Method validation
When assessing the validity of measured results and determining whether a defined procedure and associated system are fit
for purpose, two concepts are central: repeatability and reproducibility. Assessing repeatability involves duplicate measurements
of the same sample. It therefore tests the precision of the instrument and the consistency of the sample. Reproducibility
is a broader concept that also encompasses sampling from the bulk.
One aspect of repeatability is the performance of the analyzer. ISO13320 (2009) provides revised accuracy acceptance criteria
for performance verification, which typically involves measurement of an appropriate standard. Because laser diffraction is
a volume-based measurement technique, sampling errors for large particles will cause greater uncertainty in the Dv90 than
in the Dv10. The revised acceptance criteria for reference materials reflect this and are:
- +/– 3% for Dv10 (and all other value of cumulative undersize distribution between the 10th and 30th percentiles)
- +/– 2.5% for Dv50 (and all other value of cumulative undersize distribution between the 30th and 70th percentiles)
- +/– 4% for Dv90 (and all other value of cumulative undersize distribution between the 70th and 90th percentiles).
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To test repeatability for a given application, duplicate measurements of the same sample are performed. The precision of laser
diffraction measurements is usually assessed using the term coefficient of variation (%COV) which is defined according to
the following equation (1):
ISO 13320:2009 states that repeatability tests should show a %COV of less than 3% on Dv50 and below 5% for Dv10 and Dv90 but
indicates that these values can be doubled for samples containing particles smaller than 10 μm, because of the difficulties
of dispersion. In ideal conditions, however, much better performance is readily achievable: a %COV of less than 0.5% for samples
larger than 1 μm and below 1% for samples finer than this, is realistic.
Reproducibility is assessed by measuring several samples from the same batch of material and therefore tests how representative
the sampling procedure is. Both USP and the European Pharmacopoeia recommend acceptance criteria for reproducibility testing
of a %COV of less than 10% on Dv50 or any similar central value and less than 15% on values toward the edge of the distribution
such as Dv10 and Dv90 (2, 6). Once again, these limits are doubled for samples containing particles smaller than 10 μm.
Conclusion
The highly valued simplicity of routine laser-diffraction measurement belies the relative complexity of method development.
During the last decade, considerable progress has been made toward securing a comprehensive understanding of how best to define
measurement methods for laser-diffraction analysis and implement them. The new ISO standard and relevant chapters of the USP and the European Pharmacopoeia provide useful summaries of the significant guidance now in place. Instrument manufacturers recognize that helping users
to access all available information—through education, direct support and smarter software—is the way to maximize the benefits
of this vital analytical technique.
Anne Virden is a product technical specialist in diffraction at Malvern Instruments, Enigma Business Park, Grovewood Road, Malvern, Worcestershire,
WR14 1XZ, UK, tel. +44 (0)1684 892456, fax + 44 (0)1684 892789, salesinfo@malvern.com
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