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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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6/15/2007 Mid-Cycle Review - Chemistry, Manufacturing, Controls - RECOTHROM

M E M O R A N D U M

Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research

Date: June 15, 2007
To: Mark Shields, HFM 380 and File STN 125248
From: Roman Drews, HFM-392
Through: Timothy Lee, HFM-392
Acting Chief, Laboratory of Hemostasis, DH, OBRR
Subject: Midcycle Review memorandum for Chemistry,
Manufacturing,Controls. Biological License
Applications for Thrombin, Topical
(Recombinant) (rThrombin), [Recothrom®],
ZymoGenetics, Inc.

Manufacturing Process and Process Validation for Bulk Drug Substance (BDS); 3.2.S.2.5

Overview

BDS manufacture

rThrombin bulk drug substance (BDS) is produced in the --------------------------------------------------------------
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The manufacture of rThrombin BDS is divided in the ----------------------------------------. --------
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-------------uses a recombinant Chinese Hamster Ovary (CHO) cell line -------------------
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BDS Manufacture Validation

Validation of BDS manufacture was primarily performed by ---------------------------------------------------- ZGI. This was a prospective validation study that included modular tests of the scale down model operational units. The validation study performed at commercial scale was used to determine acceptable operational ranges for process parameters, and identification of critical operating parameters. The scaled-down models were also used in lifetime studies for chromatography resins and --------------------------------.

Cell Culture

Development of Cell Line, Cell Banking System
The expression construct used by ZGI consists of an expression --------------------------- ------------------------ genome of the CHO cells. The expression -----------------------------------------------------------------------------------------------------------
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--------------------. The DNA sequence of the expression ------------ has been performed.

The parental cell line is CHO -----, which was obtained from ---------------------------------------------------------------------------
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---------------------------. The detailed information regarding origin of the host cells, transfection procedure, and cloning is acceptable.

Master Cell Bank
Master Cell Bank (MCB), --------------------------------------------------------------------------------------------------------------------------
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Working Cell Bank

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Furthermore, the genetic characterization of WCB has been demonstrated by --------------------------------------------------------------------------------------------------------. ZGI provided ---------------------- data for WCB that are acceptable.

Post-Production Cell ------ ---------------------------------------------------------------------------------------------------------------------------
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Controls of Critical Steps and Intermediates (3.2.S.2.4)

ZGI identified following in-process critical parameters and specifications:

Specifications - Safety Related Parameters 

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The critical process parameters have been adequately selected and validated by ZGI.

Adventitious Agents Safety Evaluation (3.2.A.2)

Viral Safety

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Recommendation

The Information Request (IR) containing the following items should be communicated to the firm:

Regarding the post-production cell ----- please provide: 

  1. --- images with clearly indicated -------------------------------------------------------

     

     

  2. Results of genetic characterization studies that demonstrate the integrity of the expression -----------. The results should include, but not be limited to, images of ------------------------ from ------------- analysis, and the results should be compared to those obtained from the corresponding MCB.

     

     

  3. Additional data demonstrating that the observed differences in the ---------------------------------------- between the MCB and post-production cell bank are resulted from the variability of the ------------ method

     

Regarding the production bioreactor:

  1. Please clarify how you derived the minimum acceptable limits for ---------------------------------------------------------------------------- at the harvest stage. These proposed limits are not justified by results from conformance lot manufacture and scale-down validation study.

     

     

  2. Please establish the limit for the maximum duration of the cell culture campaign as an in-process control parameter/specification. This limit can be expressed in doubling generation time or cell culture days. It should be justified by the duration of the conformance lot campaigns and genetic stability of the expression construct.

     

Regarding the ----------------------------:

  1. As indicated in Table 51 (Page 48 of 51; 3.2.S.2.5), in-process -------------------- ------------------------------------------------------------------------- were performed only as "additional testing during process validation study". Since the generation of -------------------- is a critical step in the manufacture of -------------, please include the referenced tests as routine in-process control testing for the manufacturing process. The necessity of these tests can be evaluated periodically when more data are available.

     

     

  2. In addition, please provide the current standard operating procedures for the investigation of deviations in action limits.

     

Regarding the -------------- columns:

  1. The validation runs performed at commercial and small scale demonstrate that the combined yield of --------- for -------------------------------------------- chromatography columns is above -------. However, the proposed action limit for the combined yield of ------------------------------. Please describe how you derived the proposed action limit.

     

     

  2. The Acceptable Operating Range for the combined ------------ chromatography load has been proposed as ----------------------------------. However, the critical parameters studies, based on validation runs, estimated the Acceptable Operating Range as --------------------------------------. Please describe how you derived the proposed load limit of ----------.

     

     

  3. Please establish an in-process control parameter for -------------- yield expressed in --------------------------------------------------------------.

     

Regarding process operational parameters: 

  1. Please explain the difference between the following terms: Acceptable Operating Range, Acceptance Criteria, and Action Limit in relation to the control of operation unit performance. Please describe also the difference in investigational procedures and resultant actions when the limits defined by these terms are breached.

 

 

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