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E&L Chemical Characterization & Hexane Extracts: GC vs. LCUVMS Analysis

July 18, 2018

As a contract laboratory providing extractables and leachables (E&L) services we are often asked about the time and cost required to perform chemical characterization of a medical device.

Per FDA definition and guidance: Latest Guidance on Device Classification “Medical devices range from simple tongue depressors and bedpans to complex programmable pacemakers with micro-chip technology and laser surgical devices.”

Herein lies the challenge to set up E&L study design, especially on complex finished products.  Since the material composition of each device is different as is its intended use, each device should have a unique study design, time required for execution and total cost. We all agree that before designing an analytical plan for E&L, a critical design and manufacturing information should be collected around which an extractable and leachable plan can be designed.  This entails a thorough evaluation of the chemical composition of the materials of construction, agents used including synthesis and polymerization, critical manufacturing processes, packaging, adhesives, storage conditions, thermal stability, etc.

It is common practice for most analytical laboratories providing E&L chemical characterization to follow industry guidance documents such as ISO10993 part 12 for sample preparation and part 18 for chemical characterization of materials; ISO 10993-1, for Biological evaluation of medical devices;  International Council for Harmonization (ICH), Organization for Economic Co-operation and Development (OECD) guidelines;  compendia monographs such as United States Pharmacopeia (USP), American Society for Testing and Materials (ASTM); or other recognized guidelines such as Product Quality Research Institute (PQRI), and the published literature, etc.

As directed in these guidance documents, the extraction is often performed with polar, non-polar, and aqueous media or a mix of solvents of various polarities to ensure extraction of all of the E&L components. The analysis of the extracts is routinely accomplished with gas chromatography mass spectrometry (GCMS), high-pressure liquid chromatography coupled to Ultraviolet and mass spectrometry detection (HPLC/UV/MS) and inductively coupled plasma spectrometry (ICPMS) for the separation, identification and quantification of volatile and semi-volatile organic compounds (VOC, SVOC), semi-volatile and non-volatile organic compounds (SVOC, NVOC), and for elemental analysis, respectively.  In addition other techniques as deemed appropriate such as headspace, ion chromatography, Total Organic and Inorganic Carbon (TOC and TIC), FTIR, etc., are also brought to bear on selected devices.

The extracts resulting from non-polar solvents such hexane are routinely and successfully analyzed by GCMS for detection of volatiles and semi-volatiles. However, we often observe that the hexane extracts are also analyzed by LCUVMS, either by direct injection or following evaporation and reconstitution in a suitable solvent compatible with the aqueous mobile phase used in reverse-phase liquid chromatography.  These chromatograms seldom yield usable information or identify compounds not seen in other analytical methods, therefore we believe that any analysis of the hexane extracts by LC-UV/MS limited to direct injection or evaporation and reconstitution, is an extra expense, is time consuming and does not add value to the GCMS data for the following reasons:

  • Hexane is a non-polar solvent used to extract non-polar compounds and to lesser extent, semi-polar compounds.
  • The semi-polar compounds are more soluble in semi-polar solvent such IPA, which is commonly used solvent for the extraction and IPA extract are analyzed by GCMS in addition to LCUVMS.
  • Non-polar compounds are not amenable for LCMS analysis because they are minimally charged or ionized, significantly reducing the sensitivity obtained in the detection of these compounds by MS.
  • Evaporation of hexane and reconstitution in a suitable solvent risks loss of volatile and semi-volatile compounds as well as contamination from handling and sample transfer potentially leading to identification of introduced contaminants which would add ambiguity to the results.

E&L extraction is based on the rule of solubility that like dissolves like, therefore:

  • Nonpolar substances are likely to dissolve in nonpolar solvent such as hexane and tend to be volatile and semi-volatile compounds.
  • Semi-polar compounds are more soluble in semi-polar solvents such as IPA and tend to be semi-volatile, and to less extent non-volatile organic compounds.
  • Small polar compounds are mostly ionic compounds soluble in water and tend to be organic salts, organic-metal complexes, ionic elements, cations and anions. Larger polar compounds are insoluble in hexane.

Here at APS, we pay great attention to the interest and needs of our clients. We do not recommend analysis of hexane extracts by LCUVMS as justified in the table below. Any analysis that does not add value to the final chemical characterization should be discussed in the protocol and eliminated from the final extraction design with an appropriate justification.

 

Type of Substance Soluble in Water  (Polar) Soluble in  Hexane (non-Polar) Soluble in  IPA    (semi-Polar)
Ionic Compounds Yes (LCUVMS, ICPMS) No Slightly
Polar Compounds Yes (LCUVMS, ICPMS) No Yes (LCUVMS)
Semi-Polar Compounds Slightly Slightly (GCMS) Yes (LCUVMS)
Non-Polar Compounds No Yes (GCMS) Slightly