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A Risk-Based Approach to Management of Leachables Utilizing Statistical Analysis of Extractables

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Abstract

To incorporate quality by design concepts into the management of leachables, an emphasis is often put on understanding the extractable profile for the materials of construction for manufacturing disposables, container-closure, or delivery systems. Component manufacturing processes may also impact the extractable profile. An approach was developed to (1) identify critical components that may be sources of leachables, (2) enable an understanding of manufacturing process factors that affect extractable profiles, (3) determine if quantitative models can be developed that predict the effect of those key factors, and (4) evaluate the practical impact of the key factors on the product. A risk evaluation for an inhalation product identified injection molding as a key process. Designed experiments were performed to evaluate the impact of molding process parameters on the extractable profile from an ABS inhaler component. Statistical analysis of the resulting GC chromatographic profiles identified processing factors that were correlated with peak levels in the extractable profiles. The combination of statistically significant molding process parameters was different for different types of extractable compounds. ANOVA models were used to obtain optimal process settings and predict extractable levels for a selected number of compounds. The proposed paradigm may be applied to evaluate the impact of material composition and processing parameters on extractable profiles and utilized to manage product leachables early in the development process and throughout the product lifecycle.

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Acknowledgments

The authors wish to thank the members of the IPAC-RS L&E Development Paradigm Working Group for their valuable contributions to this work. The ABS component molding was kindly performed by Plastiape.

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Authors and Affiliations

  1. Novartis Pharmaceuticals Corp, San Carlos, California, USA

    Cheryl L. M. Stults & William Duffield

  2. Boehringer Ingelheim, Ridgefield, Connecticut, USA

    Jaromir Mikl

  3. GlaxoSmithKline, Brentford, Middlesex, UK

    Oliver Whelehan

  4. Novartis Pharma AG, Basel, Switzerland

    Bradley Morrical

  5. IPAC-RS, Drinker Biddle & Reath, LLP, Washington, District of Columbia, 20005, USA

    Lee M. Nagao

Authors
  1. Cheryl L. M. Stults
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  2. Jaromir Mikl
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  3. Oliver Whelehan
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  4. Bradley Morrical
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  5. William Duffield
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  6. Lee M. Nagao
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Corresponding author

Correspondence to Lee M. Nagao.

Additional information

Statistical analysis of extractable data from parts processed via a design of experiments is used to investigate risk-based approaches to leachable management.

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Stults, C.L.M., Mikl, J., Whelehan, O. et al. A Risk-Based Approach to Management of Leachables Utilizing Statistical Analysis of Extractables. AAPS PharmSciTech 16, 315–326 (2015). https://doi.org/10.1208/s12249-014-0221-9

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  • DOI: https://doi.org/10.1208/s12249-014-0221-9

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