INH per 1 mL in a 20 mM sodium citrate buffer with a pH of 6.8. One IU of rhC1INH activity is defined as the equivalent C1 esterase inhibiting activity in 1 mL of pooled normal human plasma.

Ruconest is manufactured directly from -------------------------(b)(4)------------------- Pharming Group NV manufacture sites [i.e., ----------------------------------(b)(4)----------------------------------------------------)]. Ruconest is a recombinant analogue of human complement component 1 (C1) esterase inhibitor and is purified from the skimmed milk of transgenic rabbits expressing the gene encoding for human C1INH. Following the purification process of rhC1INH from skimmed milk the production lots are -----------------------(b)(4)----------------------------. Continued production involves the -----------------------------------------------------------------------------------(b)(4)-----------------------------------------------------------(b)(4)-------------------------, lyophilization and final container packaging.

The DBSQC reviews BLAs and Supplements to ensure product methods are appropriately validated, product matrix is suitable for the intended test method, and release specifications reflect process capability and are compliant with referenced regulations. These review activities support DBSQCs lot-release mission, which is the confirmatory testing of submitted product samples and review of manufacturers lot-release protocols to ensure they are released according to licensed test methods and product specifications. In the case of this bioburden method validation review: DBSQC was asked to review the --(b)(4)-- processing bioburden method performed --------(b)(4)----------------- by the product office, in addition to our review of the bioburden methods performed on the -------------------------------------------------(b)(4)--------------------------------------------. Therefore, this review will focus on the qualification of the bioburden performed on the ------------------------------------(b)(4)----------------.

Review
Bioburden Test Qualification in ---------------------(b)(4)-------------------------------
 The bioburden test method qualification on their ------------------------------------(b)(4)------------------------- was performed by the contract testing facility ---------------------------(b)(4)---------------------------to verify the methods suitability. The test was performed according to ---(b)(4)--- using the ---------------------------------------------
---------------(b)(4)------------------------------------------------------------------------------- bioburden test specification was ----(b)(4)----.

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-------------------------------------------. Therefore, the bioburden test method for the -------------(b)(4)------------- was performed in accordance with ---(b)(4)--- and the results indicate the product matrix is suitable for the intended test method.

Bioburden Test Qualification on Ruconest --------------(b)(4)--------------- Site
 ----(b)(4)---- qualified their ------(b)(4)------ bioburden test method by testing -----------------------------------------------(b)(4)------------------------------------------------------------------- according to their protocol PVAL/MIC/2011-10 Ver.2, ------------(b)(4)------------ and reported these results in validation report VAL-R-03-262.

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 -------------------------------------------------. Therefore, the bioburden test method for the -----------------------------(b)(4)---------------------- site was performed in accordance with ---(b)(4)--- and the test results indicate their ------(b)(4)-- matrix is suitable for the intended test method.

Bioburden Test Qualification on --------------(b)(4)------------------
 ------(b)(4)------ qualified their -----(b)(4)----- for their bioburden test method by testing ----------------------------------(b)(4)--------------------------------- to verify the methods suitability. The test was performed according to ---(b)(4)--- using the ----------------------------------------------------------------------------
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 ---------------------------------(b)(4)-------------------------------------------------
 -------------------------------------------. Based on my review the bioburden test method for the --------------(b)(4)-----------, qualified at ----(b)(4)---- site, was performed in accordance with ---(b)(4)--- and the results indicate the ------(b)(4)----- matrix is suitable for the intended test method.

Summary
 After a thorough review of the information submitted in this BLA, this reviewer concludes that the bioburden qualification tests on Pharming Group NVs -----------------------------------------(b)(4)---------------------------------------- at (b)(4) manufacturing facilities were performed in accordance with ---(b)(4)--- and the test results indicate the product matrix is suitable for the intended test method.

The review of their BET and sterility test qualifications will be completed as an amendment to this review memo after the IR responses are received by CBER.
