Particulate Matter in Injectable Drug Products

Route of Administration

The route of pharmaceutical product administration can influence the deposition of the injected particles, the total particle load administered to the patient, and the overall risk to the patient. Immunologically inert particles, such as glass or cellulosic fibers, delivered via intramuscular and subcutaneous routes have received little attention with regard to their potential for causing adverse events due to the fact that the delivered volumes (and the overall particle load) are relatively small, the risk of a systemic reaction is low, and the ability of these particles to migrate far from the injection site is negligible (23). However, vascular injections make possible the delivery of greater volumes of fluids and the broader dissemination and deposition of particulate matter throughout the body.

Because the size of veins increases in the direction of blood flow, most particles injected intravenously will travel through the venous system to the heart on their way to the lungs via the pulmonary artery. The diameter of capillaries is approximately 6–8 um. As a result, most particles larger than 6–8 um will remain in the pulmonary capillaries, with smaller particles passing through the lungs and depositing in organs such as the liver and spleen, where they are processed by phagocytic cells of the reticuloendothelial system (16). Phagocytic overload of the reticuloendothelial system by large numbers of particles has the potential to block the system and lead to secondary infections in a debilitated host (3). There is little information in the literature regarding the ability of the immune system to clear relatively large (>10 um) inorganic particles (e.g., rubber, glass, and metal) lodged in organs such as the lung or what effect, if any, the accumulation of such particles in vital organs may have over time.

Because arteries decrease in size with the direction of blood flow, the inadvertent administration of intra-arterially injected particles that are too large to pass through arterioles and capillaries may cause occlusions that could affect blood flow to tissues downstream of the injection site. The physiological effects of any such occlusion will depend upon the size of the particle and the collateral circulation available to the affected area (23). Ironically, smaller particles capable of blocking terminal arterial vessels—and causing infarctions—may be more detrimental than larger particles capable of arteriole occlusion due to the reduced collateral blood supply available to the affected tissue (24). The inadvertent intravascular injection of corticosteroid formulations containing particles has been linked to adverse central nervous system sequelae in humans not observed with non-particulate steroid formulations (24). A study involving pigs injected in the vertebral artery with particulate- or non-particulate-based steroids yielded similar results, with pigs receiving the particulate-containing steroids displaying brain stem edema and significant tissue damage (25).

Other routes of administration, such as the intrathecal, epidural, intraocular, and intracranial routes, may carry different risks due to the direct delivery of the particulate matter to specific areas of the body. The risks of particulate matter delivered via these routes of administration should be considered during product development when assessing the critical quality attributes for a given product (26).

Size and Shape

The size and shape of an injected particle can affect both its deposition within the body and its clinical effects on the subject. Rabbits injected with radiolabeled polystyrene particles of different sizes showed rapid deposition of 15.8 um particles in the lungs while 1.27 um particles were deposited mainly in the liver (16). Similar results were obtained when dogs were injected intravenously with radiolabeled microspheres of 3, 5, 7, and 12 um in diameter. The 7 and 12 um particles were deposited primarily in the lungs, while the 3 and 5 um particles migrated mainly to the spleen and liver. As expected, clearance from the bloodstream was size-dependent, with the larger particles clearing first (27). Rabbits injected with 5 um diethylaminoethyl (DEAE) cellulose fibers demonstrated deposition primarily in the lungs, but also in the liver and kidneys (16). Rabbits injected intravenously with 30 um DEAE cellulose fibers died within 4 minutes of administration due to an acute toxic response (tachycardia, dyspnoea, dystaxia) caused by pulmonary emboli (16). In contrast, 40 to 60 um DEAE cellulose microspheres, although entrapped by the lung, caused no adverse reactions and each of the rabbits injected survived until the completion of the study (16). These studies suggest that the shape of a particle may be just as important as its size when determining its potential for harm. Certainly the total particle load must be considered as well.

Due to the obvious challenges associated with controlled clinical studies to investigate the effects of injected particles in humans, little is known about the risk to diverse patient populations posed by particles of various sizes, shapes, and composition injected via different routes of administration. Adverse event reports and autopsy results are the only sources of information about the effects of larger particles on patient populations. Visible particulate matter composed of calcium salt precipitates in drug admixtures has caused a number of serious clinical events (21). In 1994, two young female patients undergoing treatment for pelvic infections died of pulmonary emboli following intravenous administration of total nutrient admixtures containing FreAmine III as an amino acid source (14, 20). Analysis of the precipitate isolated from the admixtures administered to each patient revealed the presence of calcium and phosphorous salts matching those found in the pulmonary microvasculature of the autopsy specimens. Co-administration of the antibiotic ceftriaxone and calcium-containing intravenous solutions to neonates resulted in eight adverse event reports and seven deaths. One patient experienced cardiopulmonary arrest after a white precipitate in the patient's intravenous tubing was pushed into the infant in an effort to clear the tubing (28). Pulmonary emboli were reported in multiple cases, and autopsies revealed the presence of white crystalline precipitates in the lungs, heart, kidney, and liver (21, 28). Both the ceftriaxone and FreAmine III incidents resulted in the issuance of U.S. Food and Drug Administration (FDA) drug safety warnings regarding the potential for calcium precipitation in these drug products (28, 29). Cant et al. (22) reported the case of a premature neonate who was treated with an umbilical artery catheter shortly after birth. Injections were made into the catheter using polypropylene syringes. The catheter was removed on day 4, but the patient soon developed abdominal distension and died at 52 days of age. An autopsy revealed acute infarction of the small bowel and the presence of polypropylene fragments of 50 to 200 um in size. Although this may be the only documented case of a fatality resulting from injection of material derived from a pharmaceutical container closure system, the case underscores the vulnerability of neonates to sequelae resulting from the infusion of particles and suggests that the intra-arterial route of administration may carry additional risks.

Number

Estimates are that patients in intensive care receive more than a million injected particles >2 microns in size daily (18, 30, 31). One method for controlling the particle load administered to critically ill patients has been through the use of final filters. A controlled clinical study of 88 infants receiving either filtered or unfiltered infusions via a central line revealed significant reductions in the incidence of complications such as thrombi and necrotizing enterocolitis (32). Studies on adult patients using 0.22 and 0.45 um intravenous in-line filters seem to indicate that the use of in-line filters reduced the incidence and time of onset of particle-induced phlebitis (3). In vitro studies also showed that human macrophages and epithelial cells displayed decreased cytokine production following exposure to silicone particles mimicking those obtained from intravenous line filters obtained from pediatric intensive care units (18). However, the use of final filters may present other problems, such as the possibility of drug product reaction with or absorption by the filter material or impaired fluid flow through the filter. Opinions vary regarding the economic benefit of in-line filtration to remove microorganisms and particulate matter during drug product infusion (32⇓⇓⇓–36). Nevertheless, a review of clinical case reports involving calcium phosphate precipitation in intravenous admixtures revealed that the use of in-line filtration made the difference between non-fatal and fatal cases (37). Thus, the use of in-line filtration for extemporaneously prepared, multi-component intravenous admixtures may be prudent.

Composition

Barber (23) provides an excellent review of several pre-1980 animal studies involving different types of particulate matter (filter paper, glass, rubber, hair, polystyrene, plastic, and insoluble drug residues) in various animal models (rabbits, dogs, rats, mice, guinea pigs, and hedgehogs). The clinical effects seen in these studies range from relatively minor tissue damage associated with the administration of silicone and polystyrene particles to rabbits and dogs, to more serious reactions such as local inflammation, the formation of pulmonary granulomas, and death in rabbits, dogs, and rats injected with plastics, ground filter paper, or large numbers of polystyrene particles >40 um in size.

One of the most common contaminants of injectable drug products is glass derived from the manufacturing process, reaction of the drug with the container closure system, or that produced by opening glass ampoules (36, 38, 39, 40). Recent glass delamination issues involving multiple drug products have increased concern about the risk posed by glass particles and interest in developing methods to control the formation of glass lamellae over the product shelf life (40, 41). Sequelae attributed directly to glass particles include phlebitis (3), pulmonary granulomas (31), systemic inflammatory response syndrome (18), and adult respiratory distress syndrome (34). Studies have also suggested that glass particle–induced sequelae may require considerable time to develop and, as a consequence, may often be overlooked (38, 39, 42).

Another common pharmaceutical contaminant is metal particles (43, 44). Although the most common source of metal particles is processing equipment, they have also been found to contaminate the raw materials used in drug product formulation (43). Lead and chromium are considered among the most dangerous metal contaminants, but serious adverse events related to aluminum ingestion have also been well documented (43⇓⇓–46). Aluminum toxicity in premature infants has been linked to total parenteral nutrition admixtures (45, 46) and contributed to the issuance of FDA regulations regarding the aluminum content of drug products used for total parenteral nutrition (47). By far, the most common and expected type of metal particles found in liquid injectables is stainless steel (44). Recent drug product recalls due to the presence of stainless steel particles in lipid emulsions requiring high sheer force manufacturing processes have necessitated the development of modified manufacturing processes and visual inspection methods to detect potentially harmful levels of metallic particles (48).

In the class of inherent particles, proteinaceous particulate matter poses a unique risk to the patient because of the unintended host immune responses it may elicit (49). Host responses resulting in antibody-mediated neutralization of the protein's active site or the production of drug-induced antibodies to the therapeutic version of an endogenous protein have the potential to cause catastrophic cross-reaction and neutralization of the endogenous protein (49, 50). Although the precise characteristics of proteinaceous particles associated with immune response elicitation are not well understood (50, 51), it is believed that protein aggregation and the formation of repetitive arrays of antigens are contributing factors in the elicitation of an immune response (49).

The causative factors of protein aggregation are also poorly understood. However, the complex manufacturing and purification methods used in the processing and handling of therapeutic proteins can influence a number of different product characteristics, including particle size (49, 50, 52). One potential cause of protein aggregation is the presence of extrinsic particulate matter that may serve as nucleation sites for the formation of larger particles (52). The overall net charge of the protein solution has also been shown to influence the degree of protein aggregation and the type of protein aggregates formed in a given solution. Studies have shown that solubilized proteins held under conditions near their isoelectric point may be prone to aggregation into spherical particles due to exposure of hydrophobic residues to the solvent caused by the solution's low net charge (52, 53). Alternatively, proteins held under conditions of high net charge tend to organize into amyloid fibrils due to electrostatic repulsion and slow aggregation (53). The potential for aggregation and the monitoring of subvisible protein particles in the 0.1 to 10 um size range should be considered during biologic product development and surveillance programs (49).

Finally, it is important to distinguish between hard and soft particles. A hard particle is a rigid structure that often has a non-spherical, irregular shape. Such particles are inflexible and, if large enough (>5 μm), are more likely to produce mechanical obstruction and vascular emboli. All of the particles described above would be considered hard particles capable of inducing embolic phenomena upon intravascular (i.e., intravenous, arterial) infusion. In contrast, a soft particle is a flexible, or deformable, structure that is spherical, such as an emulsified oil droplet. As with hard particles, soft particles may also produce embolic phenomena upon intravascular infusion, but due to their deformable characteristics, the embolism is incomplete, that is, when large hard particles flow towards a vessel with a smaller diameter, the occlusion cannot be overcome by compensatory increases in venous and/or arterial pressures. When the same-sized soft particles flow towards the same small vessel, the occlusion can be overcome due to the malleability of the lipid droplet. As the occlusion clears, however, the large-diameter droplets can accumulate in downstream vital organs, such as the liver, producing a systemic inflammatory response (54, 55).

Patient Population

The patient populations that may be most at risk for particulate matter–related sequelae include patients with existing tissue damage, critically ill patients, and neonates (3, 15, 18, 31, 38, 55). Two recent animal studies investigated the effects of injected particles in the presence of pre-existing tissue damage. Schaefer et al. (15) demonstrated that the injection of particles from two generic antibiotics containing particulate matter levels 4 to 50 times higher than those found in the innovator drug resulted in a nearly 50% loss of damaged capillary networks in the ischemic muscle tissue of hamsters as compared to muscle treated with the innovator drug product. Passing the generic formulations through a 0.2 um filter prior to administration eliminated the damaging effect of the generic antibiotics (15). Lehr et al. (56) conducted a similar study comparing the clinical effects of particles from the innovator and generic manufacturers of cefotaxime. Although the capillary perfusion of healthy muscle was not affected by the intravenous injection of the concentrated antibiotic particles, post-ischemic muscle tissue demonstrated reduced capillary perfusion following intravenous treatment with the concentrated particle solutions. Histological sections revealed that particulate matter caused mechanical disruption of the circulation to striated muscle. These findings suggest that injected particles could be more detrimental to patents with existing tissue damage, such as in the case of trauma, surgery, or sepsis (13).

The heavy particle loads incurred by critical care patients due to the sheer volume of administered intravenous solutions have been linked to adult respiratory distress syndrome (34), systemic inflammatory response syndrome (SIRS) (57), and immune system dysfunction (3). Walpot et al. (34) used energy-dispersive x-ray analysis to show that critical care patients may be more susceptible to particulate matter deposition in pulmonary tissue than healthy subjects. Additional studies have suggested that in-line filtration may benefit critically ill infants by offering protection against SIRS and other glass particle–induced adverse events (38, 57).

The potential effect of heavy particle loads on neonates was also reported by Puntis et al. (31), who compared the necropsy results of 32 infants who died of sudden infant death syndrome with those of 41 infants who died following total parenteral nutrition therapy. Two of the 41 parenterally fed patients showed widespread pulmonary granulomas containing material such as glass fragments and cotton fibers. No such granulomas were identified in the patients who expired due to sudden infant death syndrome. Although the capillary diameter of neonates is the same as those of adults, the overall number of blood vessels and the diameter of the major blood vessels are smaller in children as compared to adults, a factor that could accentuate the effects of injected particles relative to the effects seen in adult patients.