Analytical method development, validation, and out-of-specification investigations for polyethylene glycol

Area of Science:

• Analytical Chemistry
• Pharmaceutical Analysis
• Quality Control

Background:

• Current compendial methods (USP-NF, Ph. Eur.) for residual ethylene oxide in polyethylene glycol (PEG) are inadequate.
• An out-of-specification (OOS) investigation revealed methyl formate co-eluting with ethylene oxide, hindering accurate impurity testing.
• Ethylene oxide is a genotoxic impurity and a known human carcinogen (IARC Class 1).

Purpose of the Study:

• To develop and validate a novel analytical method for the accurate quantification of residual ethylene oxide in PEG.
• To achieve baseline separation of ethylene oxide from its degradant, methyl formate, and other process impurities.
• To establish a stability-indicating method for PEG release and stability testing under Current Good Manufacturing Practice (cGMP) conditions.

Main Methods:

• Development of a static headspace gas chromatography with flame ionization detection (HS-GC-FID) method.
• Application of the method to various grades of PEG.
• Validation of the method according to International Council for Harmonisation (ICH) guidelines, including forced degradation studies.

Main Results:

• The novel HS-GC-FID method successfully resolved ethylene oxide from methyl formate and other PEG degradants, achieving baseline separation (>1.5 resolution).
• The method demonstrated high selectivity and was proven to be stability-indicating through forced degradation studies (acid, alkali, heat, light, oxidation).
• Identified PEG degradants include methyl formate, formaldehyde, formic acid, and methanol.

Conclusions:

• The developed HS-GC-FID method is the first stability-indicating method capable of separating critical impurities in PEG in a single run.
• This validated method is suitable for cGMP batch release and stability testing in regulated quality control laboratories.
• The method addresses limitations of current pharmacopeial methods, ensuring more reliable quality assessment of PEG.