CASCADE IMPACTION AND PARTICLE SIZE DISTRIBUTION

Cascade Impaction Lean Data Analysis Presentation at RDD 2008 Conference

Results of a systematic study of aerodynamic particle size distribution (APSD) data from several orally inhaled aerosols show that a simple metric comprising information from fine (small) and coarse (large) particle size fractions may be adequate to detect changes in both central tendency (MMAD) and in the impactor-sized mass (ISM), as an in vitro critical quality attribute (CQA) for these products. Results also show that compared to the stage-groupings, this two-metric approach provides better intrinsic precision by virtue of having adequate mass in each fraction, and also has a better predictive value for detecting size-related shifts in APSD and ISM changes. These findings suggest that the two-fraction approach should be preferred as a quality control tool.

Cascade impaction testing and profile comparisons of aerodynamic particle size distributions (APSDs) of aerosol drug products have been addressed through several internal IPAC-RS working groups as well as through the Product Quality Research Institute (PQRI), in which IPAC-RS actively participated along with other representatives from the industry, academia, FDA and USP.

The ongoing work of the IPAC-RS Cascade Impaction Working Group is on the program of the Respiratory Drug Delivery-2008 Conference (RDD ). The Working Group's extensive review is presented in the following publication: Minimizing Variability of Cascade Impaction Measurements in Inhalers and Nebulizers. M. Bonam, D. Christopher, D. Cipolla, B. Donovan, D. Goodwin, S. Holmes, S. Lyapustina, J. Mitchell, S. Nichols, G. Pettersson, C. Quale, N. Rao, D. Singh, T. Tougas, M. Van Oort, B. Walther, B. Wyka. AAPS PharmSciTech. DOI: 10.1208/s12249-008-9045-9 (http://www.springerlink.com/content/t22701k84w1665q4/. (2008)

The APSD Profile Comparisons Working Group of PQRI has carried out a systematic investigation of a number of statistical approaches that had been proposed by the Agency for in vitro determinations of APSD equivalence. This Working Group has made a number of public presentations at scientific conferences, presented posters, and published several papers, the main ones being:

• Product Quality Research Institute Reports in AAPS PharmSciTech. 2007; 8(1): Article 6.DOI: 10.1208/pt0801005
• Product Quality Research Institute Evaluation of Cascade Impactor Profiles of Pharmaceutical Aerosols, Part 1: Background for a Statistical Method. in AAPS PharmSciTech. 2007; 8(1): Article 4. DOI: 10.1208/pt0801004
• Product Quality Research Institute Evaluation of Cascade Impactor Profiles of Pharmaceutical Aerosols: Part 2 - Evaluation of a Method for Determining Equivalence. in AAPS PharmSciTech. 2007; 8(1): Article 5. DOI: 10.1208/pt0801005
• Product Quality Research Institute Evaluation of Cascade Impactor Profiles of Pharmaceutical Aerosols: Part 3 – Final Report on a Statistical Procedure for Determining Equivalence. in AAPS PharmSciTech. 2007; 8(4): Article 90. DOI: 10.1208/pt0804090.
  
  The Cascade Impaction Mass Balance Working Group of PQRI, has been reporting on its work and findings in the Journal of Aerosol Medicine:
• the "Good Cascade Impactor Practices" paper ( Considerations for the Development and Practice of Cascade Impaction Testing Including a Mass Balance Failure Investigation Tree. J. Aerosol Medicine, Vol. 16, No. 3, pp. 235-247 (2003) with a follow-up letter in J Aerosol Med. 16 (4):433), and
• Comparison of Two Approaches for Treating Cascade Impaction Mass Balance Measurements J. Aerosol Med. Vol.20, No. 3, pp 236-256 (2007).
  
  Results of an earlier survey related to particle size testing, which was conducted by the ITFG/IPAC Collaboration, are summarized in a paper entitled, Initial Assessment of the ITFG/IPAC Aerodynamic Particle Size Distribution Database. That paper was submitted to the FDA in 2000. It suggests that orally inhaled products do not in general comply with the proposed mass balance requirement in the draft CMC Guidances, and that the proposed requirement is not suitable as a drug product specification.