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Monday, September 21, 2009

USP 788 Test Particulate Matter Injections Large Volume Parenteral LVP

While performing the USP <788> Test for Particulate Matter in Injections for a Large Volume Parenteral (LVP), You cant take the average among the units tested to determine if the batch meets its specification for this Test?

The answer provided by US FDA is as follows.

1.We can not average results among the test units as particulate matter is assumed to be non-uniformly dispersed throughout the lot.
2.The intention of assessing results from each individual unit is to ensure adequate representation of the lot and to detect potential variation within a lot.

US FDA in its answer says , It is not at all acceptable to take a average amongst the LVP units tested in given batch / lot when following this method because the purpose of this method is to measure and limit intra-batch variability.
"Particulate matter" are small, sub-visible particles. USP <788> has given two tests for detecting particulate matters , 
1.particulates--light obscuration and 
2.microscopic particle count determination.  

Both the tests are normally accepted for use in testing LVPs and small volume parenterals (SVP) for the determination of sub-visible particulate matter.  

Samples are first tested by the light obscuration method; if the sample fails the specified limits, the microscopic assay method can then be used. However, the microscopic method can be the sole test if there is a documented technical reason or interference from the product under test that would make the light obscuration method unsuitable or the results invalid.

Many peoples get confusion about when averaging data is or is not acceptable , this is probably becouse of the sample preparation method for the light obscuration test (USP <788>).  

Minimum 2, 5-mL aliquots from each sampled unit or the pooled sample are to be used in the particulate count determination, and the results from these aliquots are to be averaged for comparison with the specification.  

Note that the average is of the results from examining each aliquot and not between units. (The results of the first aliquot examined by light obscuration are to be discarded, and the subsequent aliquots--2 or more--are retained.) 

Pooling units prior to analysis is permitted only when the volume in each unit is less than 25 mL, in this case 10 or more units may be pooled. If the volume in the SVP or LVP is 25 mL or more per unit, single units are to be examined by this method (USP <788>).


As for the number of individual units to be tested for LVP and SVP units having a volume of 25mL or more, the USP states that the number of units tested depends on "statistically sound sampling plans," and "sampling plans should be based on consideration of 
1.Product volume, 
2.Numbers of particles historically found to be present in comparison to limits, 
3.Particle size distribution of particles present, and variability of particle counts between units.

" The USP also suggests that the total number of units tested for any given batch may be less than 10 units (for LVP and pooled SVPs) with proper justification.  This is consistent with the CGMP requirement for statistical sampling plans (see 211.165).

Which are the references for above answer.

1.21 CFR 211.160: General requirements (laboratory controls) 

2.21 CFR 211.165(c),(d): Testing and release for distribution USP <788> Particulate Matter in Injections 

3.For information only: Draft Guidance: Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production

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