Evaluation
The values below are derived historically from general chapters á788ñ and á789ñ. If specifications are different from tho stated below, they will be indicated in an individual monograph where available.
For parenteral products that are therapeutic protein injections for infusion or injection supplied in containers with a nominal content of less than or equal to 100 mL:
The average number of particles prent in the units tested should not exceed 6000 per container equal to or greater than 10 m m and should not exceed 600 per container equal to or greater than 25 m m.
For therapeutic protein injections supplied in containers with a nominal content of more than 100 mL, and parenteral infu-sion preparations or injections with a nominal content of more than 100 mL:
The average number of particles prent in the units tested should not exceed 25/mL equal to or greater than 10 m m and should not exceed 3/mL equal to or greater than 25 m m. Also, total particle lo
ad should not exceed 6000 per container equal to or greater than 10 m m and should not exceed 600 per container equal to or greater than 25 m m.
Products that are ud with a final filter during administration (in-line) are exempt from the requirements, providing that scientific data are available to justify the exemption. However, filtrates are expected to comply with the guideline. For products supplied or first reconstituted in <100 mL, and then diluted for infusion in a volume >100 mL, particle content should be as-sd both before and after dilution and evaluated bad on their final volume.
MICROSCOPIC PARTICLE COUNT TEST
As noted, the LO method is the preferred method for therapeutic protein injections and parenteral infusions. However, the microscopic method may be ud when appropriate, such as determination of extrinsic and intrinsic particle types only. It
should be demonstrated, however, that particular class of particles (e.g., inherent) are also being counted when using this
method. For the determination of product acceptability, apply the limits for the membrane microscopic test in general chapter
á788ñ. Becau of the interference of some protein particles and their physical characteristics (fragile or translucent), the results of the Microscopic Particle Count Test are not equivalent to tho of the Light Obscuration Particle Count Test , and the two meth-
ods cannot be considered interchangeable.
á788ñ PARTICULATE MATTER IN INJECTIONS
Change to read:
This general chapter is harmonized with the corresponding texts of the European Pharmacopoeia and/or the Japane Phar-macopoeia . The pharmacopeias have undertaken not to make any unilateral change to this harmonized chapter. Portions of the prent general chapter text that are national USP text, and therefore not part of the harmonized text, are marked with symbols (♦♦) to specify this fact.
Particulate matter in injections and parenteral infusions consists of extraneous mobile undissolved particles, other than gas bubbles, unintentionally prent in the solutions.
♦As stated in Injections and Implanted Drug Products á1ñ(CN 1-May-2016), solutions for injection ad
ministered by the intramuscu-lar or subcutaneous route must meet the requirements of Particulate Matter in Injections á788ñ. This requirement has been in-definitely postponed for products for veterinary u. Parenterals packaged and labeled exclusively for u as irrigating solutions are exempt from the requirements of Particulate Matter in Injections á788ñ. Radiopharmaceutical preparations are exempt from the requirements of Particulate Matter in Injections á788ñ. Parenteral products for which the labeling specifies u of a final filter prior to administration are exempt from the requirements of Particulate Matter in Injections á788ñ, provided that scientific data are available to justify this exemption.
♦For the determination of particulate matter, two procedures, Method 1 (Light Obscuration Particle Count Test) and Method 2(Microscopic Particle Count Test), are specified hereinafter. When examining injections and parenteral infusions for subvisible particles,
Method 1 is preferably applied. However, it may be necessary to test some preparations by the Light Obscuration Par-ticle Count Test followed by the Microscopic Particle Count Test to reach a conclusion on conformance to the requirements.Not all parenteral preparations can be examined for subvisible particles by one or both of the methods. When Method 1 is not applicable, e.g., in the ca of preparations having reduced clarity or incread viscosity, the test should be carried out according to Method 2. Emulsions, colloids, and liposomal preparations are examples. Similarly, products that produce air or gas bubbles when drawn into the nsor may also require microscopic particle count testing. If the viscosity of the preparation to be tested is sufficiently high so as to preclude its examination by either test method, a quantitative dilution with an appro-priate diluent may be made to decrea viscosity, as necessary, to allow the analysis to be performed.
608 á787ñ Subvisible Particulate Matter / Physical Tests USP 39
The results obtained in examining a discrete unit or group of units for particulate matter cannot be extrapolated with cer-tainty to other units that remain untested. Thus, statistically sound sampling plans must be developed if valid inferences are to be drawn from obrved data to characterize the l
evel of particulate matter in a large group of units.
♦For the purpo of this chapter, small-volume parenteral is synonymous with small-volume injection, and large-volume pa-renteral is synonymous with large-volume injection.
♦
METHOD 1 LIGHT OBSCURATION PARTICLE COUNT TEST
tplogin路由器设置U a suitable apparatus bad on the principle of light blockage that allows for an automatic determination of the size of particles and the number of particles according to size. The definition for particle-free water is provided in Reagents, Indicators, and Solutions—Reagent Specifications.
The apparatus is calibrated using dispersions of spherical particles of known sizes between 10 m m and 25 m m. The stand-ard particles are disperd in particle-free water. Care must be taken to avoid aggregation of particles during dispersion. ♦Sys-tem suitability can be verified by using the USP Particle Count RS.
♦
General Precautions
The test is carried out under conditions limiting particulate matter, preferably in a laminar flow cabinet.
Very carefully wash the glassware and filtration equipment ud, except for the membrane filters, with a warm detergent solution, and rin with abundant amounts of water to remove all traces of detergent. Immediately before u, rin the equip-ment from top to bottom, outside and then inside, with particle-free water.
插入单元格Take care not to introduce air bubbles into the preparation to be examined, especially when fractions of the preparation are being transferred to the container in which the determination is to be carried out.
伯牙绝弦原文In order to check that the environment is suitable for the test, that the glassware is properly cleaned, and that the water to be ud is particle-free, the following test is carried out. Determine the particulate matter in five samples of particle-free water, each of 5 mL, according to the method described below. If the number of particles of 10 m m or greater size exceeds 25 for the combined 25 mL, the precautions taken for the test are not sufficient. The preparatory steps must be repeated until the envi-ronment, glassware, and water are suitable for the test.苏联分裂
Method
Mix the contents of the sample by slowly inverting the container 20 times successively. If necessary, cautiously remove the aling closure. Clean the outer surfaces of the container opening using a jet of particle-free water, and remove the closure, avoiding any contamination of the contents. Eliminate gas bubbles by appropriate measures such as allowing to stand for 2 min or sonicating.
For large-volume parenterals, single units are tested. For small-volume parenterals less than 25 mL in volume, the contents of 10 or more units are combined in a cleaned container to obtain a volume of NLT 25 mL; the test solution may be prepared by mixing the contents of a suitable number of vials and diluting to 25 mL with particle-free water or with an appropriate parti-cle-free solvent when particle-free water is not suitable. Small-volume parenterals having a volume of 25 mL or more may be tested individually.
Powders for parenteral u are reconstituted with particle-free water or with an appropriate particle-free solvent when parti-cle-free water is not suitable.
♦For pharmacy bulk packages for parenteral u labeled “Not for Direct Infusion”, proceed as directed for small-volume pa-renterals when the volume is 25 mL or more. Calculate the test result o
议付
n a portion that is equivalent to the maximum do given in the labeling. For example, if the total bulk package volume is 100 mL and the maximum do volume is 10 mL, then the average particle count per mL would be multiplied by 10 to obtain the test result bad on the 10-mL maximum do. [N OTE—For the calculation of test results, consider this maximum do portion to be equivalent to the contents of one full container.]
Products packaged with dual compartments meant to hold a drug product and a solvent should be prepared and tested as directed for large-volume parenterals or small-volume parenterals, depending on container volume. Mix each unit as directed in the labeling, activating and agitating to ensure thorough mixing of the parate components and drug dissolution.
♦
The number of test specimens must be adequate to provide a statistically sound asssment. For large-volume parenterals or for small-volume parenterals having a volume of 25 mL or more, fewer than 10 units may be tested, using an appropriate sampling plan.
Remove four portions, NLT 5 mL each, and count the number of particles equal to or greater than 10 m m and 25 m m. Disre-gard the result obtained for the first portion, and calculate the mean number
of particles for the preparation to be examined.
如何锻炼右脑
Evaluation
For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 1.A
.
USP 39Physical Tests / á788ñ Particulate Matter in Injections609
For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 1.B .
For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 1.B . [N OTE —Test 1.A is ud in the Japane Pharmacopoeia.]
If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test .
Test 1.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles prent in the units tested does not ex-ceed 25 per mL equal to or greater than 10 m m and does not exceed 3 per mL equal to or greater than 25 m m.
Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100mL)—The preparation complies with the test if the average number of particles prent in the units tested does not exceed 6000 per container equal to or greater than 10 m m and does not exceed 600 per container equal to or greater than 25 m m.
METHOD 2MICROSCOPIC PARTICLE COUNT TEST
U a suitable binocular microscope, a filter asmbly for retaining particulate matter, and a membrane filter for examina-tion.
The microscope is adjusted to 100±10 magnifications and is equipped with an ocular micrometer calibrated with an objec-tive micrometer, a mechanical stage capable of holding and traversing the entire filtration area of the membrane filter, and two suitable illuminators to provide episcopic illumination in addition to oblique illumination.
The ocular micrometer is a circular diameter graticule (e Figure 1) and consists of a large circle divided by crosshairs into quadrants, transparent and black reference circles 10 m m and 25 m m in diameter at 100 magnifications, and a linear scale关于兔的歇后语
graduated in 10-m m increments. It is calibrated using a stage micrometer that is certified by either a domestic or international
standard institution. A relative error of the linear scale of the graticule within ±2% is acceptable. The large circle is designated
the graticule field of view (GFOV).高空断桥
Figure 1. Circular diameter graticule. The large circle divided by crosshairs into quadrants is designated the graticule field of view (GFOV). Transparent and black circles having 10-m m and 25-m m diameters at 100× are provided as comparison scales for
particle sizing.
Two illuminators are required. One is an episcopic brightfield illuminator internal to the microscope, the other is an external,focusable auxiliary illuminator that can be adjusted to give reflected oblique illumination at an angle of 10°–20°.
The filter asmbly for retaining particulate matter consists of a filter holder made of glass or other suitable material, and is equipped with a vacuum source and a suitable membrane filter.
The membrane filter is of suitable size, black or dark gray in color, nongridded or gridded, and 1.0 m m or finer in nominal pore size.
General Precautions
The test is carried out under conditions limiting particulate matter, preferably in a laminar flow cabinet.
Very carefully wash the glassware and filter asmbly ud, except for the membrane filter, with a warm detergent solution,and rin with abundant amounts of water to remove all traces of detergent. Immediately before u, rin both sides of the membrane filter and the equipment from top to bottom, outside and then inside, with particle-free water .
In order to check that the environment is suitable for the test, that the glassware and the membrane filter are properly
cleaned, and that the water to be ud is particle-free, the following test is carried out. Determine the particulate matter of a
610 á788ñ Particulate Matter in Injections / Physical Tests USP 39
50-mL volume of particle-free water according to the method described below. If more than 20 particles 10 m m or larger in size or if more than five particles 25 m m or larger in size are prent within the filtration area, the precautions taken for the test are not sufficient. The preparatory steps must be repeated until the environment, glassware, membrane filter, and water are suita-ble for the test.
Method
Mix the contents of the samples by slowly inverting the container 20 times successively. If necessary, cautiously remove the aling closure. Clean the outer surfaces of the container opening using a jet of particle-free water, and remove the closure, avoiding any contamination of the contents.
For large-volume parenterals, single units are tested. For small-volume parenterals less than 25 mL in volume, the contents of 10 or more units are combined in a cleaned container; the test solution may be prepared by mixing the contents of a suita-ble number of vials and diluting to 25 mL with particle-free water or with an appropriate particle-free solvent when particle-free water is not suitable. Small-volume parenterals having a volume of 25 mL or more may be tested individually.
Powders for parenteral u are constituted with particle-free water or with an appropriate particle-free solvent when particle-free water is not suitable.
The number of test specimens must be adequate to provide a statistically sound asssment. For large-volume parenterals or for small-volume parenterals having a volume of 25 mL or more, fewer than 10 units may be tested, using an appropriate sampling plan.
Wet the inside of the filter holder fitted with the membrane filter with veral mL of particle-free water. Transfer to the filtra-tion funnel the total volume of a solution pool or of a single unit, and apply a vacuum. If needed, add stepwi a portion of the solution until the entire volume is filtered. After the last addition of solution, begin rinsing the inner walls of the filter hold-er by using a jet of particle-free water. Maintain the vacuum until the surface of the membrane filter is free from liquid. Place the me
mbrane filter in a Petri dish, and allow the membrane filter to air-dry with the cover slightly ajar. After the membrane filter has been dried, place the Petri dish on the stage of the microscope, scan the entire membrane filter under the reflected light from the illuminating device, and count the number of particles that are equal to or greater than 10 m m and the number of particles that are equal to or greater than 25 m m. Alternatively, partial membrane filter count and determination of the total filter count by calculation is allowed. Calculate the mean number of particles for the preparation to be examined.
The particle sizing process with the u of the circular diameter graticule is carried out by estimating the equivalent diameter of the particle in comparison with the 10 m m and 25 m m reference circles on the graticule. Thereby the particles are not moved from their initial locations within the graticule field of view and are not superimpod on the reference circles for com-parison. The inner diameter of the transparent graticule reference circles is ud to size white and transparent particles, while dark particles are sized by using the outer diameter of the black opaque graticule reference circles.
In performing the Microscopic Particle Count Test, do not attempt to size or enumerate amorphous, miliquid, or otherwi morphologically indistinct materials that have the appearance of a stain or discoloration on the membrane filter. The materi-als show little or no surface relief and prent a g
elatinous or film-like appearance. In such cas, the interpretation of enumer-ation may be aided by testing a sample of the solution by the Light Obscuration Particle Count Test.
Evaluation
For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 2.A.
For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 2.B.
For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 2.B. [N OTE—Test 2.A is ud in the Japane Pharmacopoeia.]
Test 2.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles prent in the units tested does not ex-ceed 12 per mL equal to or greater than 10 m m and does not exceed 2 per mL equal to or greater than 25 m m.
Test 2.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nomi
nal content of less than 100 mL)—The preparation complies with the test if the average number of particles prent in the units tested does not exceed 3000 per container equal to or greater than 10 m m and does not exceed 300 per container equal to or greater than 25 m m.
á789ñ PARTICULATE MATTER IN OPHTHALMIC SOLUTIONS Particulate matter consists of mobile, randomly sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis becau of the small amount of material they reprent and becau of their heterogeneous
composition. Ophthalmic solutions should be esntially free from particles that can be obrved on visual inspection. The USP 39Physical Tests / á789ñ Particulate Matter in Ophthalmic Solutions611
