
From :
Felice D’Agnillo, LBVB/DH/CBER, HFM-343 

Through :
Abdu Alayash, Chief, LBVB/DH/CBER, HFM-343 

To :
Nannette Cagungun, Regulatory Project Manager, CBER/DH, HFM-380 

Sponsor :
CSL Behring 

Product :
C1 Esterase Inhibitor (human) or Berinert 

STN# :
125287/0 

Subject :
Validation of Manufacturing Process 

RECOMMENDED ACTION

Based on my review of the process validation information submitted in the BLA and the responses submitted by the sponsor to FDA information requests as well as to questions conveyed during the pre-approval inspection, the process validation component in the CMC section of this BLA is approvable. Other outstanding issues related to stability, assay validation, viral validation studies and some unresolved inspectional issues are outlined in other discipline specific review memos that have been filed.

SUMMARY

This original BLA from CSL Behring for C1-esterase inhibitor (human) or Berinert for the treatment of patients with hereditary angioedema (HAE) was received in CBER/DCC on March 6, 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, 2002. 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. The action due date was changed to December 5, 2008.

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, and chromatography steps. 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) (supplied in the package). 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 inhibitor (human)

Proposed Proprietary Name: Berinert

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

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.

CHEMISTRY, MANUFACTURING, AND CONTROLS

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.

II. Manufacturers/Facilities
1.CSL Behring GmbH, Emil-von-Behring-Stra b e 76, 35041 Marburg, Germany
 Role: Drug substance and product manufacturing and testing
2.--------b(4)-------------------------------------------------------------------------------------------------------------------------------------------------
3.------------b(4)--------------------------------------------------------------------------------------------------------------------------------------------------

III. Method of Manufacture and Packaging
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). In addition, plasma --b(4)-- are tested by ---b(4)----- for genomic material of HCV, HBV, HAV, HIV-1 and parvovirus B19. Manufacturing -b(4)- are tested for hepatitis B surface antigen and anti-HIV1/2. Only manufacturing -b(4)- non-reactive for HCV RNA, HBV DNA, HAV RNA, HIV-1 RNA and high titers of parvovirus B19 are released. Viral reduction steps in the manufacturing process include; pasteurization (10 h at 60 ° C), and hydrophobic interaction columns (-b(4)------------------------------).
 *Note: B19 limit in manufacturing pool was set at 10 5 logs. This is now set at 10 4 logs based on response to comments issued during pre-approval inspection.
 *Note: Issues related to viral validation studies were conveyed during pre-approval inspection. These will be further detailed below.
2.Materials used in processing:
 ------b(4)-------------------------------------, Glycine, -b(4)- , NaCl, -----------b(4)-----------------------------------------------------------------------------
 Note: The specifications for most of these materials are Ph. Eur/ USP or NF.
3.Other materials (without reference to a monograph)
 DEAE-Sephadex A50, QAE-Sephadex A50, -----b(4)---------------------, Ammonium sulfate.
4.Description of Manufacturing Process:
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Critical Process Steps:
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-------------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------.

*Note: The subject of the viral validation studies being a possible issue came up during the preapproval inspection (details reviewed in the Viral Validation memo). Further discussions with the sponsor on the need to supplement the manufacturing process with regard to viral clearance capacity took place in October 2008.

IV. Validation of Manufacturing Process

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11 Pages determined to be not releasable: b(4)


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V. Questions for Sponsor (Note: These were satisfactorily addressed during review cycle)

1. Please provide comparability data for in-process testing and final release testing for lots manufactured in 2004 -----b(4)------------ and more recent lots including ---b(4)---------.
Comment : CSL Behring submitted Study#CR-617-002-01 (June 3, 2008). This document contains comparability data for Lots# -----b(4)-------- (2004 validation lots), Lot# -----b(4)----------(2007 “routine production” lots), and recent Lot# -----b(4)------------ (2008 planned initial lots for US). This document compares the critical process control parameters and product quality attributes as well as the final release test results for these lots. Lots#-----b(4)------------ are referred to as full scale validation lots that were manufactured after implementation of -----b(4)------------ ---------------------------chromatography, and--b(4)-- batch size manufacturing. CSL states that the production process remained unchanged since that time (2004) except for minor equipment changes. The information and data submitted in this document provide acceptable evidence that these lots are comparable.

2. Please provide a draft copy of a lot release protocol for Berinert, and a list of lots that would be available for FDA release testing. Please indicate whether there are lots identified as potential launch lots for the US market.
Comment: In Amendment 125187/0.9 (June 12, 2008), the sponsor provided a draft release protocol and identified Lots# ------------b(4)--------------------------------- as lots that would be possible launch materials.

3. Please implement ---b(4)------ testing at the -----b(4)--- stage.
Comment: In Amendment 125187/0.9, the sponsor indicated that they had implemented ----b(4)---- testing in --b(4)---. They provide SOP #565577. The ----b(4)---- limit is this document is shown as ----b(4)-----. This is not the same as the ----b(4)---- that was used in process validation studies. This point will be addressed in future communications with the sponsor.

4. Please provide the missing attachments for the manufacturing batch record for Lot# ----b(4)----
Comment: CSL Behring submitted these attachments in Amendment 125187/0.9.

5. Please amend information in the BLA on the -b(4)- test for parvovirus B19 in the fractionation pool. We note that your parvovirus B19 specification in the fractionation pool is ----b(4)----. Please be note that this limit should be set at 10 4 logs.
Comment: The relevant information in the BLA has been changed to reflect the B19 limit of 10 4 logs.

6. Please consider implementing an alert limit for ammonium sulfate concentration prior to the start of the ----b(4)---- ------- chromatography.
Comment: In Amendment 125187/0.9, the sponsor indicated that an alert limit (----b(4)----) has been implemented beginning with Lot# ----b(4)----. This was derived based on the analysis of -b(4)- consecutive lots.

7. Please provide rationale for listing Lot# ----b(4)---------------- as conformance lots in the BLA.
Comment: In Amendment 125187/0.9, CSL indicated that the designation of these lots as “conformance lots” by definition was not appropriate. These lots were provided as representative examples of more recently manufactured consecutive lots that were tested according to US specifications and released for marketing in EU. CSL amended the information in the BLA accordingly.

8. Please provide a plan for how the stability of your product will be monitored after approval.
Comment: In Amendment 125187/0.9, CSL proposed a stability plan that would entail placing one lot of final product on stability per year and tested according to the US stability protocol that includes the additional tests of -----------b(4)-------------------------------. This plan proposes to test only the 25 ºC and not the lower 2 ºC condition. This proposal is acceptable given that 25 ºC is the higher temperature and given the extensive stability data the manufacturer already has for the product.
