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Vaccines, Blood & Biologics

CMC Final Review Memo and Recommendation - Berinert, October 9, 2009

From:Felice D’Agnillo, LBVB/DH/CBER, HFM-343
Through:Abdu Alayash, Chief, LBVB/DH/CBER, HFM-343
ToNannette Cagungun, Regulatory Project Manager, CBER/DH, HFM-380
Sponsor:CSL Behring
Product:C1 Esterase Inhibitor (human) or BERINERT
Subject:Final CMC Recommendation: Approval


Final Recommendation

We recommend the final approval of the chemistry, manufacturing and control (CMC) section of this Biologics License Application (BLA).  This recommendation is based on the review of the CMC sections of this application and the sufficiency and acceptability of the data and the responses that have been provided by the sponsor to the issues and questions outlined in the Complete Response (CR) letter (Items 2 - 4) as well as responses to additional information requests (CMC-related review memos are on file). Furthermore, as detailed in the viral validation memo, the sponsor has agreed to a post-marketing commitment to implement a --------------b(4)----------------------------------------------------------------------------------------------------------------------------------.


This original Biologics License Application (BLA) from CSL Behring for C1-esterase inhibitor (human) or Berinert, indicated for the treatment of acute attacks in patients with hereditary angioedema (HAE), was received in CBER/DCC on March 7, 2008 and was assigned as STN 125287/0. The offices for CSL Behring are located in King of Prussia, PA, and the manufacturing facilities are located in Marburg, Germany. Orphan drug status was granted on October 16, 1992. The clinical studies for this BLA were conducted under IND --b(4)--. The BLA submission qualified for priority review with an action due date of September 5, 2008. CSL Behring submitted an amendment on June 20, 2008, within 3 months of this action due date, that was classified as a Major Amendment and extended the review clock by 3 months.

On the action due date of December 5, 2008, FDA issued a Complete Response (CR) letter to the sponsor. The sponsor responses to the CR letter were received by CBER on April 10, 2009. The submission was classified as a Class II response with a review deadline of October 9, 2009.

Berinert is a purified, pasteurized, lyophilized preparation of human plasma-derived C1 esterase inhibitor derived from U.S. Source Plasma. The manufacturing process steps include --b(4)----------, precipitation, filtration, heat treatment, and chromatography steps. Viral clearance capacity of the manufacturing process has been demonstrated by validation studies on the pasteurization step, hydrophobic interaction chromatography, and a combination of steps involving chromatography and ammonium sulfate precipitation.  Berinert is supplied as a lyophilized powder in single-use glass vials. Berinert is administered by intravenous injection after reconstitution with the appropriate volume of Sterile Water for Injection (USP). Berinert is indicated for the treatment of acute attacks in patients with hereditary angioedema (HAE), a disease characterized by low levels of endogenous or functional C1 esterase inhibitor. The CMC sections of this application were reviewed by four reviewers and each generated memos that have been filed. 

Active Ingredient: C1 esterase inhibitor (derived from U.S. Source Plasma)

Established Name: C1 esterase inhibitor (human)

Proposed Proprietary Name: Berinert

Dosage Form: Lyophilized powder, 500 U/vial to be dissolved in 10 ml sterile water for injection.

Container/Closure System: Berinert is supplied in 17 mL vials made of colorless molded Type b(4) glass and closed with ---b(4)-- rubber stoppers and sealed with aluminum caps.

Proposed Shelf Life/Storage Conditions: 30 months at 2 - 25°C (8 hours at room temp when reconstituted)

Proposed Indication for Use: Treatment of patients with hereditary angioedema (HAE)

Route of Administration: Intravenous

Mechanism of Action: Plasma C1 esterase inhibitor regulates the activation of complement, contact, and fibrinolytic systems. Patients with HAE have low levels of endogenous or functional C1 esterase inhibitor. Replacement therapy with C1 inhibitor is intended to increase plasma levels of C1-esterase activity and restore control over the complement, contact, and fibrinolytic systems.


I. Introduction

Berinert is a sterile, pasteurized, lyophilized product of C1 esterase Inhibitor. The overall starting material is U.S. Source Plasma collected at FDA-licensed and inspected plasma collection centers from qualified plasma donors. The composition of each vial of Berinert is as follows: 500 U C1 inhibitor, 50-80 mg total protein, 85-115 mg glycine, 25-35 mg sodium chloride, and 70-100 mg sodium citrate. The product package consists of one carton containing a single-use vial of Berinert and one 10 ml vial sterile water for injection, and an additional carton with a Mix2Vial filter transfer set, a disposable 10 ml syringe, infusion set, and two alcohol swabs.


1 Page determined to be not releasable: b(4)


2 DEAE-Sephadex A50 chromatography, QAE-Sephadex chromatography and ammonium sulfate precipitation steps in the manufacturing process were validated for their combined capacity to clear HIV and PRV in response to FDA review comments (see below).


III. Review Comments and Manufacturing Information Updated During the Review Cycle

1. Starting Materials:

U.S. Source Plasma from FDA-approved and inspected blood centers. All units are tested and found non-reactive to hepatitis B surface antigen, negative for antibodies to human immunodeficiency virus (HIV-1/2), hepatitis C virus (HCV). All plasma is tested by FDA-licensed Nucleic Acid Tests (NAT) for HCV and HIV-1 and found to be nonreactive (negative). Manufacturing plasma pools are also tested for B19 DNA by NAT to ensure that the level in the pool does not exceed 104 IU/mL

Review Comments:

The sponsor accepted the FDA recommendation to change the specification for Parvovirus B19 in the fractionation pool from a value of 105 logs to 104 logs.

2.    Viral Clearance Capacity of Manufacturing Process:

The BLA provided validation data supporting the viral clearance capacity of two steps in the manufacturing process; pasteurization (10 h at 60 °C) and hydrophobic interaction chromatography (HIC).  The combined effect of pasteurization and HIC (----b(4)----------------------------) provided acceptable degree of clearance for the panel of viruses tested by the sponsor. However, the data pointed to unexpected heat stability of HIV and PRV in the pasteurization step under the current manufacturing conditions.


Review Comments:

Based on these findings and the inherent limitations associated with HIC, we asked the sponsor to validate additional manufacturing steps for their capacity to clear HIV and PRV. The sponsor provided validation data for DEAE-Sephadex A50 chromatography, QAE-Sephadex chromatography and ammonium sulfate precipitations steps in the manufacturing process for their combined capacity to clear HIV and PRV. These manufacturing steps were studied separately (as a single step) to determine their individual contribution to clearance of HIV and PRV.  Validation data demonstrated that these manufacturing steps contribute to the removal of HIV and more significantly to the removal of PRV.  The sponsor also agreed to a post-approval commitment to include a ------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- (for further details, please see viral validation-specific memo on file).

3.; In-Process Tests and Specifications:

The Table below summarizes the updated in-process tests and specifications.

1 Page determined to be not releasable: b(4)






Review Comments:

The overall manufacturing process for Berinert has not been changed since the submission of the BLA in 2008. Only changes to in-process tests as indicated above have been implemented. The sponsor submitted the updated CTD section in amendment 125287/0.35 (dated August 14, 2009).

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