Editor's Note: In Part 1 of this 2-part series, we outlined the issues faced by ophthalmologists and other practitioners who depend on a safe, reliable supply of sterile compounded drugs. This article addresses the government's response to the current controversy, and how clinicians can best avoid "compounding their risk" when using drugs supplied by compounding pharmacies.
Buying Compounded Drugs
In the wake of the tragic episode of contaminated methylprednisolone traced to the New England Compounding Center (NECC) pharmacy, there was plenty of blame to go around, but the clinicians who purchased the products of compounding pharmacies got off relatively lightly.
Few clinicians were aware that these facilities were operating without any apparent oversight of practice, or that they were not registered with the US Food and Drug Administration (FDA) or required to report adverse events associated with their products.[1] Many of these pharmacies were not even obliged to adhere to USP Chapter <797> standards nor be inspected for compliance,[2] a fact that took many clinicians by surprise.
Clinicians who purchased drugs from compounding pharmacies might not have been aware of these regulatory deficiencies, but they are not entirely absolved from responsibility for the outcomes. "This was fueled by greed," says Charles Leiter, PharmD, of Leiter's Compounding Pharmacy. "Everyone wants the cheapest product they can find, not really considering how the low price is reflected in the manufacturing process."
Leiter cites the example of a drug commonly purchased for ophthalmology clinic use -- bevacizumab -- and how the fractionating process followed by the compounding pharmacy can affect the safety and cost of the final product. Leiter follows the method of Phillip J. Rosenfeld,[3] which uses a vial spiking device to aseptically aliquot multiple tuberculin syringes after piercing the vial only once. The device also contains a bacterial retentive air-venting filter to sterilize the air that is pulled into the vial. The downside is that a significant amount of drug is lost in the transfer process, raising the per-syringe cost of the drug, although delivering a safer product.
Furthermore, the type of syringe used is critical. Tuberculin syringes are recommended, but some compounders use insulin syringes as a cost-saving measure. Bevacizumab is stable in tuberculin syringes for 6 months, but the stability in insulin syringes is unknown. With insulin syringes, the compounder must puncture the vial repeatedly (raising the risk for contamination), or remove the vial's rubber stopper, which exposes the drug to air. A needle that has been used to penetrate a rubber stopper can lose some of its silicone, making subsequent injection more painful for the patient. Small droplets of drug that remain in the hub of the insulin syringe can also crystallize over time, blocking the needle or causing particulate material to be injected into the patient.[3]
After the NECC incident, clinicians are receiving help from the FDA to find out which compounding pharmacies are not up to par. In recent months, the FDA has increased scrutiny and stepped up both proactive and reactive inspections of compounding pharmacies, inspecting 31 pharmacies so far in 2013.[4] Violations have been found in at least 18 states, involving compounding pharmacies that were producing so-called sterile products. Inappropriate conditions for sterile processing, inadequate environmental monitoring, and failure to test products for sterility or the presence of endotoxin were problems frequently reported by inspectors. Sterile product "beyond use dates" were found to be applied arbitrarily, without supporting data, often on products that contained no preservatives. Among the many concerns found during these inspections, the FDA reported observing "unidentified black particles" in vials of "sterile" injectables, insufficient handwashing practices, and technicians handling sterile products without wearing gloves. In one instance, the earbuds of a technician's headphones came into contact with the field where sterile products were being prepared.
FDA inspection reports are publicly available at the FDA's Pharmacy Inspections Website. Actions taken by the FDA as a result of these inspections, and recalls of compounded products, can be found at thePharmacy Compounding: FDA Actions Website.
Another consequence of the NECC outbreak, which has affected clinical practice, is that some state Boards of Pharmacy have begun to enforce existing regulations requiring that an individual prescription be submitted to the compounding pharmacy for each requested compounded drug. Clinics are no longer able to stock frequently used compounded drugs for use on an as-needed basis. Ophthalmologists report that having to submit a specific patient prescription for every dose of bevacizumab procured from a compounding pharmacy adds significantly to the workload and overhead of an ophthalmology practice.
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