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Vaccines, Blood & Biologics

Preliminary review of Nycomed’s BLA for Fibrin Sealant Patch (TachoSil) - TachoSil, July 29, 2009






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

Date:                 July 29, 2009

To:                     File (STN 125351/0) and Jie He, OBRR/DBA/RPMB      
From:                Natalya Ananyeva, Ph.D., Visiting Scientist, Laboratory of Hemostasis (LH), Division of Hematology (DH)/OBRR                           

Through:         Timothy Lee, Ph.D., Acting Chief, LH/DH/OBRR

Subject:            Preliminary review of Nycomed’s BLA for Fibrin Sealant Patch (TachoSil)

This memorandum summarizes the preliminary review of an original Biologics License Application (STN 125351/0) for Fibrin Sealant Patch (FDA-recommended name) submitted by Nycomed, Denmark. The proposed trade name is TachoSil. Nycomed claims the following indications for Fibrin Sealant Patch: ---------------------------------(b)(4)--------------------------------; (2) as an adjunct to hemostasis in cardiovascular surgery.

Recommendation: The cursory review of the CMC information in the application indicates that the Sponsor has addressed major recommendations of the Agency from the pre-BLA stage and the submitted data appear sufficient to permit further in-depth review.  No outstanding CMC deficiencies have been identified at this time. The submission is suitable for filing.


Fibrin Sealant Patch (TachoSil) from Nycomed, Denmark, is a new ready-to-use, degradable fibrin sealant product developed for topical use with the proposed indications as -------(b)(4)-----------------------------------------------------; (2) an adjunct to hemostasis in cardiovascular surgery. TachoSil consists of two active substances - human fibrinogen and human thrombin – coated onto a collagen sponge.  The Collagen Sponge serves as a flexible and mechanically-stable carrier for the active substances to ensure their in-place position. Riboflavin is present as a yellow colorant to indicate the active side of the patch. Human Fibrinogen Active Substance and Human Thrombin Active Substance are supplied by -----------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------. Fibrin Sealant Patch is a combination product where the Collagen Sponge is classified as a Medical Device.

TachoSil is the third-generation Fibrin Sealant products with its predecessors TachoComb (which used bovine thrombin and bovine aprotinin) and TachoComb H (human thrombin but bovine aprotinin). TachoComb was first marketed in Austria and Germany in 1991/1992. TachoComb H was marketed in Germany and Austria from 2001 – 2005. Compared to the predecessor products, TachoSil is free of bovine components as both active substances are of human origin and does not contain bovine aprotinin as the antifibrinolytic agent.

TachoSil was approved in Europe in June, 2004. In February 2009, the European Commission approved the extended scope of TachoSil indications “for supportive treatment in surgery for improvement of hemostasis, to promote tissue sealing, and for suture support in vascular surgery where standard techniques are insufficient”.

The submitted BLA seeks licensing TachoSil for the US market. Compared to the European product, the active substances Human Fibrinogen and Human Thrombin contained in TachoSil US are manufactured from plasma derived from FDA licensed centers only. TachoSil is produced in three sizes: Standard (9.5 cm x 4.8 cm = 45.6 cm²), Midi (4.8 cm x 4.8 cm = 23.0 cm²) and Mini (3.0 cm x 2.5 cm = 7.5 cm²).


The manufacture and packaging of TachoSil: NYCOMED Austria GmbH, St. Peter Strasse 25, A-4020 Linz, Austria.
Sterilization by gamma-irradiation: --------------------------------(b)(4)----------------------------------------------------------------------------------------.
The analytical testing (in-process, release and stability): NYCOMED Austria GmbH except for:
-----------------------------------------------(b)(4)-----------------------------------------------         ------------------------------------------------------                                                                       -----------------------------------------------------------------------------------------------

Initial Comments

The initial review of the BLA submission for Fibrin Sealant Patch has identified the following aspects for the further in-depth analysis:

1. In the manufacturing process of Fibrin Sealant Patch: the effect of gamma irradiation on Fibrinogen and Thrombin Active Substances. TachoSil is sterilized by gamma-irradiation based on the following:
(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------                                  ---------------------------------------------------------------------------------------------------------------------
Gamma-irradiation is performed with an adjusted dose of -------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------.

The described -(b)(4)- thrombin activity during irradiation and coating/drying stages in the manufacturing process (-----(b)(4)----) and application of thrombin overages raise a potential safety concern with regard to immunogenicity of inactive or denatured proteins. This aspect requires further analysis.

2. In Specifications for TachoSil Drug Product: analysis of justification of Methods and Acceptance Criteria set for the following parameters:

  • Assays used for Potency determination for Fibrinogen and Thrombin
  • Assessment of Adhesiveness of the coating (measured -----------------(b)(4)-----------------------------------------------------------------------------------------------)
  • -----(b)(4)------ Release Limit set at -(b)(4)-. As this limit is higher than generally recommended by FDA for similar products (-(b)(4)-), a reliable test-system is needed to detect a -----------(b)(4)-------------- of fibrinogen. Therefore:

- The -(b)(4)- test method for ------(b)(4)------- as a marker of ---(b)(4)--- fibrin     --(b)(4)-- requires detailed review
- Control of -----(b)(4)---- determination must be an item of the Pre-Approval Inspection of Nycomed

3. Collagen Sponge is classified as a Medical Device. An Inter-Center Request for Consultative Review was sent to CDRH on July 7, 2009. The equine origin of the collagen sponge is another concern with regard to potential immunogenicity of TachoSil.

4. Batch analysis is presented for three Validation Lots and three Conformance Lots. Validation Lots were manufactured to validate the manufacturing process for TachoSil US and to perform a stability program. Conformance Lots were manufactured after implementation of the Change-over procedure between manufacture of TachoSil US and TachoSil EU to minimize a potential risk of cross-contamination.

5. Stability data are presented for three Validation Lots for 12 months for storage conditions (5° ± 3°C and 25°C/-(b)(4)- RH), elevated temperature (---(b)(4)--- RH) and for 6 months for accelerated conditions (--(b)(4)-- RH). The study is designed according to the ICH Guideline Q1D (Bracketing and Matrixing) and includes 3 pivotal batches each for the largest size (Standard) and the smallest size (Mini) and -(b)(4)- for the intermediate size (Midi).

Conformance batches were put on stability in February 2009; the data are not presented for these batches. I plan to request the updated stability data (for 6, 9 and subsequently 12 months) for these Conformance batches.

6. Considering that TachoSil has been used in clinical practice in the European Union since 2004 with ≥ 400,000 clinical applications, I plan to request the summary of post-marketing clinical experience (in terms of efficacy, safety, adverse effects, complaints and their resolution) for TachoSil in the European Union.

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