Product Approval Information - New Drug Applications
M E M O R A N D U M
| DATE: | August 31, 2007 |
| FROM: | Janie Russell, Review Biologist, CBER/OCBQ/DMPQ/MRB2, HFM-676 |
| SUBJECT: | Final Review Memo - Fresenius Kabi, NDA for 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion (Voluven), a plasma substitute for the treatment of hypovolemia |
| THROUGH: | Chiang Syin, Ph.D., Chief, DMPQ, MRB II, HFM-676 |
| TO: | NDA File - STN: BN070012/0.0 |
| DUE DATE: | December 26, 2007 |
RECOMMENDED ACTION:
Recommend approval of Fresenius Kabi, NDA for 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion (Voluven), a plasma substitute for the treatment of hypovolemia pending outcome of inspection, successful completion of validation studies for the flush volume for redesigned solution delivery system, successful manufacture of three validation batches, and product office concurrence. The firm should be notified to perform microbiological (biological indicators) testing for their new autoclave --. Although the firm has some stability studies on ----------, the contain closure identified uses the --------. Therefore licensing should clearly delineate the -------- for the container closure.
An inspection request was submitted to Janet Ishimoto, Branch Chief, Division of Inspections and Surveillance (DIS), on 4/6/07 for Field Assignment for prior approval inspection through DIS for the Halden, Norway facility. Specific items to be addressed during the inspection were requested in a memorandum dated 27 July 2007.
SUMMARY:
Fresenius Kabi has submitted a NDA for 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion (Voluven), a plasma substitute for the treatment of hypovolemia. This review encompassed sterility/sterilization, pyrogenicity, packaging integrity, equipment, facilities, validation, and environmental assessment in Module 3 (volumes 1 through 3), Module 1 (sections 1.38 and 1.39) and Methods Validation Package (volume 1 of 1). The review also included MF# -----, Master File Type III for "Freeflex® Packaging System (Polyolefine Bag)", volumes one through three; and BB-MF -----, Type II Master File for "Hydroxyethyl Starch 130/0.4 for Injection" for container closure, facilities and equipment and executed batch record for Linz Austria facility (2 volumes). The NDA packaged followed the CDER Guidance for the Format and Content of the CMC Section of an Application, February 1987. The firm has requested categorical exclusion.
Additional information was requested from firm on 9 April 2007, for BI certificates (section 3.2.P.3.5.2) for study N-1986 and N 1989, and on 30 July 2007. This was submitted by the firm on 26 July 2007 as STN BN070012/0.2 and on 16 August 2007 as STN BN70012/0.3.
REVIEW:
Facilities:
The following facilities perform segments of manufacturing:
- Drug Substance HES 130/0.4 manufacturer:
Fresenius Kabi Austria GmbH
Estermannstrasse 17
A-4020 Linz
Austria - Container Closure:
Freeflex® bags-unprinted:
Fresenius Kabi Deutschland GmbH
D-61169 Friedberg
Germany
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------- - Formulation/Fill and Finish with Testing and Release:
Drug establishment registration no.: NO 980 250 008
Fresenius Kabi Norge AS
Svinesundveien 80
NO-1753 HALDEN
Norway
Overpouch foil --------:
Fresenius Medical Care
Plant St. Wendel
D-66606 St. Wendel
Germany
Batch Analyses:
Batch analyses are present for the following:
- Relevant batches manufactured at Linz Plant, Austria
- Nonclinical batches manufactured at Friedburg Plant, Germany
- Clinical batches manufactured at Friedburg Plant, Germany, most --------------- ------- with one batch filled in PE bags. Two batches were manufactured by Fresenius Kabi in Louviers, France for a clinical study conducted in France.
- Stability batches manufactured at Linz Plant, Austria and in Halden, Norway
Note the firm initially termed the product -----------, however the actual degree of molar substitution is 0.4 therefore the product was named HES 130/0.4. The US product is to be produced in Halden, Norway (3.2.P.2.3.5). Stability batches were made in Norway however the batch sizes are different, ---------- versus ------------, and used ----- 500 mL containers which were --------------- on-site with pre-made empty Freeflex bags on a ------ filling line.
Manufactured Conformance Lots:
The following lots were termed stability lots by the manufacturer and used for validation.
| DS Lot No. of HES 130/0.4 | DP Lot No. of Voluven | Date Voluven Manufactured | Voluven Volume Manufactured (L) | Fill Volume (mL) |
|---|---|---|---|---|
----------- non-clinical and -- clinical batches/Trials (NDA section 3.2.S.4) of the drug substance were manufactured at the Friedburg plant. Four batches of the HES 130/0.5 for the non-clinical product exceeded the specification of ---------------------- at a maximum reported of -------, however were accepted. Two batches of the HES 130/0.5 for the clinical product exceeded the specification of ---------------------- at a maximum reported of -------, however were accepted.
Lots of HES 130/0.4 drug substance manufactured at the Linz (Austria) facility (per NDA section 3.2.S.4.4.1) for commercial use with results for ------------------------:
| ------- | ------------------- | --------------- | ---- ----------------- |
--------- ----------------- |
|---|---|---|---|---|
Manufacturing Process and Process Controls (NDA sections 3.2.S.2.2 and 3.2.P.3):
HES 130/0.4 (BB-MF ----- section 2.3):
HES 130/0.4 is manufactured in the Linz Austria facility. No materials of animal origin are used in the process. Total batch size is ---------------------------------------------. The manufacturing process is as follows:
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