Risks of Compounded Drugs

Abstract

A nurse notices “floaters” in an infusion bag of magnesium sulfate, initiatingachainofdiscoveries that causesasinglehospital to recall 12 000unitsof44 typesofproducts sourced from thesamecompoundingpharmacy. In this issue, Boyce et al1 describe how this drug quality problem, which was eventually identified as fungal contamination, led to the readmission of 545 potentially exposedpatients and cost thehospital system15 000hours of personnel time and nearly $900 000. The case illustrates the risks and potential costs of substandard compounded drugs, evenwhenpatients are exposed to contaminatedproductsbut do not become infected. Elsewhere in this issue, Moehring et al2 describe an outbreakofBurkholderiacontaminansbacteremia in7patientssuccessfully traced to intravenous fentanyl compoundedat an inhouse hospital pharmacy. Their subsequent investigation identified the need for major changes in the pharmacy: revised sterility testing procedures, new equipment, a redesigned clean room, retraining of staff, and updated audit and review procedures. Serious failings were also identified at an external reference laboratory used as part of the investigation.As theauthorsnote, this compoundingquality failurewas identifiedonlybecause thepathogenwasunusual; similaroutbreaks caused by more common species likely would not be detected. Manypatients andphysicians areunaware thatmore than 90%ofUShospitalsuse compoundedsterilepreparations,3 including prescriptions tailored to the needs of individual patients and batch-produced injectable or ophthalmic products for routine use. Large hospitals or hospital systemsmay compoundhundredsof thousandsofunitsperyear, and73%ofhospitals purchase at least some sterile compounded products from outside pharmacies. The prevalence of quality problemswith sterile compounded drugs is unknown andmay be higher thanpublished reports suggest.Thesmall scaleofmuch compounding activity and the fact that many outbreaks are confined to a particular hospital or health care system make it likely thatmanycompounding-associatedoutbreaksandadverse events are never detected or reported. Given the potential serious consequences of contaminated drugs, physicians andpharmacists should take steps to reduceanypotential risk to patients. Manyclinicianswill be reassessing these risks after thenationwide outbreak of fungal meningitis traced to contaminated corticosteroid injections from the New England CompoundingCenter thathas so farbeenassociatedwith64deaths and 751 illnesses across 20 states.4 Although this outbreak is notable for its scale, at least 21 reports of patient illnesses and deaths associated with compounded drugs have been published since 2001.5 Despitenational attention to theNewEnglandCompoundingCenter outbreak, regulatoryoversight remains limited and variable. The practice of pharmacy is overseen by state pharmacy boards, but standards on compounding quality differ widely. For example, approximately half of the states require compliance with United States Pharmacopoeia (USP) standards developed to guide sterile production.6 Hospital pharmacies are also subject to JointCommissionaccreditation, but this does not include assessment of full compliancewith USP standards, and accreditationdoesnot specifically address the outsourcingofcompoundedpreparations.A2011 surveyof894 hospitals found an overall 72.4% compliance level with USP standards for sterile compounding.7Approximatelyhalf of the respondents reported meeting surface sampling requirements and compliance with bacterial endotoxin testing was similarly lacking. Moehring et al2 provide a clear example of the challengeshospitals continue to face andmustwork to address. USFoodandDrugAdministration (FDA)oversight of compounding has been similarly limited, in part because a series of court rulings created confusion about whether applicable provisions of the Food, Drug, and Cosmetic Act were still in force. In the wake of the multistate meningitis outbreak, the FDA stepped up its oversight of large compounding pharmacies, issuingmore than50 findings of quality problems in 2013 and citing failures at laboratories usedbymanyof these pharmacies for sterility testing.8 In November 2013, the US Congress passed a new measure, theDrugQuality andSecurityAct,whichaddresses compounding in 2 ways. First, it immediately reinstates previous provisions of the Food, Drug, andCosmetic Act that had been struckdownby court rulings,9 clarifying that pharmaciesmay compound only pursuant to a patient-specific prescription or in “limited quantities” in advance of a prescription and that such facilities cannot regularly copy commercially available drugs. Although the FDA has authority to take action when compounders violate the law, the agency has limited ability to inspectpharmacyrecords,enforcequalitystandards,oreven determine which facilities are producing specific products. Second, the law also creates a new category of “outsourcing facilities” thatmaynowvoluntarily registerwith theFDA, meet good manufacturing practice (GMP) standards establishedby theagency, andundergo routine inspection. Such facilities could legally produce drugswithout a prescription for sale to health care entities, serving as a source of high-quality compounded products for hospitals and physicians. An immense chasm separates the USP quality standards from the GMP standards that guide the production of FDAapproved generic and brand-name drugs.10 The USP standards are broadly defined protocols for small-batch pharmaceutical compounding by pharmacies. In contrast, the GMP standards are a system of routine operating procedures deRelated articles pages 606 and 630 B contaminans Bacteremia Linked to Fentanyl Original Investigation Research