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Article CommentaryPQRI Special Section

Perspectives on the PQRI Extractables and Leachables “Safety Thresholds and Best Practices” Recommendations for Inhalation Drug Products

Daniel L. Norwood, Lee M. Nagao and Cheryl L. M. Stults
PDA Journal of Pharmaceutical Science and Technology September 2013, 67 (5) 413-429; DOI: https://doi.org/10.5731/pdajpst.2013.00934
Daniel L. Norwood
International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) 1500 K Street, NW, Suite 1100 Washington, DC 20005-1209
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  • For correspondence: daniel.norwood@boehringer-ingelheim.com
Lee M. Nagao
International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) 1500 K Street, NW, Suite 1100 Washington, DC 20005-1209
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Cheryl L. M. Stults
International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) 1500 K Street, NW, Suite 1100 Washington, DC 20005-1209
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Abstract

In 2006, the Product Quality Research Institute's (PQRI) Leachables and Extractables Working Group released a comprehensive and detailed recommendation document related to leachables and extractables for inhalation drug products. The document includes best pharmaceutical development practice recommendations regarding container closure/delivery system component composition and selection, controlled extraction studies, drug product leachables studies, and routine extractables testing for component release. Also included in the document are two safety-based thresholds for leachables in inhalation drug products, the qualification threshold (QT) and the safety concern threshold (SCT), the first such safety-based thresholds for leachables in any drug product type. A process was described for converting the SCT into an analytically useful threshold for leachables/extractables characterization, the analytical evaluation threshold (AET), with consideration of individual drug product dosing parameters and container closure system component characteristics.

This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other high risk drug product types (e.g., large and small volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered.

LAY ABSTRACT: The recommendation document released by the Product Quality Research Institute's (PQRI) Leachables and Extractables Working Group in 2006 includes the first safety-based thresholds for leachables in any drug product type, along with comprehensive best practice recommendations for inhalation drug product pharmaceutical development related to extractables and leachables. The best practice recommendations encompass a number of important functional areas, including container closure/delivery system component composition and selection, controlled extraction studies, drug product leachables studies, and routine extractables testing for component release. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other drug product types (e.g., large- and small-volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered.

  • Extractables
  • Leachables
  • Inhalation
  • OINDP
  • PQRI
  • Qualification threshold
  • Safety concern threshold
  • Analytical evaluation threshold
  • © PDA, Inc. 2013
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PDA Journal of Pharmaceutical Science and Technology: 67 (5)
PDA Journal of Pharmaceutical Science and Technology
Vol. 67, Issue 5
September/October 2013
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Perspectives on the PQRI Extractables and Leachables “Safety Thresholds and Best Practices” Recommendations for Inhalation Drug Products
Daniel L. Norwood, Lee M. Nagao, Cheryl L. M. Stults
PDA Journal of Pharmaceutical Science and Technology Sep 2013, 67 (5) 413-429; DOI: 10.5731/pdajpst.2013.00934

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Perspectives on the PQRI Extractables and Leachables “Safety Thresholds and Best Practices” Recommendations for Inhalation Drug Products
Daniel L. Norwood, Lee M. Nagao, Cheryl L. M. Stults
PDA Journal of Pharmaceutical Science and Technology Sep 2013, 67 (5) 413-429; DOI: 10.5731/pdajpst.2013.00934
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  • Article
    • Abstract
    • Introduction
    • Industry Consortia—IPAC and IPAC-RS
    • The Product Quality Research Insitiute (PQRI)
    • Content of the PQRI OINDP Recommendations
    • Acceptance of the PQRI OINDP Recommendations
    • Scientific and Regulatory Initiatives Since 2006
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Keywords

  • Extractables
  • Leachables
  • Inhalation
  • OINDP
  • PQRI
  • Qualification threshold
  • Safety concern threshold
  • Analytical Evaluation Threshold

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