INJECTION TROUBLE A compounded steroid-antibiotic formulation may be the cause of vision loss in dozens of patients who underwent surgery at 2 Dallas-area surgery centers.

If all you know about compounding pharmacies is what you've read in the news, recent headlines have probably left you shaken. After all, a compounding pharmacy prepared the epidural steroid injections for patients with back pain that led to a 2012 meningitis outbreak that killed dozens and sickened hundreds. And this year, a compounding pharmacy prepared the "dropless" steroid-antibiotic combinations that diminished the visual function of more than 40 patients who received the intravitreal injections at the end of cataract surgery. The patients developed various symptoms, including vision impairment, poor night vision, loss of color perception, light sensitivity, glare, halos, flashing lights, ocular discomfort, pain, loss of balance, headaches and nausea, according to an FDA alert. In some cases, symptoms didn't appear until more than a month after surgery.

When the outbreak was first discovered in April, cataract surgeon Jeffrey Whitman, MD, whose patients at 2 Dallas surgical centers were among those who suffered vision complications, told the Dallas Mercury News, "It's devastating in many ways. I've been practicing for 31 years to help people see better, and I feel a little bit hopeless. I'm more angry at the compounding pharmacy for making something that injured our patients." Dr. Whitman declined to comment for this story.

At the time of the outbreak, Jack Munn, RPh, owner and president of Guardian Pharmacy Services, which compounded the intravitreal injections, told the Dallas Mercury News that Guardian was evaluating the triamcinolone-moxifloxacin compound. In a statement to Outpatient Surgery, Guardian Pharmacy Services says it "is committed to the quality and safety of all of its compounded products and has a rigorous quality assurance program in place. The health and well-being of our patients is our foremost concern. While the pharmacy has been named as a defendant in one matter regarding compounded triamcinolone-moxifloxacin, no connection has been established between any Guardian product and the unfortunate adverse event alleged in the lawsuit."

The incidents at the Dallas surgery centers likely won't be the last time compounded drugs will be called into question. Of the estimated 4,500 U.S. outsourcing pharmacies, only 73 are currently registered with the FDA, says Roy Sturgeon, PhD, a senior advisor at Lachman Consultant Services, a pharmaceutical consulting firm based in Westbury, N.Y. He says the federal government doesn't have the manpower to regularly inspect all of the facilities unless a major incident occurs or specific complaints are made against a compounder.

"The only time healthcare providers become aware of the issue is when disaster strikes," says Dr. Sturgeon. "I don't think facility administrators are as aware of the issue as they should be."

PROACTIVE APPROACH
10 Questions to Ask Your Compounder

You can take proactive steps to reduce the risk of receiving tainted drugs from your compounding pharmacy. Start by getting to know the compounder and researching the firm's reputation within the industry, says Roy Sturgeon, PhD, a senior advisor at Lachman Consultant Services, a pharmaceutical consulting firm based in Westbury, N.Y. He also suggests you seek answers to the following questions before accepting any compounded medication.

1. What systems controls are in place to ensure you follow industry standards?
2. Are you compliant with USP Chapter 797?
3. How do you sterilize the final product?
4. Are you routinely inspected by the state board of pharmacy?
5. Has the FDA recently inspected your facility?
6. Does an outside pharmacy consultant regularly inspect your process?
7. What kind of sterility testing do you perform on compounds?
8. Do you conduct periodic challenges to your compounding processes and practices?
9. How do you mitigate the risk of cross-contamination?
10. What assurance can you provide that you'll deliver sterile products?

You can send these questions to compounders in writing and ask them to respond in kind, says Dr. Sturgeon. In addition, he says, ask compounders if they've been audited by a third-party state or federal inspector and request that they provide you with copies of the audit reports.

— Daniel Cook

Finding the right provider
Can you trust outsourcing facilities to obtain the ophthalmic medications you need? What can you do to ensure you partner with a reputable compounder?

"When dealing with compounded ophthalmic drugs, you have to worry about the sterility, potency and purity of any ingredients that are used," adds Dr. Sturgeon. "You must also make sure that no particulate matter makes its way into the formulations and ensure drugs are made in sanitary conditions."

The Drug Quality and Security Act (DQSA) was signed into law in November 2013 in response to the 2012 fungal meningitis outbreak that killed 64 people and sickened hundreds more. It's the deadliest medication contamination case in U.S. history and has been linked to tainted steroids produced at the now shuttered New England Compounding Center in suburban Boston.

The DQSA created a new section — 503B — in the Food and Drug and Cosmetic Act. Under section 503B, a compounder can become an "outsourcing facility." That created a new type of compounding pharmacy: a large-scale drug manufacturer that must adhere to strict FDA regulation, which includes current and good manufacturing practices, facility inspections, the proper labeling practices and stability testing of compounded products.

"These are standards that are very close to those in the drug manufacturing sector," says Neal Shorstein, MD, an ophthalmologist who is an associate chief of quality for Kaiser Permanente Northern California in Walnut Creek, Calif. "We now have a much higher level of quality and oversight of compounding pharmacies."

Working with 503B compounders offers some assurance of safety, but don't assume diligent oversight is taking place, says Roger Goldberg, MD, MBA, of Bay Area Retina Associates, a group of ophthalmologists who practice in and around Oakland, Calif. He advises ophthalmic surgical facilities to partner with compounded pharmacies that aren't afraid to open their doors to inspectors and follow USP 797, which is the guideline for the safe preparations of sterile compounded medications.

"Nowadays, you should also use a pharmacy accredited by the Pharmacy Compounding Accreditation Board, which performs voluntary announced or unannounced inspections of compounding pharmacies that request to be accredited," says Dr. Goldberg.

He says pharmacy consultants who are expert in aseptic processing and who have solid backgrounds in compounding systems and controls can help you find compounders with proper protocols in place with respect to facility design, staff training, enabling documentation and proper oversight (see "10 Questions to Ask Your Compounder" above).

A continuing concern
Compounded drugs are commonplace in ophthalmic ORs, where surgeons use the mixtures to provide clinical benefit or improve outcomes when faced with surgical challenges for which branded medications are unavailable.

Many surgeons, like the ones at the 2 Dallas surgery centers, inject a compounded steroid-antibiotic formulation into the eye to reduce the risk of endophthalmitis and to largely eliminate the need for post-op eye drops, says Dr. Goldberg.

Surgeons also use intraoperative intraocular vancomycin to reduce the risk of post-op endophthalmitis, but the practice is not without controversy and is being reevaluated among eye surgeons and policymakers. In October, the FDA warned against the use of intraocular vancomycin during cataract surgery to prevent endophthalmitis after reports surfaced that hemorrhagic occlusive retinal vasculitis (HORV) — characterized by sudden decreased vision, intraocular inflammation and intraretinal hemorrhage — developed in patients following injections of a compounded triamcinolone, moxifloxacin and vancomycin formulation at the end of otherwise uncomplicated cataract surgeries.

There is no FDA-approved vancomycin formulation for intraocular injection. The FDA, which is unaware of any adequately controlled studies demonstrating the safety and efficacy of intraocular vancomycin in preventing endophthalmitis, recommends against the prophylactic use of the antibiotic alone or in a compounded drug during cataract surgery because of the risk of HORV.

"We're still trying to get a handle on the scope of the problem," says Dr. Goldberg. "Vancomycin makes an already low rate of infection even lower, but the therapy introduces its own risk. It's a balancing act, and at some point, the injections don't provide additional benefit in relation to the risk it introduces."

Dr. Shorstein points out that some cataract surgeons use an intracameral lidocaine-phenylephrine combination for mydriasis in patients with small pupils or in patients who've had exposure to tamsulosin. "There are no FDA-approved injectable products for those indications, so injectable versions must be obtained from a compounding pharmacy," he adds.

The No. 1 reason surgeons don't use intracameral antibiotics? Because there's no manufactured FDA-approved product, according to a survey conducted by the American Society of Cataract and Refractive Surgery. "We know that's the biggest hurdle," says Dr. Shorstein. "Many cataract surgeons depend on compounding pharmacies to fill that gap."

The onus is on you to ensure that the gap is filled safely. OSM