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Research ArticleTechnology/Application

The Implications of Chromatographically Screening Medical Products for Organic Leachables Down to the Analytical Evaluation Threshold Adjusted for Response Factor Variation

Dennis Jenke and Ted Heise
PDA Journal of Pharmaceutical Science and Technology May 2021, 75 (3) 273-288; DOI: https://doi.org/10.5731/pdajpst.2020.012013
Dennis Jenke
1Triad Scientific Solutions, LLC, Hawthorn Woods, IL; and
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  • For correspondence: dennisjenke@triadscientificsolutions.com
Ted Heise
2MED Institute Inc, West Lafayette, IN
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Abstract

A drug product is chromatographically screened for organic leachables, derived from the product’s packaging system, as leachables might adversely impact the health of a patient to whom the drug product is administered. Similarly, medical device and packaging system extracts are chromatographically screened for organic extractables as probable leachables. To be protective of patient health, the screening methods must produce recognizable responses for all potentially unsafe substances. To be efficient, the screening methods should provide a means of differentiating between the responses linked to likely to be safe substances and to potentially unsafe substances. The analytical evaluation threshold (AET) was established as a means of differentiating chromatographic peaks, based on concentration, that are unlikely to be unsafe (and thus do not need safety assessment) and that are possibly unsafe (and thus require safety assessment). Thus, the AET manages the competing objectives of protection and efficiency. Although the AET is based on concentration, it is applied based on response. As no chromatographic detection method applied to extractables and leachables screening produces a uniform response to all potential analytes (thus, the magnitude of the response differs across analytes), the objectives of protection or efficiency can be compromised by false negatives and positives. To ensure protection at the expense of efficiency, the AET can be adjusted to address response variation. This article addresses the practical issue that the protectiveness of the AET is affected both by response factor bias and variation and thus correction for only variation is incomplete and ineffective. The article illustrates the proper adjustment of the AET for bias and variation.

  • Extractables
  • Leachables
  • Analytical evaluation threshold
  • AET
  • Response factor variation
  • Uncertainty factor
  • © PDA, Inc. 2021
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PDA Journal of Pharmaceutical Science and Technology: 75 (3)
PDA Journal of Pharmaceutical Science and Technology
Vol. 75, Issue 3
May/June 2021
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The Implications of Chromatographically Screening Medical Products for Organic Leachables Down to the Analytical Evaluation Threshold Adjusted for Response Factor Variation
Dennis Jenke, Ted Heise
PDA Journal of Pharmaceutical Science and Technology May 2021, 75 (3) 273-288; DOI: 10.5731/pdajpst.2020.012013

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The Implications of Chromatographically Screening Medical Products for Organic Leachables Down to the Analytical Evaluation Threshold Adjusted for Response Factor Variation
Dennis Jenke, Ted Heise
PDA Journal of Pharmaceutical Science and Technology May 2021, 75 (3) 273-288; DOI: 10.5731/pdajpst.2020.012013
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  • Article
    • Abstract
    • Introduction: Extractables, Leachables, and the Analytical Evaluation Threshold
    • Problem Statement: The Analytical Evaluation Threshold Gap
    • Filling the Analytical Evaluation Threshold Gap with the Uncertainty Factor
    • Current Practice with Regard to Establishing the Magnitude of the Uncertainty Factor
    • Issues with the Use of Large Uncertainty Factors to Adjust the Analytical Evaluation Threshold
    • Managing the Uncertainty Adjustment
    • Conclusion
    • Conflict of Interest Declaration
    • References
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Keywords

  • Extractables
  • Leachables
  • Analytical evaluation threshold
  • AET
  • Response factor variation
  • uncertainty factor

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