Crackdown!

As part of its crackdown on the use of unapproved drugs in the US, the FDA is warning all but two makers of balanced salt solution (BSS) to discontinue its manufacture and sale. In a notice of the Federal Register issued on 23rd September 2008, the FDA warned that companies making unapproved BSS after 25th November 2008 and shipping it after 21st January  2009 would face enforcement action.

BSS is a sterile, isotonic irrigating solution used during ophthalmic surgery. It was developed during the 1960s as an alternative to saline solution and is intended to provide a temporary replacement for the aqueous humour. In its warning, the FDA noted that approved solutions have been available since 1997.

Who are the culprits?The two BSS makers exempt from the warning are Akorn Inc. and Alcon Laboratories, whose solutions have been approved by the FDA. A spokeswoman for the FDA said that she is aware of at least three US companies making unapproved BSS: B. Braun, Baxter, and Hospira.

“We had reports of consumers having permanent loss of vision because some of the products weren’t being manufactured up to current good manufacturing practices; they were contaminated, they weren’t sterile,” said FDA spokeswoman Rita Chappelle. “The safety and efficacy of the product had not been demonstrated. When people start to lose their sight, that’s a serious concern for us, so we took action.”

What do they have to say?Hospira spokesman Dan Rosenberg told Ophthalmology Times that the company plans to comply but was surprised by this action because it works closely with the FDA.

“We will stop manufacturing it by November 24th and stop shipping it by December 31st, and then we’ll evaluate what our next steps will be in relation to the product,” he said. “Hospira has been working with the FDA to get specific unregistered drugs approved. We just haven’t received any communication with them in the past with regard to this drug. Quality assurance is our highest priority, and this product is manufactured with high-quality standards […] at an FDA-inspected facility in North Carolina.”

Susan Olinger, corporate vice president, regulatory affairs for B. Braun, relayed to Ophthalmology Times in a statement that the company has been manufacturing BSS “in accordance with the Grandfather Clause of the Food, Drug and Cosmetic Act as amended in 1962, because BSS was generally recognized as safe and effective.” B. Braun will comply with the FDA’s directive and is investigating alternatives to returning the product to the market, she said.

Baxter spokeswoman Erin Gardiner told Ophthalmology Times that the company’s solution was “an older niche product” that it had decided earlier this year to discontinue.“We had notified customers in May that we were discontinuing it, so the FDA warning has no impact,” she said, adding that the company’s irrigating solution was an older product developed “decades” before the FDA started an approval process.

300 reportsChappelle said that, as of 31st January 2008, the FDA had received more than 300 reports of adverse events associated with all BSS, including toxic anterior segment syndrome (TASS), bacterial endophthalmitis, corneal oedema, and corneal opacity. In some cases, these events led to permanent loss of visual acuity.

After announcing its intention to crack down on all unapproved drug manufacturing in 2006, the FDA tried to encourage companies to submit their products for approval and, as an incentive, even waived many fees associated with the approval process. The agency is working through its risk-based list of such drugs, and the ophthalmic solution was near the top, she said.

“They’ve known this was coming,” Chappelle said of the drug manufacturers, who could now face seizure and injunction if they continue to make and ship the solution. The companies would also face penalties for any other unapproved drugs they manufacture.

In late 2005, BSS manufactured by Cytosol Laboratories in Braintree, Massachusetts, US was associated with an increased number of TASS cases. The solution was found to contain elevated levels of endotoxins, and the FDA subsequently ordered a recall, which included 1 million units of the solution distributed between December 2003 and December 2005. According to company spokesman Court Lewis, Cytosol Laboratories discontinued manufacturing BSS following the recall.

TASS tormentTASS can range from a mild to a serious problem for ophthalmic surgeons and their patients, said Nick Mamalis, MD, professor of ophthalmology, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, US.

“This inflammation can cause difficulty with corneal oedema or corneal clouding. You can get a large amount of inflammation in the anterior chamber of the eye and the subsequent problems that inflammation can cause, and you can get problems with glaucoma,” said Dr Mamalis, who is co-chairman of the American Society of Cataract and Refractive Surgery’s TASS Task Force.

Although the task force had worked with the FDA before the 2006 recall, it was not consulted prior to this action.

“Since that time, there’s been a large amount of TASS going on. We’ve looked at it, and we’ve not found a link to any particular brand of BSS,” Dr Mamalis said.Discontinuing the manufacture and sale of all but two makers’ solutions will affect many eye surgeons, he said.

“We certainly use BSS in every single cataract and every anterior segment surgery we do, so it is one of those materials vital to our surgeries,” Dr Mamalis said. “This is going to have a large impact.”