2.9.19. PARTICULATE CONTAMINATION: SUB-VISIBLE …

1 PARTICULATE contamination : SUB-VISIBLE particlesEUROPEAN PHARMACOPOEIA Calculations for Apparatus E. Use q = (60/Q)x, where Q is the test flow rate in litres per minute,and x is listed in the tableCut-off diameter( m)xMass of active substancedeposited per dischargeCumulative mass of active substancedeposited per dischargeCumulative fraction of activesubstance (per cent)d7= from MOC or terminalfilter, m8c7=m8F7=(c7/c) 100d6= from stage 7, m7c6=c7+m7F6=(c6/c) 100d5= from stage 6, m6c5=c6+m6F5=(c5/c) 100d4= from stage 5, m5c4=c5+m5F4=(c4/c) 100d3= from stage 4, m4c3=c4+m4F3=(c3/c)

2 100d2= from stage 3, m3c2=c3+m3F2=(c2/c) 100d1= from stage 2, m2c1=c2+m2F1=(c1/c) 100mass from stage 1, m1c=c1+m110001/2008 PARTICULATECONTAMINATION: SUB-VISIBLEPARTICLESP articulate contamination of injections and infusionsconsists of extraneous, mobile undissolved particles , otherthan gas bubbles, unintentionally present in the the determination of PARTICULATE contamination2procedures,Method1(LightOb scuration Particle CountTest) and Method 2 (Microscopic Particle Count Test),are specified hereinafter. When examining injections andinfusions for SUB-VISIBLE particles , Method 1 is preferablyapplied.

3 However, it may be necessary to test somepreparations by the light obscuration particle count testfollowed by the microscopic particle count test to reach aconclusion on conformance to the all parenteral preparations can be examined forsub- visible particles by one or both of these methods. WhenMethod 1 is not applicable, in case of preparationshaving reduced clarity or increased viscosity, the test iscarried out according to Method 2. Emulsions, colloids, andliposomal preparations are examples. Similarly, productsthat produce air or gas bubbles when drawn into the sensormay also require microscopic particle count testing.

4 If theviscosity of the preparation to be tested is sufficiently highso as to preclude its examination by either test method,a quantitative dilution with an appropriate diluent maybe made to decrease viscosity, as necessary, to allow theanalysis to be results obtained in examining a discrete unit or groupof units for PARTICULATE contamination cannot be extrapolatedwith certainty to other units that remain untested. Thus,statistically sound sampling plans must be developed ifvalid inferences are to be drawn from observed data tocharacterise the level of PARTICULATE contamination in a largegroup of 1.

5 LIGHT OBSCURATION PARTICLE COUNTTESTU seasuitableapparatusbasedontheprincipleo flightblockage which allows an automatic determination of thesize of particles and the number of particles according apparatus is calibrated using suitable certified referencematerials consisting of dispersions of spherical particles ofknown sizes between 10 m and 25 m. These standardparticles are dispersed inparticle-free water to avoid aggregation of particles during precautionsThe test is carried out under conditions limiting particulatecontamination, preferably in a laminar-flow carefully wash the glassware and filtration equipmentused, except for the membrane filters, with a warm detergentsolution and rinse with abundant amounts of water toremove all traces of detergent.

6 Immediately before use, rinsethe equipment from top to bottom, outside and then inside,withparticle-free water care not to introduce air bubbles into the preparationto be examined, especially when fractions of the preparationare being transferred to the container in which thedetermination is to be carried order to check that the environment is suitable for thetest, that the glassware is properly cleaned and that thewater to be used is particle-free, the following test is carriedout: determine the PARTICULATE contamination of 5 samplesofparticle-free water R, each of 5 ml, according to themethod described below.

7 If the number of particles of10 m or greater size exceeds 25 for the combined 25 ml,the precautions taken for the test are not sufficient. Thepreparatory steps must be repeateduntil the environment,glassware and water are suitablefor the the contents of the sample by slowly inverting thecontainer 20 times successively. If necessary, cautiouslyremove the sealing closure. Clean the outer surfaces ofthe container opening using a jet ofparticle-free water Rand remove the closure, avoiding any contamination of thecontents. Eliminate gas bubbles by appropriate measuressuch as allowing to stand for 2 min or large-volume parenterals, single units are tested.

8 Forsmall-volume parenterals less than 25 ml in volume, thecontents of 10 or more units are combined in a cleanedcontainerto obtain a volume of not less than 25 ml; wherejustified and authorised, the test solution may be prepared bymixingthe contents of a suitable number of vials and dilutingto 25 mlwithparticle-free water Ror with an appropriatesolvent without contamination of particles whenparticle-freewater Ris not suitable. Small-volume parenterals having avolume of 25 ml or more may be tested for parenteral use are reconstituted withparticle-free water Ror with an appropriate solvent withoutcontamination of particles whenparticle-free water Risnot number of test specimens must be adequate to provide astatistically sound assessment.

9 For large-volume parenteralsor for small-volume parenterals having a volume of 25 mlor more, fewer than 10 units may be tested, based on anappropriate sampling the information section on general monographs (cover pages)EUROPEAN PHARMACOPOEIA PARTICULATE contamination : SUB-VISIBLE particlesRemove 4 portions, each of not less than 5 ml, and countthe number of particles equal to or greater than 10 mand 25 m. Disregard the result obtained for the firstportion, and calculate the mean number of particles for thepreparation to be preparations supplied in containers with a nominalvolume of more than 100 ml, apply the criteria of test preparations supplied in containers with a nominalvolume of less than 100 ml, apply the criteria of test preparations supplied in containers with a nominalvolume of 100 ml, apply the criteria of test the average number of particles exceeds the limits.

10 Test thepreparation by the microscopic particle count Solutions for infusion or solutions for injectionsupplied in containers with a nominal content of morethan 100 mlThepreparationcomplieswiththetestifthe averagenumberof particles present in the units tested does not exceed 25 permillilitre equal to or greater than 10 m and does not exceed3 per millilitre equal to or greater than 25 Solutions for infusion or solutions for injectionsupplied in containers with a nominal content of less than100 mlThepreparationcomplieswiththetestifthe averagenumberof particles present in the units tested does not exceed6000 per container equal to or greater than 10 m and doesnot exceed 600 per container equal to or greater than 25 2.