Isolation, structural determination, synthesis and quantitative determination of impurities in Intron-A, leached from a silicone tubing.
Investigation of unexpected levels of impurities in Intron product has revealed the presence of low levels of impurities leached from the silicone tubing (Rehau RAU-SIK) on the Bosch filling line. In order to investigate the effect of these compounds (1a, 1b and 2) on humans, they were isolated identified and synthesized. They were extracted from the tubing by stirring in Intron placebo at room temperature for 72 h and were enriched on a reverse phase CHP-20P column, eluting with gradient aqueous ACN and were separated by HPLC. Structural elucidation of 1a, 1b and 2 by MS and NMR studies demonstrated them to be halogenated biphenyl carboxylic acids. The structures were confirmed by independent synthesis. Levels of extractable impurities in first filled vials of actual production are estimated to be in the range of 0.01-0.55 microg/vial for each leached impurity. Potential toxicity of these extractables does not represent a risk for patients under the conditions of clinical use.
Chan
Tze-Ming
TM
Structural Chemistry Department, Schering Plough Research Institute, Kenilworth, NJ 07033, USA.
Pramanik
Birendra
B
Aslanian
Robert
R
Gullo
Vincent
V
Patel
Mahesh
M
Cronin
Bart
B
Boyce
Chris
C
McCormick
Kevin
K
Berlin
Mike
M
Zhu
Xiaohong
X
Buevich
Alexei
A
Heimark
Larry
L
Bartner
Peter
P
Chen
Guodong
G
Pu
Haiyan
H
Hegde
Vinod
V
D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004340:Drug Contamination; D005612:Freeze Drying; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry* / Q000302:isolation & purification*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry*; D011208:Powders; D011786:Quality Control; D011994:Recombinant Proteins; D012828:Silicones / Q000737:chemistry*; D013696:Temperature; D013997:Time Factors
D002021:Buffers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009930:Organic Chemicals; D011208:Powders; D011994:Recombinant Proteins; D012828:Silicones