FAQ - Pharmaceutical/Life Sciences Particle Counting

Question
Did the specifications actually evolve over time? What were the reasons for tightening the specifications? In particular, why were the specifications lowered from 10,000/1000 to 6,000/600 for 10 μm/25 μm size particulate in 1995?

Answer

There was no real evolution of the limits, the original adoption of automated particle counting over microscope techniques meant that assigned limits needed to be adopted by available technology. At the time this was the Hiac Royco unit and was named in an early USP22, during the change from USP22 to USP23 the manufacturer specific model was dropped in favour of a type of device - Light obscuration particle counting.

Al Lieberman (Particle Measuring Systems in California and long time consultant) released a paper showing that the maximum count limits that can confidently be seen by light obscuration is 10,000/ml and that a limit which is lower than this should be adopted.

"The prerequisites for estimating the effect of signal coincidence on both particle undercounting and the injection of false counts in the implementation of U.S.P. 788 contaminating particle assays by light extinction particle counters are defined. These include a particle concentration measure that varies with particle size and a new model of the counting process. Both prerequisites have been verified empirically: a single normalized equation describes the coincidence effect in all single particle counters. The single parameter of the normalized equation is the number of effective detector volumes per milliliter. A maximum undercount limit of 5% is proposed based on adequately suspended particles. Using the SVP U.S.P. XXII acceptance limits of 10,000 particles per container or the PMA propose 6,000 particles per container maximum for particles > 10 microns in U.S.P. XXIII, undercount errors are estimated for the smallest container sizes. The large concentration of particles below the controlled 10 microns particle size, that has been documented in injectable solutions, can pose an additional 788 measurement hazard. A Poisson model is used to estimate and control the injection of false particle counts into the mandated measurement through particle coincidence. Acceptable counting accuracy limits with present particle counting systems can be achieved by understanding the capabilities of the particle counter measurement system and using a dilution technique when appropriate. The new model of the counting process and the new particle concentration measures can result in standard, conservative, instrument specifications for use in Pharmacopeial contamination testing and in GLP user evaluation tests."

I have downloaded this paper off the PDA website and it eludes to counting efficiency specifically at the 10 um level.

Further to this, in 1995 a second paper showing that a 1.5x (half count) method should be used to accurately determine the maximum concentrations that particle counters should be used at was published (Osama Fujishita et al).

I hope this helps, it does not however allow change from the prescribed 6000/600 limit that the FDA insist on imposing and the same technology used then is still used now. It is comporting to note however that in the second paper the Particle Measuring Systems' product was chosen for its accuracy.

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