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Executive SummarySterile injectable products are used extensively in health care. Patients, caregivers, manufacturers, and regulators havean inherent expectation for safe and effective injectable drug products.
This expectation requires injectable pharmaceuticalsto be produced to standards of quality, purity, and sterility that include being essentially free of extraneous matter suchas particles. Despite guidance in producing product that is “essentially free” of particles, manufacturing such product isvery challenging. In many instances, the observation of particles in pharmaceutical products has resulted in product recalls.While medical warnings have accompanied these recall notices, the specifics of these warnings have varied. The medical literatureis sparse with respect to case reports and experimental studies providing data to support the safety risk of particles (intrinsicor extrinsic) in humans. A gap exists between the observation of small quantities of particles in injectable pharmaceuticalproducts and patient-documented safety concerns resulting from the inadvertent administration of particles to patients.
Thus,a need exists to create a framework to describe and assess the potential risk of administering particles to patients.This paper provides a review of current compendial inspection requirements for visible particles along with a review of themedical literature associated with any observed harm from such particles. IntroductionSterile injectable products are used extensively in health care; in fact, more than 15 billion injectable doses are administeredannually worldwide. Patients, caregivers, manufacturers, and regulators have an inherent expectation for safe and effective injectable drugproducts. This expectation requires injectable pharmaceuticals to be produced to standards of quality, purity, and sterilitythat include being essentially free of extraneous matter such as particles.
( For the purposes of this paper, the meaning of the term particle includes particulate and particulate matter) The standards of producing pharmaceutical products are described within the various pharmacopeias. Manufacturers strive toproduce injectable products with the requisite quality outlined in these standards to ensure their safe and effective use.Despite guidance in producing product that is “essentially free” of particles, manufacturing such product is very challenging.
For example, over the period of 2008–2012, particle-related issues led to 22% of product recalls for injectable products. In 2007, the European Medicines Agency (EMA) performed an analysis of product quality defects reported in 2005 and notedthat 6% of all product quality defects were attributed to particles. Those particle defects that resulted in a recall would have been classified by EMA as either a class 2 (defects which couldcause illness or mistreatment, but are not Class 1, e.g., mislabeling such as incorrect text) or class 3 (defects which maynot pose a significant hazard to health, but where a recall has been initiated for other reasons e.g., faulty packaging) (EUrecall) (, ).
Between January 2013 and June 2014, the Medicines and Healthcare Products Regulatory Agency (MHRA) Drug Alert website issuedforty-two drug alerts, with eleven alerts relating to particles. Of these, alerts reported in 2014 were all class 2 and included metal particles, small white particles, fiber and glassparticles, and silicone fragments (–). Other agencies, such as FDA, have different class definitions for recalls: Class I Recall - A situation in which thereis a reasonable probability that use of, or exposure to, a violative product will cause serious adverse health consequencesor death. § 7.3(m)(1)); Class II Recall - A situation in which use of, or exposure to, a violative product maycause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequencesis remote. § 7.3(m)(2)); and Class III Recall - A situation in which use of, or exposure to, a violative productis not likely to cause adverse health consequences (21 C.F.R. § 7.3(m)(3)).Parenteral solutions withdrawn from glass ampoules routinely expose patients to numerous glass particles of variable size.As an example, a 1972 study by Turco and Davis showed that opening a single 2 mL glass ampoule and withdrawing the medicineincluded 292 glass particles between 5 μm and 50 μm and 21 particles that were greater than 50 μm.
Vial presentations may contain particles from the rubber closure, a risk that is present with every injection. These are known risks that may result from the packaging and use of the product and are not manufacturing related. Thetechnology to produce, package, and store completely particle-free products on a large scale is not currently available. Additionally,Davis et al. Identified 86 to 2,200 particles of 5 μm per liter following filtration from a wide variety of sterile infusionsolutions in glass and plastic containers. Based on the study by C.M. Backhouse et al., intensive care patients would likely often receive more than 10 7 foreign particles 2μm per 24 hours with their intravenous therapy.In many instances, the observation of particles in pharmaceutical products has resulted in product recalls.
While medical warnings have accompanied these recall notices, the specifics of these warnings have varied (–). Typically, these warnings are described as “potential” and are not accompanied by published reports of patient harm. Themedical literature is sparse with respect to case reports and experimental studies providing data to support the safety riskof particles (intrinsic or extrinsic) in humans.
Turco and others have demonstrated mechanisms for the inadvertent introductionof particles, sometimes in large quantities, to parenteral fluids prior to administration. The in-line filter articles suggest a potential relationship of the reduction of particles and decrease in rate on infusionsite phlebitis when filters are used. The older literature on large volume infusion and parenteral nutrition and the literature on intravenous drug addicts (IVDA),which have very limited general use for current medical practice show that mass, chronicity and unique characteristics ofthe particle may have a role in these special situations (, ). The paucity of current medical literature detailing harms from particulate in pharmaceutical products might in part reflectthe high standards of current manufacturing processes.A recently observed exception is the reaction of subvisible (. Current Defined RulesThe current inspection methods and acceptance criteria for particle matter in injectable products may be found in the nationalor regional pharmacopeias. Market, the U.S. Pharmacopeia (USP) General Chapter Particulate Matter in Injectionshas been official for many years.
It defines two methods for counting subvisible particles and sets limits of 6,000 and 600particles per container for ≥10 μm and ≥25 μm particles, respectively. These limits apply to containers ≤100 mL. For containerslarger than 100 mL, limits are set on a per milliliter basis. As this is a harmonized chapter, the same methods and limitsare found in the European Pharmacopeia (EP) and the Japanese Pharmacopeia (JP).Requirements for visible particles are found in USP General Chapter Injections. The requirement set in this chapter isthat every final container is inspected for particles to the extent possible, and any showing the presence of observable foreignand particulate matter are rejected. It further requires that “the inspection process shall be designed and qualified to ensurethat every lot of parenteral preparations is essentially free from visible particulates”.
General Chapter Visible Particulates in Injections was published in the first supplement to USP 37 and became officialAugust 1, 2014. This chapter establishes reference inspection conditions and provides quantitative limits based on acceptance samplingto meet the expectation for every lot to be essentially free from visible particles.
The inspection conditions are harmonizedwith those found in the EP.Additional requirements for products marketed in Europe can be found in the Finishing of Sterile Products section of the EuropeanMedicines Agency Annex 1. This section sets the requirement that “filled containers of parenteral products should be inspectedindividually for extraneous contamination or other defects.” It also sets an expectation that inspectors pass regular visiontests and that frequent breaks be given to avoid fatigue. The EP, in Parenteral Preparations-Injections (0520), specifies“solutions for injection, examined under suitable conditions of visibility, are clear and practically free from particles.”It follows with an inspection method described in 2.9.20 Particulate Contamination: Visible Particles. This section specifiesillumination intensity, background, and pace for the conditions suitable for inspection. The EP monograph Monoclonal Antibodiesfor Human Use (2013) aligns with the EP monograph Parenteral Preparations for Injections, allowing for an appearance specificationof “practically free from particles.” The specification must be “justified and authorized”.The requirements for product marketed in Japan are contained within the JP. It specifies inspection with the unaided eye withlight coming from an incandescent source with intensity below that stated in the EP and USP. The acceptance criterion forthis inspection is “injections or vehicles must be clear and free from readily detectable foreign insoluble matters”.All of the pharmacopeias establish the need to perform 100% inspection of units in a batch or lot of product under controlledcondition, but they recognize the probabilistic nature of the inspection process in the acceptance criteria.
Evolving Stances and DriversParticles represent an ongoing challenge in drug product manufacturing. The use of clear and colorless injectable liquidsand containers permits continuous, nondestructive inspection throughout the drug product life cycle for most products. Whereproduct formulation (e.g., powders, suspensions and strongly colored solutions) and/or the container (e.g., amber glass ortranslucent plastic) limit visual inspection, supplemental destructive testing of a small sample is recommended to furtherassess the risk of particles in the batch.
Points of failure, based on particle presence, include in-process waste (rejects) and customer complaints. As seen in arecent benchmarking study, the most common cause for rejections was the presence of particles. Sources of particles include the manufacturing environment, primary packaging components, processing equipment, and thedrug product itself. Together with cosmetic and other appearance defects, particles continue to impact product quality andavailability.The presence of visible particles in injectable drug products has been a matter of intense discussion, both from a regulatoryand a compliance perspective, within global regulatory agencies as well as industry over recent years. There is an expectation to not only reduce particles but also control them, including those in the subvisible range. Tobetter understand the particles' source, and thus aid in their reduction, particle detection and identification are importantparts of regulatory compliance and product quality assurance. Lot release acceptance criteria such as “free from”, “without”or “no visible particles” risk the rejection of entire batches of drug product should a single particle be detected in a singlecontainer of product.
Further, current inspection methods and technologies, including human manual inspection and fully automatedinspection systems, cannot provide this level of absolute assurance. Visual inspection is a probabilistic process (, ), with detection probabilities less than 100%, especially for particles less than 200 μm in diameter (, ). This 100% inspection is supported by acceptance sampling methodology (“AQL inspection”), which again does not support absoluteassurance of the absence of all particles. These practical limitations should be considered when establishing any visual inspectionlimit.Industry has been working with regulatory agencies worldwide to update guidelines and monographs to reflect these pharmaceuticaldevelopments and to gain improvements in control and methods for identification of visible particles.
Industry has begun toadvocate for regulatory distinction between particles introduced into a product as an intrinsic or extrinsic contaminant versusthe formation of inherent particles from the drug product, recognizing that inherent particles should have been fully characterizedby the application holder during product development and described in the product application.Despite these efforts, the published guidance from regulatory bodies has limited specificity on allowable particle size, numbers,and types of visible particles (, ), or on visible particle investigations. There is no published guidance on the potential impact of small numbers of visible particles to patient safety. In a generalsense, this is the most common issue facing manufacturers.
While the published literature contains a number of anecdotal reportsdescribing exposure to large numbers of particles, none of these reports reflect the potential hazards of more typical particleadministration via large- or small-volume parenteral pharmaceutical administration to patients. There continues to be emotionalstances lacking data around the subject; a clear understanding of the facts to benefit all is required. Particle Matter ConsiderationThe European, Japanese, and US Pharmacopeias share the following harmonized definition for particulate matter in injectableproducts:Particulate matter in injections and parenteral infusions consists of extraneous mobile undissolved particles, other thangas bubbles, unintentionally present in the solutions.Identification of the composition of the particulate matter is the first step in characterizing particulate matter risk. Basedon this information, particles can be further classified into one of three subcategories: extrinsic, intrinsic, and inherent.Both extrinsic and intrinsic particles are considered within the scope of this paper, while inherent particles are not.
Particle SizeWhile particles of varying size have been observed in injectable drug products, they are generally classified into one oftwo categories; visible and subvisible. Visible particles are defined as those that can be detected under controlled conditionsby the unaided human eye (i.e., without supplemental magnification) (, ).
As a reference, studies have demonstrated that under idealized conditions, trained inspectors performing the pharmacopeiainspection method will begin to have reliable detection of near 70% efficiency when particle sizes reach 150 μm. The 150 μm threshold should be considered a best-case threshold for human visual identification of particles in injectabledrug products given that it represents idealized inspection conditions. Any changes in product, container, or particle materialfrom those idealized conditions will cause the visible detection threshold to shift above 150 μm. There are specific nonzerolimits in the pharmacopeias for subvisible particles ≥10 μm and ≥25 μm. The subvisible particle category covers materialsranging in size from submicron up to the visible threshold. The limits are harmonized in the USP, EP, and JP and are 6,000and 600 per container, respectively, for containers ≤ 100 mL. Pathophysiological Considerations and Clinical ImplicationsThe effects of particles in injectable drug products have been discussed in the medical literature for decades (–), and are based on in vitro studies, some animal data, human case reports, and small observational studies.
Human data islimited because it is ethically impossible to prospectively test the impact of particles in injections. Further, even if particulatematter is administered to a patient, the clinical impact can be hard to assess or even may be unnoticed or asymptomatic. Potentialclinical sequella could, in some circumstances, be indistinguishable from an underlying disease or other treatment impact.The literature often contains the most extreme examples from intravenous drug abuse and hyperalimentation. Given these limitations,it's best to understand potential harm to patients based on an understanding of the pathophysiology of particle infusion.The type and degree of clinical impact is dependent on multiple factors, including the route of administration, the size andamount of the particle(s) injected, and patient factors such as underlying health status.
Although there are limited dataon human exposure to infused particles, it is estimated that “patients in intensive care units may receive more than a millioninjected particles 2 μm daily”. As such, particles could theoretically have meaningful clinical impact if highly experimental animal studies are consideredappropriate surrogates (, ). As an example, ICU patients are at greater risk of consequences of particle infusion, due to their need for continuousinfusion of parenteral solution, including that for hyperalimentation.Many injectable drugs are administered intramuscularly and subcutaneously. Intramuscularly and subcutaneously administereddrugs containing particles generally have minimal impact on patient health. Complications from subcutaneous and intramuscularmedications generally arise from the irritating properties of the drug product and are often drug-specific.
For particles that are primarily mechanical obstructions and inert (e.g., cellulose, metal, or glass), the compositionof a particle is not critical to clinical impact except for impact on sterility, which is discussed below. Subcutaneous administrationof small, inert, sterile particles would not be expected to induce a clinically significant reaction beyond minor irritationor perhaps a small granuloma. Likewise for intramuscular injections, Greenblatt and Allen looked at 26,294 hospitalized medical patients, 46% of whomreceived at least one intramuscular injection, finding that clinically apparent local complications are uncommonly (less than0.4%) associated with IM injections. In consideration of glass particles in particular, glass fragments from tubular and molded glass can generally be consideredinert, and in small quantities they are not likely to cause significant injuries.
However, the special case of glass lamellaewhich can be either visible or subvisible can be present in large numbers and can increase in number with time, can have ahigher clinical impact if administered in large volumes.Whenever a drug is injected into a contained space, for example, intraocular or intrathecal use, there may be more risk forinflammation from particles or a particle may serve as a nidus for infection, causing harm. There are limited data, but the presence of particles in solutions for intrathecal use has been reported from use of drugswithin glass ampoules.
The average number of particles was 17 (7–38) with a range in size from 15 μm to 80 μm. At the time of the study, the incidenceof central nervous system complication following subarachnoid anesthesia was low. The authors note that a foreign body reactionmay have resulted and may account for the reported events of chemical meningitis.Intravenous infusion of particles might result in phlebitis due to particles causing direct traumatic damage to the vein,or chemical damage from undissolved particles, or infection if the particle is non-sterile.
Non-dissolvable particle matterwill become trapped in small vessels or capillary beds, when the introduced particle is larger than the vessel. The diameterof the smallest capillary or blood vessel is about 7 μm in an adult and the diameter of a pulmonary capillary, which is approximately 10-15 μm, just larger than the size of red blood cellswhich are responsible for oxygenation of blood as they travel through the pulmonary vasculature. Therefore any intravenouslyadministered particles greater than 7 μm but less than 10 μm may occlude some capillaries.
If pulmonary capillaries are compromisedin the presence of microemboli (pulmonary embolism), the clinical consequence is impaired oxygen transfer and compromisedrespiratory function. Smaller particles (. Risk AssessmentTo assess the potential impact of the particle to the patient, a risk assessment should be performed in accordance with recognizedguidance documents and standards. In the International Conference on Harmonisation Quality Guideline Q9: Quality Risk Management, “risk is defined as the combination of the probability of occurrence of harm and the severity of that harm”. In relation to particles, when assessing the risk to the patient population, the assessment can be reduced into the likelihoodfor the hazard to occur and the severity of the harm or clinically significant outcome that might occur to the patient dueto the hazard.
The risk is derived after assessing the likelihood of the harm against the severity of the harm under specificcircumstances. Differentiation should be made between the likely general population and a subset of patients who might bemost at risk.Noting that post-hoc process controls should not be used as a safety-net for poor manufacturing methods, the risk assessmentneeds to consider the possible types of clinical impact the patient might experience and assess whether the harm would belikely to occur given the specific circumstances. Some products are known to have a risk for precipitant, and labeling andstandard use reflect this understanding and the importance for product inspection prior to use within the pharmacy as wellas at patient bedside. The assessment should account for standard clinical practice to reflect real-world use.The severity of harm is determined based on the potential clinical impact that the patient will experience due to administeringproduct from the affected lot. Severity can be rated as temporary discomfort all the way to patient death.
Potential harms,as discussed in the Pathophysiology section, may include phlebitis, granuloma, and occlusion or thromboembolic events, eachwith differing severity levels of harm. For example, an otherwise healthy individual receiving a subcutaneous or intramuscularinjection containing a single sterile extraneous inert particle would likely experience no adverse effect or at worst developa small granuloma.
The severity of the harm may be considered minor with no need for medical intervention. By comparison,a critically ill premature infant receiving a particle-laden infusion directly through an umbilical catheter might sufferpermanent or life-threatening injury (, ). This outcome may be considered critical, as a life-threatening situation arose. In some situations, permanent injury mayresult and should be considered in determining the degree of severity of the harm.The scope of this paper does not allow the creation of a specific template to consider risk; however, the factors presentedin should be taken into consideration in such an assessment.A key consideration is to assess the source of the particle and to assess the risk to the sterility of the drug product inthis regard. The impact might be modified by additional manufacturing variables, such as terminal sterilization (as comparedto aseptic filling) for determination of possible microbial contamination.
Thus, understanding the manufacturing process andwhere the particles were introduced into the product is important in understanding the overall risk to the sterility assuranceof the product. Microbial contamination and/or endotoxin introduction into the product should be considered in addition topathophysiological considerations for particles in order for health care professionals to have a comprehensive understandingof potential impact to the patient.As previously stated, the overall risk is determined by assessing the likelihood of harm, which may be determined qualitativelyor quantitatively, occurring against the severity of the harm. Based on the assessment, a determination can be made as tothe actions required for a particle (e.g., limit use to specific patient population, recall the lot). For particles, it mightbe possible to establish predefined acceptable risk to which manufacturers can refer; this should in no way prevent manufacturersfrom continual improvement of systems with a goal to eliminate all particles. For example, in-line filters for intravenousadministration of parenteral solutions at the point of use would reduce risk for larger particles but not all subvisible particles.Allcutt et al. (1983) showed that in-line filtration delayed the onset of infusion phlebitis which is the only well-documentedclinical complication of particle drug contaminants. When the risk to patients exceeds these established parameters, field action should be considered.
When new types of failuresor particles are discovered, a new risk assessment should be completed for the product to determine appropriate actions. Thesecan include internal manufacturer actions as well as external field actions. Patient populations should be defined as partof the intended use of the product. A determination of appropriate actions should be based on label indications for productuse rather than speculation on off-label potential uses.In addition to the risk assessment, the risk of having limited product available to the public must be considered when assessingthe true impact of product containing particles. This risk-benefit analysis provides a broader perspective with an understandingof the market conditions, including availability of an alternate product as well as potential drug shortages.During a presentation to the U.S.
Senate Committee on Health, Education, Labor and Pensions on December 15, 2011, Dr. SandraKweder, the deputy director of the Office of New Drug Development, FDA, stated that between January 2010 and September 2011,there were 127 episodes of drug shortages.
Of these, 120 of the product shortages involved sterile injectable drugs. Further, 54% of these had product quality issues (particles, microbiologic contaminants, impurities, and stability concerns).The availability of injectable drug products to patients due to potential risk from a single vial containing a particle createsan additional concern for patient safety.
An outcome of a serious adverse event may be the exception and not the rule forinjectable drug products with limited numbers of particles present in product released as “essentially free” of particles. Quality Risk ManagementThe frequency or rate at which the particle is likely to occur should be determined and based on objective data. The presenceof particles, for example, can occur as a single particle or as multiple particles contained within a single unit. One mustconsider the distribution of these particles, that is, whether the particle is an isolated event or its detection may implicateother units or batches. Further consideration should also be given to other products manufactured on the same production line.A determination needs to be made as to how often the hazard, particles in this case, is likely to occur within a lot of productor across product lots.
This assessment needs to take into account how widespread the particle hazard might be (e.g., oneparticle in one vial of one batch of product or ten particles in two hundred vials within twenty batches of product). To makethis determination, a manufacturing site needs to conservatively assess the potential causes of the hazard and determine howlong these potential causes have been occurring. Ultimately, even if the product is within the specified AQL, it is incumbenton the manufacturer to understand leading and lagging trends over time.Manufacturers are encouraged to take a life-cycle approach to understand where particles may be generated, detected, and removedin a production process. Characterization of defects at the time of manufacture can provide valuable insights into the overallunderstanding of particle generation and subsequent mitigation to reduce the level of particles in products.
Examples of itemsto review to determine a failure rate include, but are not limited to, the following: complaint data (trends or spikes), exceptionreport/CAPA records, manufacturing batch records, supplier incoming reports/data, and inspection results of inventory as wellas of retained samples. From this analysis, the manufacturing site can estimate at a base level the likelihood of occurrencefor particles within the affected lot or lots of product. Conclusion: Overall Medical RiskAdvances in process capability to reduce the particle burden, and continued vigilance for particles, have resulted in reportedinjuries being rare and most appear limited to the case reports associated with the infusion of significant quantities ofprecipitated admixtures. Additionally, macroscopic particles are more likely to be discovered prior to administration or canbe too large to pass through the lumen of a needle.
Further, even when larger particles are used purposefully to occlude AVMs(and they have been shown to cross into the venous circulation), there is rarely significant sequelae observed for these patientswho are under close observation. However, clinical data suggests that product conforming to compendial particle limits cancontain subvisible particles, which, can result in patients being exposed to low levels of particles as part of the practiceof routine health care. The intravenous infusion of rigid particles greater than the 10-12 μm diameter of a pulmonary capillarywill be occlusive. Once infused or injected an aggregate number of subvisible particles might impart a similar pathophysiologicaleffect as a macroscopic particle, but more importantly, it is increasingly recognized that subvisible aggregates might inducean untoward immune response.
Thus, the often prevailing assumption, that larger particles pose a greater risk to patients rather than smaller particles,maybe a misconception.An estimated 15 billion injectable doses of medicines are administered worldwide each year (1). The evidence in this papersuggests that true patient harm associated with injections is extremely limited at the current level of particle matter containedtherein. While manufacturing processes, recall procedures, and clinical practices all contribute to this current state, currentprocesses and procedures seem adequate. Small amounts of inert particles are unlikely to cause clinically meaningful patientharm. In addition, intramuscular and subcutaneous injections of sterile inert particles are very unlikely to cause meaningfulpatient injury. Further consideration should however be given to patients with end-organ disease, immune-compromised, or neonatesand infants, as well as when particles are injected into closed spaces (e.g., intrathecal, intraocular, intraarticular) asthese situations may have a greater potential for harm. There is insufficient evidence to conclude that intravenous injectionof inert visible particles results in harm to patients (, ).As there is limited direct evidence of patient risk due to sterile, inert particles, it is reasonable to conclude zero toleranceshould not be the requirement, but instead considered as the goal in manufacturing injectable drug products (, ).
Despite manufacturing process improvements and an increased surveillance with improved detection methodology, the manufactureof particle-free injectable product is not technically feasible, but continuous process improvement is an expectation.A pragmatic approach ensuring high-quality drugs are available to patients is provided by USP. This chapter requiresa robust quality management system with a 100% inspection process, particle identification process, and a good investigationand monitoring process to ensure the occurrence and composition of particulates are understood. The composition of the particulatematter is very important when considering the medical significance when performing a risk assessment. To understand the composition,a firm would need a system to identify the particulate matter found in the drug product. USP, together with a medicalrisk-based approach, offers a practical strategy to ensure manufacturers meet expectations for visible particles.
This standardwas written considering both current manufacturing capability and patient risk. Following the recommendations in USP will provide the minimum expectations for manufacturing standards.
For low-risk routes of administration, such as intramuscularand subcutaneous injections, the acceptance criterion of an AQL of 0.65% based on USP, ensures the adequate safety ofthe product. There may be clinical circumstances where tighter AQL values (limits) may be appropriate for high-risk patientsand for other routes of administration based on an evaluation of patient risk.Globally, clinicians and patient populations are facing drug shortages, in part due to inconsistent product release and recalldecisions related to the presence of particles and a lack of understanding of the impact to patient risk. Safety considerationsrelated to particles in injectable drug products must be assessed on the basis of the factors identified in this paper, whichinclude the intended patient population and method of administration. The decision to recall product from the market shouldbe based on the context of the manufacturing trend history, complaint rate trending, and medical assessment of patient risk.Unless there are specific special circumstances, there should be no automatic requirement to recall a product lot for a singleparticle found in a single unit. While manufacturers strive to remove particles from injectable products, this paper has outlinedconsiderations important to assessing the risk-benefit ratio of administering product to a patient.
In general, notwithstandinghigh risk clinical circumstances and acknowledging there are limitations to reporting clinical events to particle infusion,the existing data suggest the overall risk to patients is generally low and the benefit of these treatments is generally significant. © PDA, Inc.