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What the 483s tell us
September 5, 2013
By: Anthony Grilli
FOCUS Scientific
A patient at Vanderbilt University Hospital was readmitted with what physicians originally misdiagnosed as bacterial meningitis. This time around, Dr. April Pettit, an astute infectious disease specialist, ordered additional tests for fungi and tuberculosis to be performed on the patient’s spinal fluid. The next day a surprising result came back from the lab — Aspergillus species.1 Fungal meningitis is very rare. Within a few days, the Tennessee Department of Health and the CDC were able to trace the infection back to an epidural injection the patient had four weeks earlier to treat back pain. Meanwhile, more cases of fungal meningitis were being reported around the country. The CDC and FDA reacted quickly. The outbreak was linked to three lots of preservative-free methylprednisolone acetate (MPA) distributed by the New England Compounding Center (NECC) in Framingham, MA. The FDA and the Massachusetts Department of Health inspected the site and found unsanitary conditions and poor manufacturing practices. Product was recalled and the plant was shut down. In December 2012 NECC filed for bankruptcy protection. A criminal probe is ongoing. But the damage was done. The CDC continues to update the status of its investigation each month, and the casualty count continues to climb, one year later. As of August 5, 2013, 749 people have been sickened by the contaminated drug in 20 different states and 63 people have died.2 How did this happen? Americans have grown accustomed to news of drug manufacturing disasters in other countries. The last few years has brought news of Asian and African patients dying from medicines contaminated with diethylene glycol, melamine, or adulterated heparin. But how could such large-scale microbial adulteration happen in North America? NECC was registered with the FDA as a compounding pharmacy, this is an important point. As a compounding pharmacy, it was not held to the same cGMP standards that drug manufacturers are. Compounding pharmacies formulate drugs for patients with special needs, patients with allergies to certain excipients in the marketed product, for example, or who may not be able to swallow the solid oral dosage form of a commonly available drug substance. Compounding pharmacies step in to produce small batch formulations for these individuals. They provide a valuable service. But NECC was no longer making individualized medicines. Before closing its doors in October 2012 it had logged $32,000,000 in annual revenue3 and its products reached patients as far from New England as Idaho, Texas and Florida. In addition, the contaminated product was not a specialty formulated medicine. Methylprednisone acetate is a well-established drug manufactured by generic giants Sandoz and Teva. NECC essentially crossed the line from specialty compounder to large-scale drug manufacturer. Presumably, a large-scale drug manufacturer would have conducted cogent hazard analysis and recognized that aseptically packaging a non-preserved immunosuppressing drug for injection directly into a patient’s spinal cavity is an extremely high risk proposition and requires strict manufacturing control. Aseptic processing of any parenteral drug is inherently difficult and risky. As the FDA says in its guidance document on aseptic processing, “Aseptic processing involves more variables than terminal sterilization. Before the aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. Sterile drug manufacturers should have a keen awareness of the public health implications of distributing a nonsterile product. Poor cGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient.”4 As a compounding pharmacy, NECC was not accountable to FDA cGMP regulations, but rather was under the inspection authority of the Massachusetts Department of Health. Current law requires compounders to register with the FDA but limits the agency’s enforcement; guidance and inspection is up to states’ Departments of Health. This difference was allowed to afford compounding pharmacies the flexibility they need to formulate small batches of specialty product. It is counterintuitive in this era of harmonization and consolidation to consider so many different state agencies legislating separate inspection codes and equally inspecting so many compounding pharmacies. USP stepped in to help standardize manufacturing quality expectations for these compounders. USP Pharma-ceutical Compounding — Sterile Prepara-tions is a comprehensive chapter, offering significant detail on environmental monitoring, gowning, validation, and storing compounded sterile preparations. It is in the mandatory section of the USP. Twenty-three states now require compounding pharmacies to comply with USP , but as useful as this chapter is, we must stress that it was written for true compounding pharmacies — pharmacists who mix small-scale specialty formulations for immediate use. The question at this point is, how wide-spread is the manufacturing risk? Are other compounding pharmacies distributing large batches of product nationally and how safe are their manufacturing practices? During the 12 months following the NECC disaster, the FDA has conducted audits of many compounding pharmacies. As of this writing, more than 50 US 483s have been issued for these companies, and each is posted on the FDA’s website at 1.usa.gov/13DqpIS. These reports not only give us a peek into current compounding pharmacy practices, they also provide valuable insight into current FDA expectations. What follows is a summary of observations related to the major microbiological control points of aseptic processing: environmental monitoring, personnel gowning, process validation and product testing. Environmental Monitoring Of the 52 483s reviewed, 47 listed deficiencies in the environmental monitoring program of the host company. Almost no company monitored viable organisms during manufacturing; most only monitored twice a year while there was no activity in the plant. Environmental control is a dynamic situation, and the quality of an ISO 5 area and supporting rooms will change as people and items enter it. HVAC performance, seasonal fluctuations, and process variety will all impact the ability of an ISO 5 area and supporting rooms or device to do its job. To test only twice a year and not during actual manufacturing does not give a clear assessment of the microbial control. Other FDA observations concerning environmental monitoring included:
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