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10.5731/pdajpst.2013.00922Access the most recent version at doi: 186-20067, 2013 PDA J Pharm Sci and Tech

Stephen E. Langille Particulate Matter in Injectable Drug Products

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REVIEW

Particulate Matter in Injectable Drug ProductsSTEPHEN E. LANGILLE, Ph.D.*

Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration 10903New 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 sincethe development of the earliest intravenous therapeutics. All parenteral products contain particulate matter, andparticulate matter contamination still has the potential to cause harm to patients. With tens of millions of doses ofinjectable drug products administered in the United States each year, it is critical to understand the types and sourcesof particulate matter that contaminate injectable drug products, the possible effects of injected particulate matter onpatients, 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 minimizethe risk of particle-induced sequelae, especially in high-risk patients, without trading unnecessary manufacturingburden 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 manufacturingprocess. The possible effects on patients of injectable drug products containing particulate matter depend on a numberof factors. However, given the large number of patients receiving injectable drug products each year in the UnitedStates and the potential for particulate matter to cause harm to patients, it is critical to continue to minimize particulatematter contamination in injectable drug products. Manufacturing standards and regulations have helped improvemanufacturing quality. Nevertheless, manufacturers, regulators, and standards-setting organizations must continue towork 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 themanufacture of drug products that are free of micro-bial, chemical, and physical contaminants. Althoughmicrobial contamination of injectable drug products isfairly well understood, defined, and measureable, itremains difficult to achieve injectable drug productsthat are free of chemical and particulate matter con-

tamination. This is due, in part, to the nature of con-taminants, the current state of pharmaceutical manu-facturing, and the availability of extremely sensitivemeasuring techniques.

Concerns about the clinical use of injectable drugscontaining particulate matter can be traced to theearliest intravenous fluid therapies employed in the1830s. An Edinburgh physician named John Mackin-tosh, while developing methods of intravenous salineinfusions to treat victims of a cholera outbreak, rec-ommended that the solutions be strained twice throughleather rather than cotton or linen, which could allow“minute portions of flakey threads” to be injected intothe patient (1). Although processing and filtrationtechnologies for intravenous injections have evolvedexponentially in the years since, concerns about thepotential effects of injected particulate matter on pa-

* Corresponding Author: Stephen E. Langille, Ph.D.,Office of Pharmaceutical Science Center for DrugEvaluation and Research Food and Drug Administra-tion 10903 New Hampshire Ave, Bldg. 51, Rm. 4158Silver Spring, MD 20993. Telephone: 301-796-1557,e-mail: [email protected]

doi: 10.5731/pdajpst.2013.00922

186 PDA Journal of Pharmaceutical Science and Technology

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tients continue, especially given the equally exponen-tial growth in the number of patients who could beaffected.

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 ofintravenous fluid are administered annually. Giventhese data, an accurate assessment is warranted of thefactors causing particulate matter contamination ofdrug products, the patient risks associated with theadministration of such contaminated drug products,and the current state of regulations and standards thatprovide the framework for achieving pharmaceuticalquality.

This article describes some of the sources of particu-late matter contamination in injectable drugs and thepossible clinical effects that can result from suchcontamination. 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, andstandards-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), definesparticulate matter as “mobile undissolved particles,other than gas bubbles, unintentionally present in thesolutions”. Groves (5) divided injectable drug partic-ulate matter into two classes based on the source of theparticulate matter: intrinsic particles, defined as thoseoriginally associated with the solution that were eithernot removed by filtration or precipitated out of thesolution, and extrinsic particles, defined as those thatenter the container or solution during manufacturing.USP Chapter �1788� Methods for the Determinationof Particulate Matter in Injections and OphthalmicSolutions (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 classifiesintrinsic particulate matter as “associated with thepackage, formulation and/or assembly process and ca-pable of change upon aging”. USP Chapter �1788�also notes that intrinsic particulate matter is not thesame as inherent product characteristics such as thehaze, coloration, or known populations of small par-

ticles common to certain high-concentration proteinformulations. This inherent particle category also in-cludes the normal particle size distribution of activepharmaceutical ingredients in suspensions and othercommon delivery forms (e.g., emulsions, lipids, etc.).Inherent particles or properties, when consistent andexpected, may be completely acceptable.

There are five general sources of particulate matter ininjectable drug products: the environment, packagingmaterials, solution and formulation components, prod-uct packaging interactions, and process-generated par-ticles. Proper product development and appropriatemanufacturing and packaging process design can suc-cessfully exclude particulate matter sourced from fourof the five categories. The fifth category, particulatematter sourced from the environment, can be excludedonly by use of highly controlled filling areas, ratherthan 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 orextrinsic depending on the point at which they enterthe container. For example, glass particles can enterthe manufacturing process from the outside (extrin-sic, e.g., through the use of broken or poorly washedincoming vials) or come from inside the containerthrough degradative change during product storageor from process-related glass breakage events (in-trinsic, e.g., lamellae, tunnel/oven, or during fill-ing). Likewise, metal particles can come from thecontainers, the manufacturing environment (extrin-sic, e.g., building materials), or the manufacturingprocess (intrinsic, e.g., blending equipment). Evenparticle levels that meet compendial or companytarget limits can be of concern. For example, so-called point-source contamination, which is the pre-domination of one particle type (7), may indicatethe presence of process contribution or packageinstability that requires investigation and remedia-tion. An overall understanding of the product andprocesses and the establishment of methods that cancontrol 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 problemsbefore they start (8, 9).

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Clinical Effects of Injected Particulate Matter

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), pulmonarygranulomas (3, 11, 17), immune system dysfunction(3, 18), pulmonary dysfunction (13, 15), infarction(15, 19), and death (14, 20 –22). The patient riskassociated with the injection of drugs containing par-ticulate matter depends on a number of factors, includ-ing the route of administration used, the particle sizeand shape, the number of particles injected, the parti-cle composition, and the patient population.

Route of Administration

The route of pharmaceutical product administrationcan influence the deposition of the injected particles,the total particle load administered to the patient, andthe overall risk to the patient. Immunologically inertparticles, such as glass or cellulosic fibers, deliveredvia intramuscular and subcutaneous routes have re-ceived little attention with regard to their potential forcausing 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, andthe ability of these particles to migrate far from theinjection site is negligible (23). However, vascular

TABLE ITypes and Sources of Injectable Particulate Matter

Source Particulate Material Intrinsic/Extrinsic

Environment (includingpersonnel)

DustFibersBiologics—insect parts, microorganisms, pollensFibers of anthropogenic originHairSkinPaint/coating chipsRustMetal (non-product contact types)MineralsPolymers (unknown source)Glass (e.g., carry over from components)Extraneous Material (e.g., carry over from

rubber stopper components)

Extrinsic

Packaging material RubberGlassPolymersSilicone

Intrinsic

Solution and formulationcomponents

PrecipitatesOligomersDegradantsAgglomeratesUndissolved material

Intrinsic

Product–packageinteractions

Glass lamellaeSilicaRubberPlastic

Intrinsic

Process-generatedparticulate matter

Metal (e.g., stainless steel from processingequipment)

Filter and Consumables fibersGlass (from breakage events)

Intrinsic




injections make possible the delivery of greater vol-umes of fluids and the broader dissemination anddeposition of particulate matter throughout the body.

Because the size of veins increases in the direction ofblood flow, most particles injected intravenously willtravel through the venous system to the heart on theirway to the lungs via the pulmonary artery. The diam-eter of capillaries is approximately 6 – 8 um. As aresult, most particles larger than 6 – 8 um will remainin the pulmonary capillaries, with smaller particlespassing through the lungs and depositing in organssuch as the liver and spleen, where they are processedby phagocytic cells of the reticuloendothelial system(16). Phagocytic overload of the reticuloendothelialsystem by large numbers of particles has the potentialto block the system and lead to secondary infections ina debilitated host (3). There is little information in theliterature regarding the ability of the immune systemto clear relatively large (�10 um) inorganic particles(e.g., rubber, glass, and metal) lodged in organs suchas the lung or what effect, if any, the accumulation ofsuch particles in vital organs may have over time.

Because arteries decrease in size with the direction ofblood flow, the inadvertent administration of intra-arterially injected particles that are too large to passthrough arterioles and capillaries may cause occlu-sions that could affect blood flow to tissues down-stream of the injection site. The physiological effectsof any such occlusion will depend upon the size of theparticle and the collateral circulation available to theaffected area (23). Ironically, smaller particles capableof blocking terminal arterial vessels—and causing in-farctions—may be more detrimental than larger parti-cles capable of arteriole occlusion due to the reducedcollateral blood supply available to the affected tissue(24). The inadvertent intravascular injection of corti-costeroid formulations containing particles has beenlinked to adverse central nervous system sequelae inhumans not observed with non-particulate steroid for-mulations (24). A study involving pigs injected in thevertebral artery with particulate- or non-particulate-based steroids yielded similar results, with pigs receiv-ing the particulate-containing steroids displaying brainstem edema and significant tissue damage (25).

Other routes of administration, such as the intrathecal,epidural, intraocular, and intracranial routes, maycarry different risks due to the direct delivery of theparticulate matter to specific areas of the body. Therisks of particulate matter delivered via these routes of

administration should be considered during productdevelopment when assessing the critical quality attri-butes for a given product (26).

Size and Shape

The size and shape of an injected particle can affectboth its deposition within the body and its clinicaleffects on the subject. Rabbits injected with radiola-beled polystyrene particles of different sizes showedrapid deposition of 15.8 um particles in the lungswhile 1.27 um particles were deposited mainly in theliver (16). Similar results were obtained when dogswere injected intravenously with radiolabeled micro-spheres of 3, 5, 7, and 12 um in diameter. The 7 and12 um particles were deposited primarily in the lungs,while the 3 and 5 um particles migrated mainly to thespleen and liver. As expected, clearance from thebloodstream was size-dependent, with the larger par-ticles clearing first (27). Rabbits injected with 5 umdiethylaminoethyl (DEAE) cellulose fibers demon-strated deposition primarily in the lungs, but also inthe liver and kidneys (16). Rabbits injected intrave-nously with 30 um DEAE cellulose fibers died within4 minutes of administration due to an acute toxicresponse (tachycardia, dyspnoea, dystaxia) caused bypulmonary emboli (16). In contrast, 40 to 60 umDEAE cellulose microspheres, although entrapped bythe lung, caused no adverse reactions and each of therabbits injected survived until the completion of thestudy (16). These studies suggest that the shape of aparticle may be just as important as its size whendetermining its potential for harm. Certainly the totalparticle load must be considered as well.

Due to the obvious challenges associated with con-trolled clinical studies to investigate the effects ofinjected particles in humans, little is known about therisk to diverse patient populations posed by particlesof various sizes, shapes, and composition injected viadifferent routes of administration. Adverse event re-ports and autopsy results are the only sources ofinformation about the effects of larger particles onpatient populations. Visible particulate matter com-posed of calcium salt precipitates in drug admixtureshas caused a number of serious clinical events (21). In1994, two young female patients undergoing treatmentfor 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 theadmixtures administered to each patient revealed the

189Vol. 67, No. 3, May–June 2013



presence of calcium and phosphorous salts matchingthose found in the pulmonary microvasculature of theautopsy specimens. Co-administration of the antibioticceftriaxone 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 thepatient’s intravenous tubing was pushed into the infantin an effort to clear the tubing (28). Pulmonary emboliwere reported in multiple cases, and autopsies re-vealed the presence of white crystalline precipitates inthe lungs, heart, kidney, and liver (21, 28). Both theceftriaxone and FreAmine III incidents resulted in theissuance 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 prematureneonate who was treated with an umbilical arterycatheter shortly after birth. Injections were made intothe 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 smallbowel and the presence of polypropylene fragments of50 to 200 um in size. Although this may be the onlydocumented case of a fatality resulting from injectionof material derived from a pharmaceutical containerclosure system, the case underscores the vulnerabilityof neonates to sequelae resulting from the infusion ofparticles and suggests that the intra-arterial route ofadministration may carry additional risks.

Number

Estimates are that patients in intensive care receivemore than a million injected particles �2 microns insize daily (18, 30, 31). One method for controlling theparticle load administered to critically ill patients hasbeen through the use of final filters. A controlledclinical study of 88 infants receiving either filtered orunfiltered infusions via a central line revealed signif-icant reductions in the incidence of complications suchas thrombi and necrotizing enterocolitis (32). Studieson adult patients using 0.22 and 0.45 um intravenousin-line filters seem to indicate that the use of in-linefilters reduced the incidence and time of onset ofparticle-induced phlebitis (3). In vitro studies alsoshowed that human macrophages and epithelial cellsdisplayed decreased cytokine production followingexposure 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 thepossibility of drug product reaction with or absorptionby the filter material or impaired fluid flow through thefilter. Opinions vary regarding the economic benefit ofin-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 intravenousadmixtures revealed that the use of in-line filtrationmade 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 severalpre-1980 animal studies involving different types ofparticulate matter (filter paper, glass, rubber, hair,polystyrene, plastic, and insoluble drug residues) invarious animal models (rabbits, dogs, rats, mice,guinea pigs, and hedgehogs). The clinical effects seenin these studies range from relatively minor tissuedamage associated with the administration of siliconeand polystyrene particles to rabbits and dogs, to moreserious reactions such as local inflammation, the for-mation of pulmonary granulomas, and death in rabbits,dogs, and rats injected with plastics, ground filterpaper, or large numbers of polystyrene particles �40um in size.

One of the most common contaminants of injectabledrug products is glass derived from the manufacturingprocess, reaction of the drug with the container closuresystem, or that produced by opening glass ampoules(36, 38, 39, 40). Recent glass delamination issuesinvolving multiple drug products have increased con-cern about the risk posed by glass particles and interestin developing methods to control the formation ofglass lamellae over the product shelf life (40, 41).Sequelae attributed directly to glass particles includephlebitis (3), pulmonary granulomas (31), systemicinflammatory response syndrome (18), and adult re-spiratory distress syndrome (34). Studies have alsosuggested that glass particle–induced sequelae mayrequire considerable time to develop and, as a conse-quence, may often be overlooked (38, 39, 42).

Another common pharmaceutical contaminant is metalparticles (43, 44). Although the most common sourceof metal particles is processing equipment, they havealso been found to contaminate the raw materials used




in drug product formulation (43). Lead and chromiumare 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 hasbeen 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, themost common and expected type of metal particlesfound 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 highsheer force manufacturing processes have necessitatedthe development of modified manufacturing processesand visual inspection methods to detect potentiallyharmful 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 mayelicit (49). Host responses resulting in antibody-me-diated neutralization of the protein’s active site or theproduction of drug-induced antibodies to the therapeu-tic version of an endogenous protein have the potentialto cause catastrophic cross-reaction and neutralizationof the endogenous protein (49, 50). Although theprecise characteristics of proteinaceous particles asso-ciated with immune response elicitation are not wellunderstood (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 animmune response (49).

The causative factors of protein aggregation are alsopoorly understood. However, the complex manufac-turing and purification methods used in the processingand handling of therapeutic proteins can influence anumber of different product characteristics, includingparticle size (49, 50, 52). One potential cause ofprotein aggregation is the presence of extrinsic partic-ulate matter that may serve as nucleation sites for theformation of larger particles (52). The overall netcharge of the protein solution has also been shown toinfluence the degree of protein aggregation and thetype of protein aggregates formed in a given solution.Studies have shown that solubilized proteins held un-der conditions near their isoelectric point may beprone to aggregation into spherical particles due toexposure of hydrophobic residues to the solventcaused 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 toelectrostatic repulsion and slow aggregation (53). Thepotential for aggregation and the monitoring of sub-visible protein particles in the 0.1 to 10 um size rangeshould be considered during biologic product devel-opment and surveillance programs (49).

Finally, it is important to distinguish between hard andsoft particles. A hard particle is a rigid structure thatoften has a non-spherical, irregular shape. Such particlesare inflexible and, if large enough (�5 �m), are morelikely to produce mechanical obstruction and vascularemboli. All of the particles described above would beconsidered hard particles capable of inducing embolicphenomena upon intravascular (i.e., intravenous, arterial)infusion. In contrast, a soft particle is a flexible, ordeformable, structure that is spherical, such as an emul-sified oil droplet. As with hard particles, soft particlesmay also produce embolic phenomena upon intravascu-lar infusion, but due to their deformable characteristics,the embolism is incomplete, that is, when large hardparticles flow towards a vessel with a smaller diameter,the occlusion cannot be overcome by compensatory in-creases in venous and/or arterial pressures. When thesame-sized soft particles flow towards the same smallvessel, 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 indownstream vital organs, such as the liver, producing asystemic inflammatory response (54, 55).

Patient Population

The patient populations that may be most at risk forparticulate matter–related sequelae include patients withexisting tissue damage, critically ill patients, and neo-nates (3, 15, 18, 31, 38, 55). Two recent animal studiesinvestigated 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 twogeneric antibiotics containing particulate matter levels 4to 50 times higher than those found in the innovator drugresulted in a nearly 50% loss of damaged capillary net-works in the ischemic muscle tissue of hamsters ascompared to muscle treated with the innovator drugproduct. Passing the generic formulations through a0.2 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 clinicaleffects 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-

191Vol. 67, No. 3, May–June 2013



nous injection of the concentrated antibiotic particles,post-ischemic muscle tissue demonstrated reduced cap-illary perfusion following intravenous treatment with theconcentrated particle solutions. Histological sections re-vealed that particulate matter caused mechanical disrup-tion of the circulation to striated muscle. These findingssuggest that injected particles could be more detrimentalto patents with existing tissue damage, such as in the caseof trauma, surgery, or sepsis (13).

The heavy particle loads incurred by critical carepatients due to the sheer volume of administered in-travenous solutions have been linked to adult respira-tory distress syndrome (34), systemic inflammatoryresponse syndrome (SIRS) (57), and immune systemdysfunction (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 matterdeposition 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–inducedadverse events (38, 57).

The potential effect of heavy particle loads on neo-nates was also reported by Puntis et al. (31), whocompared the necropsy results of 32 infants who diedof sudden infant death syndrome with those of 41infants who died following total parenteral nutritiontherapy. Two of the 41 parenterally fed patientsshowed widespread pulmonary granulomas containingmaterial such as glass fragments and cotton fibers. Nosuch granulomas were identified in the patients whoexpired due to sudden infant death syndrome. Al-though the capillary diameter of neonates is the sameas those of adults, the overall number of blood vesselsand the diameter of the major blood vessels aresmaller in children as compared to adults, a factor thatcould 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 havebeen enacted and implemented intended to control par-ticulate matter contamination of injectable drug products.Nevertheless, federal regulations pertaining to currentgood manufacturing practice (cGMP) do not specificallyaddress the subject of particulate matter, but do containseveral passages applicable to particulate matter contam-ination. With regard to the effect that the containerclosure system might have on particulate matter in a

product, regulations at 21 CFR 211.94(a) state that “drugproduct 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 officialor established requirements”. Regulations at 21 CFR211.165(a) and (f) state that “for each batch of drugproduct there shall be appropriate laboratory determina-tion of satisfactory conformance to final specificationsfor the drug product” and “drug products failing to meetestablished standards or specifications . . . shall be re-jected”. These regulations apply to the visible and sub-visible particulate matter specifications cited in drugproduct applications (see Table II).

Section 501 of the Federal Food, Drug, and CosmeticAct (FD&C Act) states that a drug or device will beconsidered adulterated (1) “if it has been prepared,packed, or held under insanitary conditions whereby itmay have been contaminated with filth, or whereby itmay have been rendered injurious to health”; (2)“if . . . the facilities or controls used for its manufac-ture, processing, packaging, or holding do not conformor are not operated or administered in conformity withcurrent good manufacturing practice to assure that thedrug . . . 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 thename of which is recognized in an official compen-dium, and its strength differs from, or its quality orpurity falls below, the standards set forth in suchcompendium”. Although a manufacturer’s level ofcompliance with Section 501 of the FD&C Act may besubject to interpretation, the emphasis on cGMP andcompendial standards is clear.

The first compendial standard for visible particles indrugs for use in the United States came in 1936 whenthe National Formulary VI stated that injectable so-lutions were to be “substantially free from precipitate,cloudiness or turbidity, specs or flecks, fibers or cottonhairs, or any undissolved material” (58). In 1942, theUSP and the American Pharmaceutical Association(publisher of the National Formulary at that time)stated that aqueous injections should be “substantiallyfree” of particles discernable with the naked eye. Thisdefinition eventually evolved into those currently usedby the three major pharmacopeia stating that injectabledrug products should be “essentially free” (USP),“practically free” (European Pharmacopeia) or free of“readily detectable” (Japanese Pharmacopeia) visibleparticles (58).




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USP standards for subvisible particles (those measur-ing �10 um and �25 um in size) were first establishedin 1975 for large-volume parenteral products. Partic-ulate matter standards for small-volume parenteralsbecame official in 1986 as part of USP General Chap-ter �788� Particulate Matter in Injections. Chapter�788� was revised in 1995 to include the currentlimits for large and small volume parenterals. In 2007,Chapter �788� was harmonized with Japanese Phar-macopeia Chapter 6.07 Insoluble Particulate MatterTest for Injections and European Pharmacopeia Chap-ter 2.9.19 Particulate Contamination: Subvisible Par-ticles. The test methodologies (light obscuration andmicroscopic particle count test) and acceptance crite-ria for �10 um and �25 um particles in this harmo-nized chapter are the most commonly cited particulatematter tests listed in FDA drug product applicationspecifications (see Table II).

Less consistent are the specifications for visible par-ticles in injectable drug products. As noted by ThomasBarber in his 1999 book Control of Particulate MatterContamination in Healthcare Manufacturing (8), the“freedom of a product from particles that can bereadily observed by an end user, given that relativelylow light intensity, short inspection times, and un-trained inspectors are involved, would seem to behighly desirable”. More important, the presence ofvisible particulate matter is an important indicator ofmanufacturing process control worthy of a rigorouscompendial standard. As shown in Table II, the spec-ifications and acceptance criteria for visible particlesin new drug applications submitted to FDA are incon-sistent or non-existent. The opposite is true for spec-ifications for subvisible particles, which nearly alwaysfollow the harmonized compendial recommendations.

USP Chapter �1� Injections states that “each finalcontainer of all parenteral preparations shall be inspectedto the extent possible for the presence of observableforeign and particulate matter in its contents”. USPChapter �1� also states that “every container whosecontents show evidence of visible particulates shall berejected” and “the inspection process shall be designedand qualified to ensure that every lot of all parenteralpreparations is essentially free from visible particulates”.Absent from USP Chapter �1� are a definition for“essentially free” or a standardized method for visibleparticle inspection. USP Chapter �790� Visible Partic-ulates in Injections, published in the March-April 2012edition of Pharmacopeial Forum (59), proposes a testmethod and acceptance criteria allowing a lot of drug

product to be considered “essentially free” of visibleparticulate matter. The test procedure is based on Euro-pean Pharmacopeia Chapter 2.9.20, which calls for theobservation of swirled units in front of black and whitebackgrounds for a defined period of time under specificlighting conditions. The test is to be conducted on asubset of units from each lot that has already beensubjected to 100% visual inspection. An acceptable qual-ity level of 0.65, using American National StandardsInstitute–American Society of Quality (ANSI/ASQ) Z1.4General Inspection Level II single sampling plans, isconsidered acceptable for batch release purposes. Chap-ter �790� also states that other procedures having equalor better sensitivity may be employed and that injectableproducts containing inherent particulate matter should betested according to the procedures established in theproduct monograph or approved regulatory submission.

Another compendial weakness with regard to particlestandards is the discrepancy in Chapter �788� be-tween the particulate matter limits in large-volumeinjectables (LVI, those containing �100 mL) andsmall-volume injectables (SVI, those containing�100 mL). The current limits for particles �10 umand �25 um in SVI using the light obscuration methodare 6000 and 600 particles per container, respectively.The limits for LVI using the light obscuration methodare 25 per milliliter for particles �10 um in size and3 per milliliter for particles �25 um. Thus a 1 L LVIcan have greater than four times the number of parti-cles �10 um and 5 times the number of �25 umparticles per container as compared to a SVI. Thisdiscrepancy in the particle limits for SVI and LVI isrelevant due to the sheer volume of parenteral solu-tions administered to critical care patients and thepotential impact of high particle loads on these pa-tients (15, 18, 30, 56). As documented by Nath et al.(60) and corroborated by the data, albeit limited, pre-sented in Table II, most injectable product particlelevel counts fall far below those allowed in USPChapter �788�. Given the clinical risks associatedwith the administration of large amounts of particulatematter to critically ill patients and the fact that im-proved cGMPs allow for better control of particleloads, tighter sub-visible particle standards for large-volume parenterals should be considered.

Continuing Efforts

Manufacturers, regulators, and standards-setting organi-zations are collaborating on several particulate matter-related projects designed to improve manufacturing stan-

195Vol. 67, No. 3, May–June 2013



dards and patient safety. One such collaboration relatesto the establishment of a standardized test method andminimum acceptance criteria for visible particles in in-jectable drug products. Members of the USP DosageForms Expert Committee, the FDA Standards WorkingGroup, industry consultants, and USP officials have metseveral times to discuss challenges faced by the pharma-ceutical industry regarding the USP Chapter �1� Injec-tions definition of “essentially free” as it pertains to thepresence of visible particles in each lot of injectable drugproduct. The pharmaceutical industry expressed a desirefor a clearer definition of the term “essentially free” andexplained that although the goal of visual inspection is tomanufacture product that contains zero visible particles,achieving this goal is nearly impossible given the currentprocess capability and inspection technology. The FDAwas able to convey its concerns about the administrationof visible particulate matter to “at–risk” patient popula-tions and emphasized the need for product-specific par-ticulate matter limits and minimum acceptable visibleparticle standards. The result was the development ofUSP Chapter �790� Visible Particulates in Injection.Chapter �1790�, the sister Chapter to �790�, is indevelopment and will provide additional information onpotential sources of visible particles, the characterizationof visible particles, and a holistic approach to minimizingthe presence of visible particles in injectable drug prod-ucts.

A second collaborative effort to address issues relatedto subvisible particulate matter standards and testmethods for the growing number of protein therapeu-tics resulted in USP Chapter �787� Subvisible Par-ticulate Matter in Therapeutic Protein Injections (61).Chapter �787� addresses the unique properties ofprotein therapeutics, such as protein aggregation, sam-ple viscosity, and limited sample volume that canmake test procedures recommended in USP Chapter�788� untenable. An informational chapter, Chapter�1787�, is under development and will provide ad-ditional information about the choice of test methodsfor protein particle characterization— especially forprotein particle populations of 1–100 micrometers,which have the potential to affect the safety and effi-cacy of the product throughout its shelf life.

Finally, representatives from the FDA’s Center forDrug Evaluation and Research actively participate aspanelists and presenters at conferences sponsored byorganizations such as the Parenteral Drug Association,the European Compliance Academy, and the USP.These conferences serve as a forum to discuss topics

such as drug product recalls related to particulatematter contamination, inspection methods for visibleand subvisible particles, and the use of compendialstandards for the establishment of suitable drug prod-uct specifications. The goal of these presentations is topromote dialog between the FDA and industry withregard to the establishment and enforcement of con-sistent particulate matter standards and the challengesfaced by both industry and regulators regarding thecontrol of particulate matter in injectable products.

Conclusion

Given the large number of patients receiving inject-able drug products each year and the potential forparticulate matter to cause harm to patients, it iscritical to monitor the presence of and reduce throughall reasonable means the presence particulate matter ininjectable drug products. Moreover, the level of par-ticulate matter present in a drug product is a keyindicator of pharmaceutical quality (62). The develop-ment of compendial standards over the past severaldecades has helped to assimilate the test methods’minimum acceptance criteria for pharmaceuticals inthe global market. Likewise, improved cGMPs havehelped to lower subvisible particle levels in injectablesfar below the compendial limits. Today, the goal ofmanufacturers, regulators, and standards-setting orga-nizations should be to minimize the risk of particle-induced sequellae, especially in high-risk patients,without trading unnecessary manufacturing burden forminimal safety gains. The many challenges associatedwith estimating the risk imparted by particles of var-ious sizes, shapes, and consistencies administered tomultiple patient populations in varying amounts bynumerous routes of administration make a one-size-fits-all approach to particle limits for all injectableproducts untenable. Nevertheless, continued collabo-ration among regulatory authorities, regulated indus-try, standards-setting organizations, and other relevantstakeholders will be crucial for the developmentand/or modernization of risk-based, particulate mat-ter–related standards, regulations, and guidance de-signed to ensure the availability of high-quality phar-maceutical products.

Acknowledgements

The author would like to thank Scott Aldrich, RoyCherris, and Leila Wieser for their editorial commentsand advice during the writing of this article.




Conflict of interest Declaration

The author declares that he has no competing interests.

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