title: Isolation, structural determination, synthesis and quantitative determination of impurities in Intron-A, leached from a silicone tubing.
abstract: 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.
authors.affiliation: Structural Chemistry Department, Schering Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: Tze-Ming
authors.initials: TM
authors.lastname: Chan
authors.forename: Birendra
authors.initials: B
authors.lastname: Pramanik
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: Vincent
authors.initials: V
authors.lastname: Gullo
authors.forename: Mahesh
authors.initials: M
authors.lastname: Patel
authors.forename: Bart
authors.initials: B
authors.lastname: Cronin
authors.forename: Chris
authors.initials: C
authors.lastname: Boyce
authors.forename: Kevin
authors.initials: K
authors.lastname: McCormick
authors.forename: Mike
authors.initials: M
authors.lastname: Berlin
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.forename: Alexei
authors.initials: A
authors.lastname: Buevich
authors.forename: Larry
authors.initials: L
authors.lastname: Heimark
authors.forename: Peter
authors.initials: P
authors.lastname: Bartner
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.forename: Haiyan
authors.initials: H
authors.lastname: Pu
authors.forename: Vinod
authors.initials: V
authors.lastname: Hegde
mesh_terms: 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
chemical_list: D002021:Buffers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009930:Organic Chemicals; D011208:Powders; D011994:Recombinant Proteins; D012828:Silicones