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CMC Review Memo

MEMORANDUM
DATE: June 10, 2007
FROM: Yiping Jia, Ph.D.; HFM-343; LBVB, DH, OBRR, CBER; (301) 451-3952, FAX (301) 402-2780
SUBJECT: NDA BN070012/0; CMC sections of the original NDA submitted by Carolina Research Group on behalf of Fresenius Kabi Deutschland GmbH for Voluven® 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion
THROUGH: Abdu Alayash, Ph.D.; HFM-343; LBVB, DH, OBRR, CBER; (301)827-3813
TO:

Cheryl Campbell, RPM; HFM-380; RPMB, DBA, OBRR, CBER; (301)827-3524

The File (NDA BN070012)

SUMMARY

This submission is an original NDA with document date 28-Feb-2007, and was received in CBER/DCC on 01-Mar-2007 (L412822). I have received a copy of Module 3 and reviewed the CMC information related to the process validation, as well as related to the DMF2 IND#------- that was dated on 12-Jan-2007 and received by CBER/DCC on 16-Jan-2007.

Hydroxyethyl starch 130/0.4 is a derivative of thin boiling waxy maize starch, which mainly consists of a glucose polymer (amylopectine) mainly consisting of α-1,4-connected glucose units with several α-1,6-branches. In addition to amylopectine small amount of amylose are present as well depending on the source of the starch. Thin boiling waxy maize starch has a particularly high content of amylopectine.

Amylopectine contains free hydroxyl groups at the 2,3 and 6 positions of the glucose moieties. These functional groups are partially subject to derivatization by hydroxyethyl groups.

Hydroxyethyl starch is a mixture of molecules of different molecular weights. This is caused by the already existing molecular weight distribution of the starting material (starch) and the cleavage of glycosidic bonds during the hydrolysis process. This distribution is commonly described by the weight average (Mw), by the number average molecular weight (Mn) and by other parameters, e.g. the Mw at the upper and lower 10% mass fraction of the molecular weight distribution curve determined by size exclusion chromatography.

On an average there are 0.42 hydroxyethyl ether groups per glucose unit (0.38 - 0.45) in this type of hydroxyethyl starch. This parameter is called the molar substitution (MS). The weight average molecular weight of HES 130/0.4 lies between 110,000 and 150,000 which corresponds approximately to 610 to 830 partially hydroxyethylated glucose units. Molecular weights 10% upper fraction and lower fraction are ---------------------------------------, respectively.

HES 130/0.4 is a white to yellowish white, odorless and tasteless, amorphous powder, soluble in water in every concentration, soluble in DMSO, practically insoluble in most organic solvents.

Hydroxyethyl starch is manufactured at the site in Linz/ Austria:

Fresenius Kabi Austria GmbH
Estermannstraße 17
A-4020 Linz
Austria, Europe

Manufacturing process can be summarized as follows.

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