Particle Size Distribution II - ACS Publications - American Chemical

Chapter 8

Instrumental Particle Size Analysis Procedures for Parenteral Solutions Some Practical Issues

Downloaded by UNIV OF ARIZONA on August 2, 2012 | http://pubs.acs.org Publication Date: September 24, 1991 | doi: 10.1021/bk-1991-0472.ch008

M. J . Groves Institute for Tuberculosis Research (M/C 964), College of Pharmacy, University of Illinois at Chicago, 115 South Sangamon Street, Chicago, IL 60607

Particulate contamination in solutions intended for injection into the human body is physiologically undesirable but inevitable. Mobile particulate contaminants have a wide size spectrum, from the visible (>50 μm) to molecular levels (100-mL) injection solutions (infu sions). In 1985, this test was followed by a method based on the HIAC/Royco light extinction (blockage) instrument for smallvolume (50

from

pm).

the molecular Because

level

(e.g.,

< 1 0 n m ) to t h e visible

o f the nature o f the

filtration

process,

region

it is likely

0097-6156/91/0472-0123$06.00/0 © 1991 American Chemical Society

In Particle Size Distribution II; Provder, T.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


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that there will be a discontinuity at around the nominal pore size of the filtration medium, but particles larger than this size will be present by chance contamination or by interactions between components of the solution or between the solution and components of the container. This "contamination" must be put in context. If a solution contains 1000 particles per m L with diameters corresponding to a 2-/im-diameter sphere and the particles have a mean density of 1.2 g/mL, the solid contamination corresponds to approximately 5 parts per billion by weight. Currently, solutions are being commercially prepared two to three orders of magnitude cleaner than this level of particulates, which actually corresponds to the limit allowed by the British Pharmacopoeia 1988 at 2 /xm when measured by the Coulter principle. Physiologically, these particles are undesirable although inevitable. The body defense mechanisms for dealing with low levels of particulates involving phagocytosis of extraneous bacteria or other particles introduced into the body can be invoked. However, rigid particles much larger than 5-7 /xm will occlude blood capillaries. Nevertheless, as discussed elsewhere (1-3), the defense systems can be overwhelmed by particulates and enough capillaries can be blocked to deny the vital blood supply to essential organs. These situations, however, are encountered only in extreme cases (e.g., intravenous drug abuse) and are generally considered to be substantially irrelevant in modern medical practice. Some workers have suggested that particulates can produce profound physiological effects, even leading to death (4-6). More recently, reversible effects noted experimentally on isolated rat heart (7-9) have been attributed to particulates. However, it will never be possible to demonstrate unambiguously the physiological dangers associated with the administration of low levels of unwanted, inadvertent particulates. Compendia throughout the world have expressed a desire to limit particulates administered to the patient without clear evidence as to the hazard. The issue is now one of relative "quality," with limits placed on amounts allowed by the compendia. The enumeration of particles is a direct measure of the success of manufacturing procedures used to prepare, package, and process the parenteral solution. The problem then becomes how to determine particulates present at very low levels with accuracy and precision. Probable Size Distributions in Parenteral Solutions The dominant feature of a very dilute suspension of insoluble particulate matter repeatedly passed through filtration systems is that very few particles at sizes above the nominal pore size of the filters are present and that the numbers of particles increase exponentially as the particle size decreases. This unusual type of distribution has been discussed elsewhere (2, 3, 10-14) but approximates to a power law in that a linear relationship exists between the logarithm of the "size" and the logarithm of the cumulative number of particles per unit volume. Here, clearly, size is determined by the method of analysis used to measure the particles. For



8. G R O V E S

Instrumental Particle Size Analysis Procedures

125

example, by Coulter, size would be the diameter of a sphere of equivalent volume, and by light extinction, it would be the size of a sphere of equivalent cross-sectional area. Although an approximation, this distribution can be tested statistically and provides a means for calculating single numerical parameters as a measure of the particulate levels (22). Although the particulates in any parenteral solution cover a wide spectrum of size, the analyst should only be concerned with particles of sizes between approximately 1 /xm and 100 /xm. Below 1 /xm the physiological significance of the particulates becomes extremely dubious, and the numbers of visible particles (approximately 50 /xm and larger) present in a quality parenteral solution are very low or nonexistent. (Japanese compendial authorities are currently suggesting that entire lots of solutions containing as little as one visible particle in one container should not be used.) Compendia throughout the world measure particulates over a size range of 2-25 /xm by different methodologies. The basic question hinges on the relative merits of the methodologies selected by the various authorities. Concerns about Particulates The first commercially prepared injectable solutions appeared in the early 1890s, and the British Pharmacopoeia of 1898 contained a number of injection monographs. The solutions were not sterilized and were only intended for subcutaneous administration. The United States Pharmacopoeia (USP) introduced injection monographs in 1905. Sterilization of injections was not required until the 1930s, and in 1936, the National Formulary (later merged into the USP) introduced a test for "clarity" based on optical inspection of ampouled products. Over the next decade increasing concern was expressed by the various compendia about the presence of visible particulates. The U S P X I I suggested that injection solutions should be substantially free of visible particulates, but the ambiguity of the term "substantially free" and the difficulty of carrying out any test based on discrimination by human observers were noted from a legal standpoint, and the requirement was abandoned. Although the undesirability of extraneous particulate matter in drug solutions introduced into the veins was recognized much earlier, the situation came to a head with the publications by the Australians Garvan and Gunner in the early 1960s (4-6). This surgeon/anaesthetist team drew attention to physiological and pathological effects produced by particulate debris encountered in locally (Australian) made intravenous fluids. These studies provoked a renewed interest in the field. Coincidentally, problems encountered by a large manufacturer in the United States resulted in deaths due to contaminated intravenous solutions. This situation resulted in the 1966 Symposium organized by the Food and Drug Administration (1). The resulting proceedings of the symposium reads today, with


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modern hindsight, as a curious mixture of science and emotion. It established the undesirability of particulates but failed to establish an unequivocal methodology for particulate quantitation. As a result, a National Coordinating Committee on Large Volume Parenterals was established with representation from industry, regulatory bodies, academia, and compendia. The particulate insult to the patient was considered to be a function of volume of injectable. Ultimately, this group recommended an inspection method based on membrane filtration followed by microscopy. The methodology was essentially an earlier method for determining particulates in hydraulic oils and, in a refined form, is still in the Pharmacopoeia today (USP X X I I , ). Instrumental methods were used elsewhere, however. The Coulter Counter had been used in the U K in 1964 (14) and was the basis of initial studies in Australia (15). The H I A C counter (16) originated from the need for an automatic instrumental method for determining particles in hydraulic oil and was also evaluated in the United States, the United Kingdom, and Australia (17). This instrument is featured in the current (1988) British Pharmacopoeia, together with the Coulter method. In the United States, the H I A C was introduced industrially in the mid-1970s because of problems experienced in measuring an amorphous precipitate that occurred in high concentrations of dextrose solutions and that was otherwise difficult to quantitate by microscopy. The compendial authorities allowed this alteration in test methodology as a special case. The H I A C was then introduced in the U S P X X I (1985) for the small-volume (

Particle Size Distribution II - ACS Publications - American Chemical

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