Product Approval Information

Final Memorandum

From: Mahmood Farshid, Ph.D., DH/OBRR, CBER . HFM-345
To: Felice D’Agnillo, Ph.D. , DH, OBRR, CBER
Re: · Manufacturer: Lev Pharmaceuticals, Inc. ·Product: C₁-Esterase Inhibitor (Human)[Cinryze™) · Issue: Evaluation of viral validation data submitted in the BLA STN# 125267/0

This review memo pertains only to viral validation studies that are submitted in this BLA.

Review Comment: Viral clearance studies are acceptable; these include choice of viruses, number and the capacity of clearance steps, validation of small scale model, and robustness studies.

Summary:

The C1INH preparation consists of a protein fraction prepared from human plasma. The C1INH is purified following -------(b)(4)------------------------------chromatography, PEG precipitation and -------(b)(4)-------- chromatography. After being dissolved in the appropriate volume of water for injection, the product contains 100 U of C1INH per ml.

C1INH is a lyophilized product that is heat treated (pasteurized) and nanofiltered followed by aseptic filling.

Manufacturing Overview:

- ------------------------------
↓
-----------------------
↓
-------------------
↓
--------------(b)(4)-----
↓
---------------------------
↓
-------------------------
↓
--------------------------------------
↓
-------------
↓
-------------------
↓
--------------------------------
↓
--------------------------
↓
---------------------------
↓
------------------(b)(4)------------
↓
-------------------------------
↓
-----------------------------------------
↓
----------------------
↓
-------------------------
↓
--------------------------
↓
-----------------
↓
-----------------------------------------------
↓
----------------------------

Viral Safety

The product is manufactured using US licensed plasma. As required, individual donations are tested for the presence of anti-HCV, anti-HIV1/2, and HbsAg. In addition, Source plasma units are also tested for HCV-RNA and HIV-RNA by (b)(4).

Viral Validation Studies

Viral clearance data include report concerning the manufacturing process of Lev Pharmaceutical Drug Product, Cinryze (C1 esterase inhibitor), which is intended for the US market, and study report concerning Cetro, the manufacturing process of Sanquin’s own product, currently marketed in Europe. Viral validation data are included in Module 1 Volume 1.2 and 1.3.

The following viruses have been used in the validation studies:

Bovine viral diarrhea virus (BVDV), enveloped RNA virus a model for HCV
Human immunodeficiency virus type 1 (HIV-1), enveloped RNA retrovirus
Pseudorabies virus (PrV), envelope DNA virus, a model for herpesviruses
Canine parvovirus (CPV), non -enveloped DNA virus, a model for B19
Hepatitis A virus (HAV), non-enveloped RNA virus

Viral clearance Steps

Three process steps in the manufacturing of C1 inhibitor product have been evaluated for their ability to inactivate and/or remove viruses:

PEG precipitation; removal was investigated using HIV, HAV, CPV, BVDV, and PRV. Robustness was investigated with --(b)(4)--.
Pasteurization (10h at 60(b)(4) kinetics were investigated using HIV, HAV, CPV, BVDV, and PRV, and robustness was investigated with (b)(4).
Nanofiltration through two serially connected Planova 15N filters: Removal was investigated using HIV, HAV, CPV, BVDV, and PRV and robustness was investigated using (b)(4).

The results of these studies are described in Module 1 Volume 1.2 and 1.3: Study Report # 036-035: Appendix 1 detail of viral clearance studies (Tables 1A to 5A: HIV, PRV, BVDV, HAV, and CPV).

-----------------------------------------(b)(4)-----------------------------------------------------------------------:

(b)(4)

---------------------------------------------------:

-----------------------------------------------------------------------------------------------------------------------------------------.

----------------------------------------------------------------------------------------

----------------------------------------------------------------

--------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------- -----------------------------------------------------------------------------------.

---------------------------------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------.

One (1) page determined to be not releasable:

(b)(4)

---(b)(4)-----

--------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------

---------------------------------- -------
------------------- -------
------------------- -------
------------------------- -------

Review comments

Viral clearance studies are acceptable; these include choice of viruses, number and the capacity of clearance steps, validation of small scale model, and robustness studies.

To further reduce the risk of parvovirus B19 infection, the manufacturing pools need to be tested for Parvovirus B19 DNA using a validated NAT assay, and it should be demonstrated that the level of B19 DNA in the pools does not exceed 4 logs (≤ 10⁴ IU/mL).

-----------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------- --------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------.

Comments # 2 and 3 were conveyed to the sponsor at the completion of mid-cycle review. The sponsor response to both comments have been received, reviewed and found acceptable. With regard to B19 NAT, the sponsor provided data demonstrating adherence to the ≤ 10⁴ IU/mL limit for B19 DNA, which is currently recommended by the FDA. The test is being conducted at the mini-pool level to detect units with high titer B19 DNA. Manufacturing pool is also re-tested to ensure that the limit of B19 DNA does not exceed 10⁴ IU/mL. -------------------(b)(4)----------------------------------------------------------------------------------------------.