by Michael R. Cohen, R.Ph. 

The deadly, multistate meningitis outbreak our country is currently dealing with brings much needed scrutiny to the compounding pharmacy business. The scale of the outbreak makes it the worst among a series of fatal or harmful infections and overdoses linked to compounding pharmacies in the U.S., rivaling other key drug safety issues in the more distant past that have led to substantial drug safety legislation. For example, in 1937, more than 100 patients died after the S. E. Massengill Co. compounded an elixir of sulfanilamide using diethylene glycol (antifreeze), which the company did not recognize as poisonous because safety testing had not been conducted. The tragedy was the driving force behind the 1938 Federal Food, Drug, and Cosmetic (FD&C) Act, which for the first time required drug safety testing.

Exactly 50 years ago this past week (October 10, 1962), in response to severe birth defects associated with thalidomide, Congress passed the Kefauver-Harris Amendment to the FD&C Act, requiring drug manufacturers to provide proof of safety and effectiveness. Up until now, there have been 200 adverse events involving 71 compounded products in the past 2 decades, many with devastating outcomes. Each case has prompted calls for federal oversight of compounding pharmacies, which are not subject to the same controls as drug manufacturers but whose regulation falls between the state board of pharmacy, the state department of health, and the FDA. While the present outbreak cannot be considered an outlier event, it should certainly be the very last event before enacting federal legislation to protect the public from preventable compounding errors and contamination. The magnitude of the current tragedy must serve as a wake-up call for Congressional action, just as it was in the above tragedies.

In April, 2011, I blogged about the need for federal and state oversight after 9 patients died in Alabama due to contamination of nutritional solutions made by a compounding pharmacy. Compounding pharmacies should be testing and monitoring the environment in which products are compounded, training and closely supervising staff, adhering to the recognized standards for compounding safety that were formulated by the United States Pharmacopeia (in Chapter <797> of the USP) and detecting process deviations before they cause harm. Yet, an analysis of recent cases of contamination of products from compounding pharmacies that have led to adverse health outcomes revealed that breaches of standards, unsafe staff behaviors, untrained and unskilled personnel, improper use of equipment, extended beyond use dating outside of manufacturer labeling without sufficient testing, and/or a general lack of good compounding skills had been involved in almost all cases. Since 2004, FDA has issued 49 warning letters to compounding pharmacies around the country for significant safety violations; 19 previous deaths may be associated with these pharmacies. Without federal oversight and/or greatly improved state oversight of compounding pharmacies, patients will continue to be harmed.

As we move forward and learn from the most recent outbreak, Congress must act quickly to address the need for laws on the federal level to fill in current regulatory gaps. Regulations must be equal to what is required of pharmaceutical companies when compounding pharmacies dispense in mass quantities without individual patient prescriptions, or manufacture sterile products from non-sterile active ingredients. These pharmacies must be registered with FDA and subject to periodic inspections. FDA must clearly articulate requirements for IV compounders to register, regulate them and subject them to periodic inspections. For pharmacies that dispense sterile products only on receipt of an individual patient's prescription, FDA must also support the state boards of pharmacy, and expectations regarding the state boards' role in helping to ensure compounding pharmacy safety.

We believe Congress should undertake a thorough examination of the construct of state boards of pharmacy, and examine their roles associated with keeping patients safe. Pennsylvania is one of only five states nationally that do not even mention the need for a compounding pharmacy to adhere to USP <797>. In many other states, the standard isn’t mentioned but aspects of it are incorporated into a state regulation. State boards of pharmacy must require compounding pharmacies to comply with all aspects of recognized sterile compounding standards and survey these pharmacies regularly to enforce compliance. To do this, state pharmacy boards must be provided with additional resources to adequately train and deploy surveyors to assess compliance. Today, many pharmacy boards are ill equipped to take on this responsibility; without additional resources, the assignment of responsibility will not result in improved oversight.

Healthcare providers must use commercially available, ready-to-use products from pharmaceutical manufacturers when available since they are approved by FDA under industry quality standards. When products are not commercially available, providers, including physicians who use these products, must carefully assess and select the compounding pharmacy it will use. All pharmacy staff have a moral and legal obligation to compound preparations using the least risky processes while adhering to the highest standards possible. Even the slightest misstep could result in a disaster such as the tragedy before us.

Selected Pharmacy Sterile Compounding Misadventures






4 patients died of a bacterial infection from non-sterile cardioplegia solution compounded in a hospital.



2 patients lost their vision after becoming infected by Pseudomonas aeruginosa found in indomethacin eye drops compounded in a drug store even though commercial non-steroidal drops were available at the time.



11 children became septic—10 tested positive for Enterobacter cloacae bloodstream infections associated with contaminated prefilled saline syringes. 



11 patients contracted Serratia marcescens infections following the injection of betamethasone compounded at a community pharmacy.



4 children contracted Enterobacter cloacae infections from IV ranitidine compounded in a hospital pharmacy.


North Carolina, South Carolina

5 patients developed Exophiala infections from contaminated injectable methylPREDNISolone that was prepared by a compounding pharmacy; one patient died.



Pharmacy preparing injectable methylPREDNISolone and baclofen recalled the products because of contamination with Penicillium mold, Methylobacterium, and/or Mycobacterium chelonae.



Bacteria contamination with Burkholderia cepacia found in at least 2 batches of a compounded inhalant solution used by 19,000 patients with chronic lung diseases.


Texas, New York, Michigan, Missouri

36 patients developed Pseudomonas bloodstream infections after receiving heparin/saline flushes from multiple lots of preloaded syringes.


New Jersey, California

Up to 25 patients contracted Serratia marcescens infections due to contarminated magnesium sulfate mini-bags prepared by a compounding pharmacy.



2 patients were blinded after receiving a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia; the injectable product is a commercially available product.



Sterile talc vials with unwashed stoppers were not sterility tested before distribution from an outsourcing compounding pharmacy.



10 patients died after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods.



1 baby died from a 1,000-fold zinc overdose (mcg and mg zinc sulfate confused) compounded in a hospital pharmacy.



1 child died after a compounding error led to administration of chemotherapy in 23.4% sodium chloride injection instead of 0.9% sodium chloride.


Washington, Oregon

2, possibly 3, patients died after receiving an intravenous colchicine product compounded at a concentration higher than standard (4 mg/mL vs. 0.5 mg/mL) in a compounding pharmacy.



21horses died after receiving a compounded substitute vitamin supplement containing vitamin B, potassium, magnesium, and selenium (product not approved in the US).



1 child died after receiving more than 60 times the amount of sodium chloride prescribed due to a compounding error in a hospital pharmacy.


California, Florida, Tennessee

16 patients being treated for wet macular degeneration developed severe eye infections due to contamination of AVASTIN (bevacizumab) during compounding; one patient blinded, another patient developed brain infection.



9 patients among 19 died when parenteral nutrition solutions that were administered were contaminated with Serratia marcescens during compounding using non-sterile components to prepare amino acids.



9 patients developed fungal endophthalmitis after use of the compounded product Brilliant Blue-G (BBG) or receiving injections of triamcinolone-containing products dispensed from the same compounding pharmacy.  



More than 200 patients contracted fungal meningitis after receiving methylPREDNISolone acetate injection prepared by a compounding pharmacy that was contaminated with Exserohilum rostratum (a brown-black mold) Aspergillus.