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Production

Oxygen exists in nature as 3 isotopes: ¹⁶O, ¹⁷O and ¹⁸O. ¹⁶O is the most abundant (>99.7%), followed by ¹⁸O (0.2%) and ¹⁷O (0.02%).

Rotem’s fractional distillation process takes advantage of the slightly different vapor pressure of each oxygen isotope. Through a closely controlled process of alternate heating and cooling over a period of approximately ten months, the ¹⁸O is isolated, yielding water with a high level of enrichment. This process takes place in a series of hundreds of specially constructed distillation columns, containing a packing material to facilitate the separation. Rotem’s proprietary packing is a key to the process, enhancing efficiency and allowing improved throughput.

In the course of its manufacture, the HYOX¹⁸ product is closely monitored for isotopic level, chemical purity, conductivity and pH. Isotopic quality is analyzed in a gaseous sample by a quadrupole mass spectrometer, while chemical analysis is carried out by one of several methods, depending on the element.

Following enrichment of the ¹⁸O level to 98% minimum, HYOX¹⁸ is further purified by ultra-filtration, additional distillation and terminal heat sterilization in a precisely controlled, aseptic clean-room environment.

The final product is fully analysed for all parameters of the specification, with typical ionic impurity levels considerably below the maximum allowed. Sterility and non-pyrogenicity are verified by an outside laboratory with expertise in microbiological testing.

Rotem's production standards meet the requirements of current Good Manufacturing Practice (cGMP) and ISO 9001:2000. Sterility is confirmed at USP XXX standards using Thioglycolate medium and Soybean-Casein digest medium and endotoxin levels are monitored by LAL.

Specification

ENRICHED NORMALIZED WATER NOMINAL ¹⁸O CONCENTRATION 98 ATOM %

GUARANTEED SPECIFICATIONS

(Version 4F)

Test

Method

Specification

Isotopic composition:

¹⁸O

MS

> 98.0%

¹⁷O

MS

< 1.5%

¹⁶O

MS

< 1.8%

Chemical composition:

H₂O

> 99.9%

Ca⁺²

ICP-AES

< 0.1 mg/lit

Mg⁺²

ICP-AES

< 0.05 mg/lit

Na⁺

AA

< 0.1 mg/lit

K⁺

AA

< 0.1 mg/lit

Fe⁺²

ICP-AES

< 0.05 mg/lit

NH₄ ⁺

Spectroph.

< 0.2 mg/lit

Zn⁺²

ICP-AES

< 0.05 mg/lit

Cu⁺²

ICP-AES

< 0.05 mg/lit

F^-

IC

< 0.1 mg/lit

Cl ^-

IC

< 0.5 mg/lit

Br^-

IC

< 0.5 mg/lit

NO₃ ^-

IC

< 0.2 mg/lit

PO₄^-3

IC

< 0.5 mg/lit

SO₄^-2

IC

< 0.5 mg/lit

C (Total Organic Carbon)

IR

< 1 mg/lit

pH

pH meter

6-8

Conductivity

Cond. meter

< 1.5 µS/cm

Pyrogenicity

LAL

< 0.25 EU/ml

Sterility

USP

Passes test

Expiration Date

One year from production

Produced in accordance with U.S. FDA Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

Appearance:

Clear
Colorless
Free of visible particulate matter

Vial packaging:

Nominal size 20, 25 and 50 ml vials
Type 1 borosilicate glass vials
Gray Butyl rubber, teflon coated stopper
Aluminum crimp seal

Label:

Product name
Weight in grams
Manufacturer's name and address
Lot number
Date of manufacture

Test	Method	Specification
Isotopic composition:
¹⁸O	MS	> 98.0%
¹⁷O	MS	< 1.5%
¹⁶O	MS	< 1.8%

Chemical composition:
H₂O		> 99.9%
Ca⁺²	ICP-AES	< 0.1 mg/lit
Mg⁺²	ICP-AES	< 0.05 mg/lit
Na⁺	AA	< 0.1 mg/lit
K⁺	AA	< 0.1 mg/lit
Fe⁺²	ICP-AES	< 0.05 mg/lit
NH₄ ⁺	Spectroph.	< 0.2 mg/lit
Zn⁺²	ICP-AES	< 0.05 mg/lit
Cu⁺²	ICP-AES	< 0.05 mg/lit
F^-	IC	< 0.1 mg/lit
Cl ^-	IC	< 0.5 mg/lit
Br^-	IC	< 0.5 mg/lit
NO₃ ^-	IC	< 0.2 mg/lit
PO₄^-3	IC	< 0.5 mg/lit
SO₄^-2	IC	< 0.5 mg/lit
C (Total Organic Carbon)	IR	< 1 mg/lit

pH	pH meter	6-8
Conductivity	Cond. meter	< 1.5 µS/cm
Pyrogenicity	LAL	< 0.25 EU/ml
Sterility	USP	Passes test
Expiration Date		One year from production

Produced in accordance with U.S. FDA Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients