BRIEFING

 〈470〉 Determination of Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Polyethylene Glycol.

 In response to the letter from the US FDA on February 10, 2023 that requests the inclusion of a Limit of Ethylene Glycol and Diethylene Glycol (EG and DEG) test in the Identification (ID) section to address the potential risk of EG and DEG contamination in Polyethylene Glycol (PEG), the Complex Excipients Expert Committee and the Excipient Test Methods Expert Committee (ETM EC) proposed to utilize a stepwise approach. As described in the chapter prospectus, EG and DEG test methods are proposed in the Polyethylene Glycol monograph revision proposal published in PF 50(3) [May–Jun. 2024], as step one. Subsequently, other available EG and DEG test methods for PEGs are proposed in this new test chapter as step two; therefore, stakeholders can evaluate the equivalency and interchangeability of these methods and use them as alternative methods as necessary.

 Here are some clarifications based on the comments received on the chapter prospectus:

 Chapter 〈470〉 is a standalone chapter that provides testing procedures without acceptance criteria. After reviewing the method validation data for EG, DEG, and triethylene glycol (TEG), the Excipients expert committees decided to expand the scope of this chapter to also include TEG analysis. Chapter 〈470〉 is not mandatory as it is currently not cross-referenced in the USP–NF monographs, e.g., Polyethylene Glycol.

 This chapter includes several EG and DEG and TEG testing procedures for Polyethylene Glycol only, whereas the existing chapter Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances 〈469〉 includes only one gas chromatography (GC) method for EG and DEG and TEG testing of a list of ethoxylated substances.

 In the Polyethylene Glycol monograph revision proposal published in PF 50(3), the actual testing procedure for EG and DEG testing, not including TEG, is described without cross-referencing to 〈469〉 or this chapter.

 All DEG and EG testing procedures described in this chapter and 〈469〉 have been validated for the specified PEG nominal molecular weight ranges. The suitability of using these procedures needs to be verified for the specified molecular weight ranges of Polyethylene Glycol. The applicability of other Polyethylene Glycol molecular weight ranges other than those specified in the chapter needs to be fully validated.

 All testing procedures proposed in this chapter are based on validated gas chromatographic methods.

1. Procedure 1 was performed with the Restek Rtx-50 brand of column with G3 phase. The typical retention times for ethylene glycol, butane-1,3-diol (internal standard), diethylene glycol, and triethylene glycol are approximately 4.4, 10.2, 13.2, and 18.2 min, respectively.

2. Procedure 2 was performed with the Agilent DB-WAX Ultra Inert brand of column with G16 phase. The pre-column was prepared by cutting one meter from the analytical column. The typical retention times for 1,2-propanediol (internal standard), ethylene glycol, diethylene glycol, and triethylene glycol are approximately 2.7, 2.9, 5.6, and 7.8 min, respectively.

3. Procedure 3 was performed with the Agilent HP1 brand of column with G1 phase. The typical retention times for ethylene glycol, diethylene glycol, capric alcohol (1-decanol) (internal standard), and triethylene glycol are approximately 4.0, 7.5, 9.2, and 10.7 min, respectively.

4. Procedure 4 was performed with the Restek Rtx-50 brand of column with G3 phase. The typical retention times for ethylene glycol, butane-1,3-diol (internal standard), diethylene glycol, and triethylene glycol are approximately 5.8, 12.8, 15.9, and 20.6 min, respectively.

5. Procedure 5 was performed with the Agilent DB-1701 brand of column with G46 phase. The typical retention times for ethylene glycol, butane-1,3-diol (internal standard), and diethylene glycol are approximately 12.4, 15.4, and 20.0 min, respectively.

 (ETM: J. Liu)

 Case ID—SUB-1203