Skip to main content
SpringerLink
Log in

Improved Quality Control Metrics for Cascade Impaction Measurements of Orally Inhaled Drug Products (OIPs)

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This study of aerodynamic mass-weighted particle size distribution (APSD) data from orally inhaled products (OIPs) investigated whether a set of simpler (than currently used) metrics may be adequate to detect changes in APSD for quality control (QC) purposes. A range of OIPs was examined, and correlations between mass median aerodynamic diameter and the ratio of large particle mass (LPM) to small particle mass (SPM) were calculated. For an Andersen cascade impactor, the LPM combines the mass associated with particle sizes from impactor stage 1 to a product-specific boundary size; SPM combines the mass of particles from that boundary through to terminal filter. The LPM–SPM boundary should be chosen during development based on the full-resolution impactor results so as to maximize the sensitivity of the LPM/SPM ratio to meaningful changes in quality. The LPM/SPM ratio along with the impactor-sized mass (ISM) are by themselves sufficient to detect changes in central tendency and area under the APSD curve, which are key in vitro quality attributes for OIPs. Compared to stage groupings, this two-metric approach provides better intrinsic precision, in part due to having adequate mass and consequently better ability to detect changes in APSD and ISM, suggesting that this approach should be a preferred QC tool. Another advantage is the possibility to obtain these metrics from the abbreviated impactor measurements (AIM) rather than from full-resolution multistage impactors. Although the boundary is product specific, the testing could be accomplished with a basic AIM system which can meet the needs of most or all OIPs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

ACI:

Andersen cascade impactor

AIM:

abbreviated impactor measurement

API:

active pharmaceutical ingredient

APSD:

aerodynamic particle size distributions

AUCAPSD :

area under the APSD curve

CI:

cascade impaction

CQA:

critical quality attribute

DPI:

dry powder inhaler

GSD:

geometric standard deviation

HRT:

human respiratory tract

IPAC-RS:

International Pharmaceutical Aerosol Consortium on Regulation and Science

ISM:

impactor-sized mass (defined as mass on all impactor components with a defined upper cutoff, i.e., from stage 1 to filter)

LPM:

large particle mass (defined uniquely for each product, from stage 1 to some defined boundary within the impactor)

MDI:

metered dose inhaler

MMAD:

mass median aerodynamic diameter

MMF:

Morgan–Mercer–Flodin

NGI:

next generation pharmaceutical impactor

OIP:

orally inhaled product

QC:

quality control

RMSE:

root mean square error

SPM:

small particle mass (defined uniquely for each product, from some defined boundary within the impactor to the filter)

References

  1. FDA. Guidance for industry PAT—a framework for innovative pharmaceutical development, manufacturing, and quality assurance. 2004. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070305.pdf. Accessed 4 Aug 2009.

  2. FDA CDER. Draft guidance for industry metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products chemistry, manufacturing, and controls documentation. 1998. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070573.pdf. Accessed 4 Aug 2009.

  3. EP 2.9.18. Preparations for inhalations: aerodynamic assessment of fine particles. Strasbourg: Council of Europe; 2008.

    Google Scholar 

  4. USP 31. Chapter <601> aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers. Rockville: USP; 2008.

    Google Scholar 

  5. Health Canada. Pharmaceutical quality of inhalation and nasal products. 2006. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/inhalationnas_e.html (Accessed 4 Aug 2009) and EMEA. 2006 EMEA/CHMP/QWP/49313/2005 Corr. http://www.emea.europa.eu/pdfs/human/qwp/4931305en.pdf (Accessed 4 Aug 2009). Also adopted by Australia: http://www.tga.gov.au/docs/pdf/euguide/qwp/4931305en.pdf. Accessed 4 May 2009.

  6. Adams WP, Christopher D, Lee DS, Morgan B, Pan Z, Singh GJP, Tsong Y, Lyapustina S. Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 1: background for a statistical method. AAPS PharmSciTech. 2007;8(1):Article 4. doi:10.1208/pt0801004. http://www.aapspharmscitech.org/default/issueView.asp?vol=08&issue=01 or http://www.aapspharmscitech.org/view.asp?art=pt0801004. Accessed 4 Aug 2009.

  7. Mitchell JP, Dunbar C. Analysis of cascade impactor mass distributions. J Aerosol Med. 2005;18(4):439–51.

    Article  PubMed  Google Scholar 

  8. Tougas T. Capabilities of aerodynamic particle size distribution (APSD) measurements based on analysis of a blinded database. RDD. 2008;1:109–23.

    Google Scholar 

  9. Christopher D, Curry P, Doub W, Furnkranz K, Lavery M, Lin K, et al. Considerations for the development and practice of cascade impaction testing including a mass balance failure investigation tree. J Aerosol Med. 2003;16(3):235–47.

    Article  PubMed  Google Scholar 

  10. Van Oort M, Roberts W. Variable flow–variable stage–variable volume strategy for cascade impaction testing of inhalation aerosols. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory Drug Delivery V. Buffalo Grove: Interpharm; 1996. p. 418–20.

    Google Scholar 

  11. Lundbäck H, Wiktorsson B. High throughput inhaler testing I: fine particle dose. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, editors. Respiratory Drug Delivery 2006. River Grove: Davis Healthcare International; 2006. p. 467–9.

    Google Scholar 

  12. Initial assessment of the ITFG/IPAC aerodynamic particle size distribution database by the CMC specifications technical team of the ITFG/IPAC collaboration. 2000. http://ipacrs.com/PDFs/Initial_Assess_of_Particle.PDF. Accessed 4 Aug 2009.

  13. Morgan PH, Mercer LP, Flodin NW. General model for nutritional responses of higher organisms. Proc Natl Acad Sci USA. 1975;72:4327–31.

    Article  CAS  PubMed  Google Scholar 

  14. Christopher D, Dey M, Lyapustina S, Mitchell JP, Stein S, Tougas TP, Van Oort M, Strickland H, Wyka B. Generalized simplified approaches for MMAD determination. Pharmacop Forum. 2009; in press.

  15. Christopher D, Dey M, Lyapustina S, Mitchell J, Stein S, Tougas T, Van Oort M. Alternative approaches for MMAD determination. Poster presented at the IPAC-RS Conference 2008. http://ipacrs.com/PDFs/Posters/Alternative%20MMAD.pdf. Accessed 4 Aug 2009.

  16. Marple VA, Willeke K. Inertial impactors: theory, design and use. In: Liu BYH, editor. Fine Particles. New York: Academic; 1976. p. 411–66.

    Google Scholar 

  17. Kamiya A, Sakagami M, Hindle M, Byron PR. Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and next generation pharmaceutical impactors and their USP methods. J Pharm Sci. 2004;93(7):1828–37.

    Article  CAS  PubMed  Google Scholar 

  18. Mitchell JP, Nagel MW, Wiersema KJ, Doyle CC. Aerodynamic particle size analysis of aerosols from pressurized metered dose inhalers: comparison of Andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 aerodynamic particle sizer aerosol spectrometer. AAPS PharmSciTech. 2003;4(4):article 54.

  19. Mitchell JP, Nagel MW, Avvakoumova V, MacKay H, Ali R. The abbreviated impactor measurement (AIM) concept: part I—influence of particle bounce and re-entrainment—evaluation with a “dry” pressurized metered dose inhaler (pMDI)-based formulation. AAPS PharmSciTech. 2009;10(1):243–51.

    Article  CAS  PubMed  Google Scholar 

  20. Mitchell JP, Nagel MW, Avvakoumova V, MacKay H, Ali R. The abbreviated impactor measurement (AIM) concept: part II—influence of evaporation of a volatile component—evaluation with a “droplet-producing” pressurized metered dose inhaler (pMDI)-based formulation containing ethanol as cosolvent. AAPS PharmSciTech. 2009;10(1):252–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors appreciate the ongoing support of the IPAC-RS Board of Directors for this project, comments from the IPAC-RS Cascade Impaction Working Group, and technical advice from the European Pharmaceutical Aerosol Group. Our appreciation for help in preparing this manuscript is also extended to Samantha Dickinson. Finally, we also wish to acknowledge the technical advice from Mårten Svensson of AstraZeneca, Lund, Sweden, regarding AIM options.

Author information

Authors and Affiliations

  1. CMC Development, Boehringer Ingelheim, Ridgefield, Connecticut, USA

    Terrence P. Tougas

  2. Statistics, Schering-Plough Research Institute, Kenilworth, New Jersey, USA

    David Christopher

  3. Trudell Medical Group, London, Ontario, Canada

    Jolyon P. Mitchell

  4. Statistics, GlaxoSmithKline, Zebulon, North Carolina, USA

    Helen Strickland

  5. SpiraPharma Consulting, Lincoln Park, New Jersey, USA

    Bruce Wyka

  6. Inhaled Product Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Mike Van Oort

  7. Pharmaceutical Practice Group, Drinker Biddle & Reath LLP, 1500 K Street, N.W., Suite 1100, Washington, DC, 20005-1208, USA

    Svetlana Lyapustina

Authors
  1. Terrence P. Tougas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Christopher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jolyon P. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Helen Strickland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruce Wyka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mike Van Oort
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Svetlana Lyapustina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Svetlana Lyapustina.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tougas, T.P., Christopher, D., Mitchell, J.P. et al. Improved Quality Control Metrics for Cascade Impaction Measurements of Orally Inhaled Drug Products (OIPs). AAPS PharmSciTech 10, 1276–1285 (2009). https://doi.org/10.1208/s12249-009-9312-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-009-9312-4

Key words

Search

Navigation