REVIEW
`
`Particulate Matter in Injectable Drug Products
`
`STEPHEN E. LANGILLE, Ph.D.*
`
`Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration 10903
`New Hampshire Ave, Bldg. 51, Rm. 4158 Silver Spring, MD 20993 ©PDA, Inc. 2013
`
`ABSTRACT: Clinicians have had concerns about particulate matter contamination of injectable drug products since
`the development of the earliest intravenous therapeutics. All parenteral products contain particulate matter, and
`particulate matter contamination still has the potential to cause harm to patients. With tens of millions of doses of
`injectable drug products administered in the United States each year, it is critical to understand the types and sources
`of particulate matter that contaminate injectable drug products, the possible effects of injected particulate matter on
`patients, and the current state of regulations and standards related to particulate matter in injectable drug products.
`Today, the goal of manufacturers, regulators, and standards-setting organizations should be to continue to minimize
`the risk of particle-induced sequelae, especially in high-risk patients, without trading unnecessary manufacturing
`burden for minimal safety gains.
`
`KEYWORDS: Injectable, Parenteral, Particulate matter, Pharmaceutical quality, Current good manufacturing practice
`(cGMP).
`
`LAY ABSTRACT: All injectable drug products are contaminated with some level of solid particulate matter, including,
`for example, fibers, dust, rubber, and silicone. These materials enter drug products primarily during the manufacturing
`process. The possible effects on patients of injectable drug products containing particulate matter depend on a number
`of factors. However, given the large number of patients receiving injectable drug products each year in the United
`States and the potential for particulate matter to cause harm to patients, it is critical to continue to minimize particulate
`matter contamination in injectable drug products. Manufacturing standards and regulations have helped improve
`manufacturing quality. Nevertheless, manufacturers, regulators, and standards-setting organizations must continue to
`work toward improving manufacturing quality and minimizing the risk of harm from particle contamination,
`especially in high-risk patients.
`
`Introduction
`
`One of the basic tenets of pharmaceutical quality is the
`manufacture of drug products that are free of micro-
`bial, chemical, and physical contaminants. Although
`microbial contamination of injectable drug products is
`fairly well understood, defined, and measureable, it
`remains difficult to achieve injectable drug products
`that are free of chemical and particulate matter con-
`
`* Corresponding Author: Stephen E. Langille, Ph.D.,
`Office of Pharmaceutical Science Center for Drug
`Evaluation and Research Food and Drug Administra-
`tion 10903 New Hampshire Ave, Bldg. 51, Rm. 4158
`Silver Spring, MD 20993. Telephone: 301-796-1557,
`e-mail: Stephen.Langille@fda.hhs.gov
`doi: 10.5731/pdajpst.2013.00922
`
`tamination. This is due, in part, to the nature of con-
`taminants, the current state of pharmaceutical manu-
`facturing, and the availability of extremely sensitive
`measuring techniques.
`
`Concerns about the clinical use of injectable drugs
`containing particulate matter can be traced to the
`earliest intravenous fluid therapies employed in the
`1830s. An Edinburgh physician named John Mackin-
`tosh, while developing methods of intravenous saline
`infusions to treat victims of a cholera outbreak, rec-
`ommended that the solutions be strained twice through
`leather rather than cotton or linen, which could allow
`“minute portions of flakey threads” to be injected into
`the patient (1). Although processing and filtration
`technologies for intravenous injections have evolved
`exponentially in the years since, concerns about the
`potential effects of injected particulate matter on pa-
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`tients continue, especially given the equally exponen-
`tial growth in the number of patients who could be
`affected.
`
`According to the American Hospital Association, U.S.
`hospitals admitted 37,479,709 patients in 2009 (2).
`Assuming an average intravenous solution administra-
`tion of 5 L per patient (3), nearly 190 million L of
`intravenous fluid are administered annually. Given
`these data, an accurate assessment is warranted of the
`factors causing particulate matter contamination of
`drug products, the patient risks associated with the
`administration of such contaminated drug products,
`and the current state of regulations and standards that
`provide the framework for achieving pharmaceutical
`quality.
`
`This article describes some of the sources of particu-
`late matter contamination in injectable drugs and the
`possible clinical effects that can result from such
`contamination. The article also reviews the develop-
`ment of standards and regulations to control contam-
`ination of injectable products and offers some prelim-
`inary next steps for manufacturers, regulators, and
`standards-setting organizations who are working to-
`gether to ensure patient safety.
`
`Classification and Sources of Particulate Matter
`
`Chapter ⬍788⬎ of the United States Pharmacopeia
`(USP), Particulate Matter in Injections (4), defines
`particulate matter as “mobile undissolved particles,
`other than gas bubbles, unintentionally present in the
`solutions”. Groves (5) divided injectable drug partic-
`ulate matter into two classes based on the source of the
`particulate matter: intrinsic particles, defined as those
`originally associated with the solution that were either
`not removed by filtration or precipitated out of the
`solution, and extrinsic particles, defined as those that
`enter the container or solution during manufacturing.
`USP Chapter ⬍1788⬎ Methods for the Determination
`of Particulate Matter in Injections and Ophthalmic
`Solutions (6) provides similar, but more specific, def-
`initions, classifying extrinsic particulate matter as “ad-
`ditive, foreign, unchanging, and not part of the formu-
`lation, package or assembly process”. It classifies
`intrinsic particulate matter as “associated with the
`package, formulation and/or assembly process and ca-
`pable of change upon aging”. USP Chapter ⬍1788⬎
`also notes that intrinsic particulate matter is not the
`same as inherent product characteristics such as the
`haze, coloration, or known populations of small par-
`
`ticles common to certain high-concentration protein
`formulations. This inherent particle category also in-
`cludes the normal particle size distribution of active
`pharmaceutical ingredients in suspensions and other
`common delivery forms (e.g., emulsions, lipids, etc.).
`Inherent particles or properties, when consistent and
`expected, may be completely acceptable.
`
`There are five general sources of particulate matter in
`injectable drug products: the environment, packaging
`materials, solution and formulation components, prod-
`uct packaging interactions, and process-generated par-
`ticles. Proper product development and appropriate
`manufacturing and packaging process design can suc-
`cessfully exclude particulate matter sourced from four
`of the five categories. The fifth category, particulate
`matter sourced from the environment, can be excluded
`only by use of highly controlled filling areas, rather
`than by an intimate understanding of the product,
`process, and container closure system. A list of poten-
`tial particle contaminants, their sources, and intrinsic/
`extrinsic natures as defined by USP Chapter ⬍1788⬎
`is presented in Table I.
`
`Note that certain types of particulate matter, includ-
`ing metal and glass, may be either
`intrinsic or
`extrinsic depending on the point at which they enter
`the container. For example, glass particles can enter
`the manufacturing process from the outside (extrin-
`sic, e.g., through the use of broken or poorly washed
`incoming vials) or come from inside the container
`through degradative change during product storage
`or from process-related glass breakage events (in-
`trinsic, e.g., lamellae, tunnel/oven, or during fill-
`ing). Likewise, metal particles can come from the
`containers, the manufacturing environment (extrin-
`sic, e.g., building materials), or the manufacturing
`process (intrinsic, e.g., blending equipment). Even
`particle levels that meet compendial or company
`target limits can be of concern. For example, so-
`called point-source contamination, which is the pre-
`domination of one particle type (7), may indicate
`the presence of process contribution or package
`instability that requires investigation and remedia-
`tion. An overall understanding of the product and
`processes and the establishment of methods that can
`control particulate matter contamination during de-
`velopment, manufacture, and packaging are essen-
`tial to be able to design systems capable of prevent-
`ing particulate matter
`contamination problems
`before they start (8, 9).
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`TABLE I
`Types and Sources of Injectable Particulate Matter
`
`Source
`
`Environment (including
`personnel)
`
`Packaging material
`
`Solution and formulation
`components
`
`Product–package
`interactions
`
`Process-generated
`particulate matter
`
`Particulate Material
`
`Dust
`Fibers
`Biologics—insect parts, microorganisms, pollens
`Fibers of anthropogenic origin
`Hair
`Skin
`Paint/coating chips
`Rust
`Metal (non-product contact types)
`Minerals
`Polymers (unknown source)
`Glass (e.g., carry over from components)
`Extraneous Material (e.g., carry over from
`rubber stopper components)
`Rubber
`Glass
`Polymers
`Silicone
`Precipitates
`Oligomers
`Degradants
`Agglomerates
`Undissolved material
`Glass lamellae
`Silica
`Rubber
`Plastic
`Metal (e.g., stainless steel from processing
`equipment)
`Filter and Consumables fibers
`Glass (from breakage events)
`
`Intrinsic/Extrinsic
`
`Extrinsic
`
`Intrinsic
`
`Intrinsic
`
`Intrinsic
`
`Intrinsic
`
`Clinical Effects of Injected Particulate Matter
`
`Route of Administration
`
`Many clinical effects have been documented in sub-
`jects who have received injections containing partic-
`ulate matter contamination. Examples include phlebi-
`tis (3, 10 –13), pulmonary emboli (14 –16), pulmonary
`granulomas (3, 11, 17), immune system dysfunction
`(3, 18), pulmonary dysfunction (13, 15), infarction
`(15, 19), and death (14, 20 –22). The patient risk
`associated with the injection of drugs containing par-
`ticulate matter depends on a number of factors, includ-
`ing the route of administration used, the particle size
`and shape, the number of particles injected, the parti-
`cle composition, and the patient population.
`
`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 re-
`ceived little attention with regard to their potential for
`causing adverse events due to the fact that the deliv-
`ered volumes (and the overall particle load) are rela-
`tively 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
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`injections make possible the delivery of greater vol-
`umes of fluids and the broader dissemination and
`deposition of particulate matter throughout the body.
`
`administration should be considered during product
`development when assessing the critical quality attri-
`butes for a given product (26).
`
`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 diam-
`eter 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 occlu-
`sions that could affect blood flow to tissues down-
`stream 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 in-
`farctions—may be more detrimental than larger parti-
`cles capable of arteriole occlusion due to the reduced
`collateral blood supply available to the affected tissue
`(24). The inadvertent intravascular injection of corti-
`costeroid formulations containing particles has been
`linked to adverse central nervous system sequelae in
`humans not observed with non-particulate steroid for-
`mulations (24). A study involving pigs injected in the
`vertebral artery with particulate- or non-particulate-
`based steroids yielded similar results, with pigs receiv-
`ing 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
`
`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 radiola-
`beled 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 micro-
`spheres 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 par-
`ticles clearing first (27). Rabbits injected with 5 um
`diethylaminoethyl (DEAE) cellulose fibers demon-
`strated deposition primarily in the lungs, but also in
`the liver and kidneys (16). Rabbits injected intrave-
`nously 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 con-
`trolled 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 re-
`ports and autopsy results are the only sources of
`information about the effects of larger particles on
`patient populations. Visible particulate matter com-
`posed 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 follow-
`ing intravenous administration of total nutrient admix-
`tures containing FreAmine III as an amino acid source
`(14, 20). Analysis of the precipitate isolated from the
`admixtures administered to each patient revealed the
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`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 solu-
`tions to neonates resulted in eight adverse event re-
`ports and seven deaths. One patient experienced car-
`diopulmonary 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 re-
`vealed 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 cal-
`cium 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 cathe-
`ter was removed on day 4, but the patient soon devel-
`oped 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 signif-
`icant 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 ob-
`tained from intravenous line filters obtained from pe-
`diatric 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 par-
`ticulate matter during drug product infusion (32–36).
`Nevertheless, a review of clinical case reports involv-
`ing 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 extempora-
`neously prepared, multi-component
`intravenous ad-
`mixtures 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 for-
`mation 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 con-
`cern 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 re-
`spiratory distress syndrome (34). Studies have also
`suggested that glass particle–induced sequelae may
`require considerable time to develop and, as a conse-
`quence, 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
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`in drug product formulation (43). Lead and chromium
`are considered among the most dangerous metal con-
`taminants, but serious adverse events related to alu-
`minum 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 reg-
`ulations regarding the aluminum content of drug prod-
`ucts 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). Re-
`cent drug product recalls due to the presence of stain-
`less 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 par-
`ticulate matter poses a unique risk to the patient be-
`cause of the unintended host immune responses it may
`elicit (49). Host responses resulting in antibody-me-
`diated neutralization of the protein’s active site or the
`production of drug-induced antibodies to the therapeu-
`tic 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 asso-
`ciated with immune response elicitation are not well
`understood (50, 51), it is believed that protein aggre-
`gation and the formation of repetitive arrays of anti-
`gens are contributing factors in the elicitation of an
`immune response (49).
`
`The causative factors of protein aggregation are also
`poorly understood. However, the complex manufac-
`turing 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 partic-
`ulate 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 un-
`der 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 sub-
`visible protein particles in the 0.1 to 10 um size range
`should be considered during biologic product devel-
`opment 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 ␮m), 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 emul-
`sified oil droplet. As with hard particles, soft particles
`may also produce embolic phenomena upon intravascu-
`lar 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 in-
`creases 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 malle-
`ability 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 neo-
`nates (3, 15, 18, 31, 38, 55). Two recent animal studies
`investigated the effects of injected particles in the pres-
`ence 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 net-
`works 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 dam-
`aging 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 man-
`ufacturers of cefotaxime. Although the capillary perfu-
`sion of healthy muscle was not affected by the intrave-
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`nous injection of the concentrated antibiotic particles,
`post-ischemic muscle tissue demonstrated reduced cap-
`illary perfusion following intravenous treatment with the
`concentrated particle solutions. Histological sections re-
`vealed that particulate matter caused mechanical disrup-
`tion 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 in-
`travenous solutions have been linked to adult respira-
`tory distress syndrome (34), systemic inflammatory
`response syndrome (SIRS) (57), and immune system
`dysfunction (3). Walpot et al. (34) used energy-dis-
`persive x-ray analysis to show that critical care pa-
`tients may be more susceptible to particulate matter
`deposition in pulmonary tissue than healthy subjects.
`Additional studies have suggested that in-line filtra-
`tion may benefit critically ill infants by offering pro-
`tection against SIRS and other glass particle–induced
`adverse events (38, 57).
`
`The potential effect of heavy particle loads on neo-
`nates 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. Al-
`though 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 rela-
`tive to the effects seen in adult patients.
`
`Relevant Regulations and Standards
`
`Over the years, a number of statutes and regulations have
`been enacted and implemented intended to control par-
`ticulate matter contamination of injectable drug products.
`Nevertheless, federal regulations pertaining to current
`good manufacturing practice (cGMP) do not specifically
`address the subject of particulate matter, but do contain
`several passages applicable to particulate matter contam-
`ination. With regard to the effect
`that
`the container
`closure system might have on particulate matter in a
`
`product, regulations at 21 CFR 211.94(a) state that “drug
`product containers and closures shall not be reactive,
`additive or absorptive so as to alter the safety, identity,
`strength, quality, or purity of the drug beyond the official
`or established requirements”. Regulations at 21 CFR
`211.165(a) and (f) state that “for each batch of drug
`product there shall be appropriate laboratory determina-
`tion of satisfactory conformance to final specifications
`for the drug product” and “drug products failing to meet
`established standards or specifications . . . shall be re-
`jected”. These regulations apply to the visible and sub-
`visible particulate matter specifications cited in drug
`product applications (see Table II).
`
`Section 501 of the Federal Food, Drug, and Cosmetic
`Act (FD&C Act) states that a drug or device will be
`considered adulterated (1) “if it has been prepared,
`packed, or held under insanitary conditions whereby it
`may have been contaminated with filth, or whereby it
`may have been rendered injurious to health”; (2)
`“if . . . the facilities or controls used for its manufac-
`ture, processing, packaging, or holding do not conform
`or are not operated or administered in conformity with
`current good manufacturing practice to assure that the
`drug . . . meets the quality and purity characteristics,
`which it purports or is represented to possess”; or (3)
`“if it purports to be or is represented as a drug the
`name of which is recognized in an official compen-
`dium, and its strength differs from, or its quality or
`purity falls below,
`the standards set forth in such
`compendium”. Although a manufacturer’s level of
`compliance with Section 501 of the FD&C Act may be
`subject to interpretation, the emphasis on cGMP and
`compendial standards is clear.
`
`The first compendial standard for visible particles in
`drugs for use in the United States came in 1936 when
`the National Formulary VI stated that injectable so-
`lutions were to be “substantially free from precipitate,
`cloudiness or turbidity, specs or flecks, fibers or cotton
`hairs, or any undissolved material” (58). In 1942, the
`USP and the American Pharmaceutical Association
`(publisher of the National Formulary at
`that
`time)
`stated that aqueous injections should be “substantially
`free” of particles discernable with the naked eye. This
`definition eventually evolved into those currently used
`by the three major pharmacopeia stating that injectable
`drug products should be “essentially free” (USP),
`“practically free” (European Pharmacopeia) or free of
`“readily detectable” (Japanese Pharmacopeia) visible
`particles (58).
`
`192
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Eton Ex. 1108
`7 of 15
`
`

`

`matter”
`particulate
`visible
`changein
`
`Criteria—“Clear”
`2.9.20Acceptance
`
`container
`
`“Nosignificant
`
`EuropeanPharmacopeia.
`
`2.3⫾2.3
`
`153⫾33.8
`
`⬍788⬎
`
`6000/600per
`
`N/A
`
`Nospecification
`
`6.8⫾11.7
`
`423⫾157.9
`
`⬍788⬎
`
`provided
`
`visible.”
`particleswhichare
`containoneormore
`Solutionmustnot
`
`“Pass”
`
`“Complies”
`
`“Solutionmustbeclear.
`Particles”USP⬍1⬎
`
`“FreeofVisible
`
`1⫾1.4
`
`0⫾0
`
`121.5⫾92.6
`
`133.3⫾57.7
`
`provided
`
`N/A
`
`N/A
`
`Nospecification
`
`11