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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Omrix Biopharmaceuticals Ltd Untitled Letter

March 26, 2010 – Corrected Copy

FEDERAL EXPRESS

Nissim Mashiach
General Manager
Omrix Biopharmaceuticals, Ltd
Tel Hashomer Hospital
Ramat-Gan, 52621
Israel

Dear Mr. Mashiach:

The Food and Drug Administration (FDA) conducted an inspection of Omrix Biopharmaceuticals Ltd, located at Mada Building, Tel Hashomer Hospital, Ramat-Gan, Israel, between October 21 and October 29, 2009.  During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of Evicel Fibrin Sealant, Evithrom Thrombin, and Biological Active Component 2 (Human Fibrinogen) (BAC2).  These deviations from CGMP include the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), Section 351(a) of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210, 211, 600-680. 

At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations that described a number of significant objectionable conditions relating to your facility’s compliance with CGMP.  Significant deviations observed during the inspection include, but were not limited to, the following:

1. You failed to follow appropriate written procedures to prevent microbial contamination of drug products purporting to be sterile. [21 CFR 211.113(b)]  For example, an operator was observed picking up an environmental monitoring settle plate from the floor and then resumed loading vials on the --(b)(4)-- table without changing gloves.

2. You failed to establish an adequate system for monitoring environmental conditions of aseptic processing areas. [21 CFR 211.42(c)(10)(iv)]  For example, depyrogenated vials in ----(b)(4)------ trays are transported using a transport trolley through an (b)(4) area to get to the (b)(4) area of filling line; however, no surface monitoring of the trays and transport trolley was performed.

3. You failed to report any event and relevant information associated with the manufacturing or distribution of a licensed biological product that represents a deviation from current good manufacturing practice, applicable regulations, applicable standards or established specifications that may affect the safety, purity, or potency of that product.  [21 CFR 600.14(b)]  For example, you failed to report to FDA that Human Fibrinogen (BAC2) lot ---(b)(4)-- was pasteurized outside the licensed pasteurization parameters and used in the manufacture of Evicel Fibrin Sealant lot N19F390 that was released to the US market.

Additionally, significant deviations in manufacture of your BAC2 that is used to manufacture Evicel were observed during the inspection.  These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act.  Specific areas of concern include, but are not limited to:

Failure Investigations

1. Your investigations into BAC2 --(b)(4)--- limit excursions are incomplete.  For example, investigations of 18 in-process product ---(b)(4)-- limit excursions for BAC2 at the ---------(b)(4)----------- step were insufficient to correct the cause of the contamination, and to prevent the contamination from recurring. 

Production and Process Controls

2. You failed to ensure that validation studies were conducted and / or documented for the manufacturing processes.  For example:

a)         Per Protocol -----------------------(b)(4)-------------------------------------------------------------- Column for BAC2/BAC2 Scale-up Production, dated April 20, 2006, validation was to be performed concurrently for -------(b)(4)----------- lots; however, --(b)(4)-- lots have been used to date, and there is no documentation that includes a discussion of test results and conclusions.  The validation currently remains open.

b)         The report of Protocol -------(b)(4)--------- (November 30, 2002) concluded that the ---------------(b)(4)--------------------------------- column used for Thrombin Production have a maximum life of -------(b)(4)-------- and a maximum life –(b)(4)-------- respectively.  However, the data in the report only supported (b)(4) uses.

c)         There are no data to support the (b)(4) year expiration date assigned to Ultrafiltration System membranes used for ultrafiltration, diafiltration and concentration of BAC2.

Cleaning and Maintenance of Equipment

3. Appropriate clean hold times have not been validated for various product contact equipment used for BAC2 and Thrombin production.  For example: ---------------------------------------------------------(b)(4)------------------------------------------------------------------------------.

We acknowledge receipt of your written responses dated November 20, 2009, and January 28, 2010, which address the inspectional observations on the form FDA 483 issued at the close of the inspection.  We also acknowledge your commitments to complete an assessment of the current “Omrix quality system” and develop a corrective action plan; and to provide quarterly update reports of the corrective actions identified in your responses.

We have reviewed your responses and have the following specific comments.  The items are numbered to correspond to the observations listed on the Form FDA 483.

Observation 1
You state that your procedures need to be more specific regarding what actions are to be taken and what information to document when in-process limits are exceeded, and to include more detailed instructions for conducting and documenting robust investigations that lead to root cause determinations.  Please describe your plan, if any, to conduct a retrospective review of the deviations identified in this observation.

Observation 6A
You state that you will restrict the number of uses of gowns to (b)(4).  Please provide the justification and rationale for your determination that (b)(4) uses is appropriate.

Neither the above deviations, nor the observations listed on the Form FDA 483 presented to your firm at the conclusion of the inspection, are intended to be an all-inclusive list of deviations at your establishment.  It is your responsibility to ensure compliance with all requirements of the laws and regulations administered by FDA.

Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448.  If you have any questions regarding this letter, please contact Mary D. Davis-Lopez in the Division of Case management at (301) 827-6201.

Sincerely,

/signature/

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research