Pharmaceutical compounding has dominated the news in the last year after a large outbreak of fungal meningitis caused by contaminated sterile drugs produced at a compounding pharmacy in Massachusetts and distributed through interstate commerce. The latest tally is 50 deaths and several hundreds of infected patients in multiple states. FDA, state administrators and pharmacy boards are under scrutiny as they did not stop the compounding center’s operation despite unsatisfactory inspections and multiple complaints.
Compounding is defined as “a process by which a pharmacist or doctor combines, mixes, or alters ingredients to create a medication tailored to an individual patient’s needs” (see U.S. Supreme Court syllabus at http://www.fda.gov). The compounding practice historically developed by compounding drugs under a doctor’s prescription that were not available as commercial products in the desired dosage form. USP devotes a whole chapter (<797>) on sterile pharmaceutical compounding outlining specific practices and requirements. The chapter is currently under revision.
There is some uncertainty regarding the regulation of pharmaceutical compounding as both FDA and states have authorities. Many states regulate compounding practices within their regulation of pharmacies and licenses are provided by the states.
The FD&C Act of 1938 provided FDA with the authority to review and approve new drugs and enforce the Act’s requirements. FDA did not interfere with state compounding regulations for many years. However, FDA noted that there were many drugs being dispensed and distributed under compounding’s pretense to avoid the Act’s requirements. In 1992, the FDA issued a Compliance Policy Guide (CPG) permitting compounding unless a pharmacy raised concerns similar to those of a drug manufacturer. If that were the case, FDA would exercise enforcement similar to that of a drug manufacturer. FDA also provided its definition or distinction between compounding and commercial manufacturing.
The Act was amended in 1997 (FDAMA) and part of FDA’s CPG policy became U.S. law. Compounded drugs were exempted from the Act’s approval requirements, provided that: prescriptions were unsolicited, compounders did not advertise and solicit patients, and compounded drugs were produced from approved ingredients in limited quantities. In addition, pharmacists could not compound regularly or in inordinate amounts commercially available drug products. Legal action ensued. The advertising clause was deemed unconstitutional violating free speech. As a result, the whole compounding provision of FDAMA was affected and rendered essentially unconstitutional.
The pharmaceutical compounding center of the recent meningitis outbreak compounded sterile drugs in large amounts and distributed to multiple states and patients without following requirements for sterile compounding and USP <797>. The drugs were contaminated with an unusual and slow-growing fungus, Exserohilum rostratum. Due to the administration of these steroid injections to the spine and other sensitive areas, the resulting infections were extremely serious.
FDA had inspected the facility several times dating back to 1999 finding many deficiencies. In 2002, after evidence of health problems, FDA and the State of Massachusetts decided to leave oversight to the state pharmacy board. The FDA conducted another inspection September 2004-January 2005 due to marketing and packaging violations. A warning letter was sent to the compounding center in December 2006, more than a year later. Both the FDA and the state are under scrutiny for their lack of action or slow action to prevent the outbreak. FDA and states have now stepped up enforcement and inspections of sterile compounding facilities across the country. Several have closed following these recent inspections after finding objectionable practices that could result in drug product contamination.