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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Review of Sponsor’s Responses to CR Letter - CINRYZE

From:

Felice D’Agnillo (Chair), 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: Lev Pharmaceuticals, Inc.
Product: C1 Inhibitor (human) or Cinryze™
STN#: 125267/0
Subject: Final Approval Memo: CMC Review of Sponsor’s Responses to CR Letter

FINAL RECOMMENDATION

We recommend the final approval of the chemistry, manufacturing and control (CMC) section of this biological license application. This recommendation is based on the review of the CMC sections of this application (CMC-related review memos are on file) and 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 (CMC Items 12-17). Furthermore, as outlined below, the sponsor has agreed to post-marketing commitments regarding continuation of stability studies.

SUMMARY

This original BLA from Lev Pharmaceuticals for C1-esterase inhibitor (human) or Cinryze for the treatment of patients with hereditary angioedema (HAE) was received in CBER/DCC on July 30, 2007. Orphan drug status was granted on July 16, 2004. The BLA submission qualified for priority review with an action due date of January 30, 2008.

Cinryze is a sterile, nanofiltered, lyophilized preparation of human plasma-derived C1 esterase inhibitor. Cinryze is manufactured from U.S. Source Plasma by a process that includes ---(b)(4)------, precipitation, filtration and chromatography steps. Cinryze is supplied as a lyophilized powder in single-use glass vials. Cinryze is administered by intravenous injection after reconstitution with the appropriate volume of Sterile Water for Injection (USP). Cinryze is indicated for the prophylactic treatment of patients with hereditary angioedema (HAE), a disease characterized by low levels of endogenous or functional C1 esterase inhibitor. Cinryze is manufactured under contract to the Sanquin Blood Supply Foundation in Amsterdam, Netherlands for Lev Pharmaceuticals. The CMC sections of this application were reviewed by four reviewers and each generated memos that have been filed.

A CR letter was issued on the action due date based primarily on unresolved pre-approval inspection issues as well as clinical issues. On April 14, 2008, the sponsor submitted responses to the CR letter as amendment 120267/0.13. Based on an initial content review, the amendment was deemed a complete response to the action letter and qualified as a resubmission. This amendment was classified as a Class II resubmission based in part on the fact that this application was presented at the Blood Products Advisory Committee meeting on May 2, 2008. By classifying this resubmission as Class II, the action due date was changed to October 14, 2008 (6-month cycle).

The CR letter contained a total of 24 items. Items 1-17 pertained to CMCs. Items 1-12 have been reviewed by DMPQ, and presented in a separate memo. This memo provides a brief summary of manufacturing process and addresses the responses to CMC items 12 through 17.

MANUFACTURING OVERVIEW

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Manufacturing Notes:

The manufacturing process submitted in the original BLA and in place at the start of the preapproval inspection allowed for manufacturing of -----(b)(4)----- at both -----(b)(4)---- and Sanquin. However, the manufacturing plans were modified partly in response to issues raised during FDA’s pre-approval inspection regarding process validation. The proposed plan submitted by the sponsor in response to FDA Form 483 and the CR letter indicates that -----(b)(4)---- will be the sole manufacturer of -----(b)(4)----. This intermediate would then be shipped to Sanquin to resume manufacturing of -----(b)(4)---- followed by the rest of the manufacturing for final product (Cinryze).

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Five (5) pages determined to be not releasable:



(b)(4)

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Item 14: Regarding the release specifications of the final product:

a. The current specification for C1INH specific activity is ----(b)(4)-. Please provide an upper limit for this specification and the rationale for selection of this limit.

b. Please include the total protein concentration of C1INH as a final release specification, to allow verification of the product specific activity upon release. This should be reported in the release protocol as well.

c. Please establish tighter ranges for sodium, sucrose, and the amino acid additives in the finished product. These ranges should reflect expected assay variations for these measurements, as have been determined in your validation studies.

Review of Response to Item 14:

a. The sponsor has set an upper limit for C1INH specific activity of ----(b)(4)---. The specific activity specification is now 4-9 U/mg. The upper limit was based on the manufacturing results obtained for (b)(4) lots. The mean value was ----(b)(4)------. This response is acceptable.

b. The total protein concentration is now included in the release protocol. The limit is set at ---(b)(4)----.

c. The ranges for sodium, sucrose, threonine, and valine have been adjusted based on historical data. These new ranges were included in the updated lot release protocols. The alanine range has not changed. This response is acceptable.

Item 15: Sections 3.2.S.2.4-Amsterdam and 3.2.S.2.4----(b)(4)--- show that several limits/ranges for in-process/control parameters do not correspond to the specifications provided in the BSB036-Lev/1.4 document and other related Reports. Please update all relevant documents and provide a list of the amended documents in your response.

Review of Response to Item 15:

The sponsor has provided a list of al the ----(b)(4)---- and Sanquin documents that have been updated. Table 1 provides revisions to the relevant ----(b)(4)---SOPs including; ----(b)(4)---- (manufacturing flow chart), ----(b)(4)----- sampling plan), ----(b)(4)----, and ----(b)(4)--------------- specifications). Table 2 provides a summary of the specific changes made to these documents. The list of amended documents for Sanquin (since 11/2006) includes; BSB036LEV, CBP036BLEV (----(b)(4)----), CBP036CLEV (nanofiltration), CBP036DLEV, CBP036F, CBP036GLEV, and ST036C-R. This response is acceptable.

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One (1) page determined to be not releasable:


(b)(4)