Drug contamination cases spur scrutiny of compounding pharmacies

Compounding pharmacies were propelled into the national spotlight last year when a fungal meningitis outbreak was traced to contaminated steroids produced at a compounding pharmacy in Massachusetts.

The Centers for Disease Control and Prevention continues to maintain a case count of fungal infections associated with the contaminated steroid injections. At last count, 745 cases were reported and 58 of those people had died, although deaths were due to a variety of causes and not necessarily fungal infection.

In ophthalmology, use of contaminated drugs can lead to endophthalmitis and blindness.

Recent examples include a series of fungal endophthalmitis cases traced to contaminated triamcinolone prepared at a compounding pharmacy, bacterial endophthalmitis infections associated with contaminated compounds of Avastin (bevacizumab, Genentech) and fungal infection of brilliant blue G dye.

State boards of pharmacy, not the U.S. Food and Drug Administration, regulate and oversee compounding pharmacies. However, the FDA and various other organizations do have guidelines on drug compounding, and in the wake of the fungal meningitis outbreak, federal and state legislation was introduced to address the regulation and oversight of compounding pharmacies.

Enforcement of existing regulations, not new legislation, is needed to ensure compounding pharmacies comply with product standards, ophthalmologist Kent W. Small, MD, told colleagues in a presentation.

“Compounding pharmacies are regulated by state departments and that, basically, is where one of the failures occurred in this [fungal endophthalmitis 
outbreak],” Small said at Hawaiian Eye 2013. “We don’t need more regulations; we don’t need more laws. We just need our current regulations to be properly applied.”

Charles Leiter, PharmD, owner of Leiter’s Compounding Pharmacy, calls for sensible, coordinated national regulation of compounding pharmacies.

“I am not in the majority as far as compounding pharmacies go,” Leiter told Ocular Surgery News. “There needs to be more oversight. Right now, Leiter’s Compounding Pharmacy does business in 49 states. We have to abide by 38 different sets of laws in those 49 states. In order to keep up with the changing regulations, we had to hire an additional employee.”

Eric D. Donnenfeld, MD, OSN Cornea/External Disease Board Member, voiced concern that increased regulation may reduce access to much-needed medications.

“Access to these medications is very important to all ophthalmologists and all patients,” Donnenfeld said. However, he agreed that compounding pharmacies should be regulated for quality.

“There should be inspections of these companies because they need to meet stringent quality control measures,” Donnenfeld said. “Pharmacies that don’t meet these measures are a black eye for all compounding pharmacies and need to be weeded out and eliminated.”

Problems with compounding pharmacies can extend beyond contamination, according to Judy E. Kim, MD, OSN Retina/Vitreous Board Member, who said that regulation involves quality control, not just safety.

“There is a possibility of getting medications that are sub-par, that are not as efficacious and may even be toxic,” Kim said. “Currently, compounding pharmacies are not sufficiently regulated for us to know what they say they’re giving us is really what we are getting.”

Various organizations represent compounding pharmacies, such as the International Academy of Compounding Pharmacists, American Pharmacists Association and Pharmacy Compounding Accreditation Board.

Ophthalmic compounding

Compounding pharmacies fill an unmet need in ophthalmology by making available formulations that otherwise might be unobtainable or that might be more expensive in noncompounded form, according to Donnenfeld.

“Compounded medications are a very important part of our practice,” he said, with use of compounded agents translating into “enormous cost savings to society,” as well as increased efficacy by allowing for treatment options.

Ophthalmologists use a variety of compounded drugs, including Avastin (bevacizumab, Genentech), triamcinolone, brilliant blue, vancomycin, riboflavin and several antibiotics.

“We use compounded drugs almost every day in our practice,” Donnenfeld said. “We use mitomycin for PRK. We use riboflavin for cross-linking.

“In my retina practice, we use Lucentis (ranibizumab, Genentech); I use it occasionally for corneal neovascularization. My retina specialist uses it constantly.

“We use antibiotics for corneal ulcers on a very routine basis and for treating endophthalmitis. We also use intracameral mitomycin in cataract surgery.”

Kim said she works in a university hospital-based practice, where an in-house pharmacy provides all medications and outside compounding pharmacies are not used. However, the practice’s satellite offices use bevacizumab from a compounding pharmacy.

“Ironically, the initial compounding pharmacy that we were using was the New England Compounding Center (NECC), which had that huge outbreak of deadly meningitis,” Kim said. Patients who may have received bevacizumab from the New England facility were contacted when news broke in October 2012 regarding the steroid contamination.

“We told them that they had received Avastin from NECC, but we haven’t seen any problems with Avastin, and they were asked to contact us with any concerns. We have terminated purchasing from that company,” Kim said.

Recent outbreaks

In April 2011, a cluster of endophthalmitis infections was linked to repackaged intravitreal bevacizumab. The outbreak affected 12 patients. Injections were administered at four sites, but the contaminated bevacizumab was traced to a single pharmacy. Ten patients tested positive for Streptococcus mitis/oralis.

The 2011 cluster prompted the American Academy of Ophthalmology to recommend that ophthalmologists select pharmacies approved by the Pharmacy Compounding Accreditation Board and record the lot numbers of medication vials and syringes.

The FDA advised providers to be aware that repackaging sterile drugs without taking proper aseptic measures could compromise drug sterility and increase the risk of infection.

In 2012, Small reported a series of 15 patients who received contaminated intravitreal triamcinolone injections prepared at a compounding pharmacy in Florida. Ultimately, 88% of those patients showed signs or symptoms of fungal endophthalmitis.

“Endophthalmitis is a rare complication, but when it occurs, it can be devastating,” Small told colleagues. In this series, the cause was fungal rather than bacterial, which confounds the diagnosis, he said.

Whereas bacterial endophthalmitis presents dramatically within about a week of a procedure, fungal endophthalmitis has a more insidious presentation and delayed onset, Small said. The infectious agent was identified as Bipolaris hawaiiensis.

“The temporal association is lost,” he said. “When you have a case show up with vitritis 10 months after injection, you kind of forget that the patient had an injection 10 months ago.”

Small was able to make the association for his patients after the compounding pharmacy informed him weeks later that he had received several syringes that were potentially contaminated with fungus. Small and his staff called patients into the office to undergo tap injections and culture testing.

The infections were somewhat of a surprise because the cases presented with quiet eyes and relatively good vision. Small said that he might have overlooked the diagnosis if he had not known that patients had received a contaminated dose.

Both the CDC and state health department were helpful in identifying the pathogen, Small said, but neither offered adequate guidance on managing cases of fungal endophthalmitis.

Donnenfeld said that he has seen few complications with compounded drugs.

“I’ve had many more complications related to solutions and medications that were … created by pharmaceutical companies,” Donnenfeld said, pointing to complications and epidemics of infection associated with balanced salt solution and contact lens solutions.

Safety hinges on using compounding pharmacies that meet current standards, he said.

“When you make a decision to use a compounded medication, you have to have faith in the compounding pharmacy that you work with that they will deliver a premium product,” Donnenfeld said. “Infections can occur regardless of whether it’s [made by] a compounding pharmacy or big pharma. The risk is there, but it is mitigated by using quality companies and using standard preparation patterns that are recommended by the peer-reviewed literature.”

In 2012, Franck’s Compounding Lab in Ocala, Fla., recalled all lots of brilliant blue G because of fungal contamination, according to the FDA website; brilliant blue G is not an approved drug in the U.S. The CDC advised health care personnel “to avoid use of compounded products labeled as sterile from Franck’s during the ongoing investigation.”

“The most important thing we’re buying from these compounding pharmacies is their guarantee of sterility,” Small said.

Drug availability

At the annual American Medical Association (AMA) meeting in Chicago in June, the AMA’s House of Delegates approved a report recommending that compounding pharmacies comply with current U.S. Pharmacopeia and National Formulary compounding regulations concerning uniformity, quality and safety, according to the association’s website.

The report encouraged state boards of pharmacy to require compounding pharmacies to meet sterile compounding standards and recommended that large compounding pharmacies that ship products over state lines be regulated by the FDA.

Ophthalmologists at the meeting agreed with the AMA report in principle but called for exceptions that allow ophthalmologists to have a ready supply of compounded medications on-hand for emergency use without prescriptions. The AMA report was revised to take into consideration the ophthalmologists’ concerns.

A bill introduced in the U.S. Senate would require named prescriptions for many uses of compounding drugs. The AAO has called for exceptions to that requirement.

On May 29, the AAO issued a news release calling for provisions in the proposed federal law that would allow for the use of compounded ophthalmic drugs without a specific patient designation.

“The American Academy of Ophthalmology shares the concerns of Congress regarding the need to ensure that these products are compounded in the most sterile and safest manner possible in order to protect public health,” David W. Parke II, MD, CEO of the AAO, said in the release. “As part of that process, however, the Academy urges the continued availability of these sight-saving medications without requiring patient-specific prescriptions, as time is often a critical element in preventing irreversible blindness.”

Kim voiced agreement that exceptions should be made for ophthalmology.

“Safety regulations are important, but some provisions should be made for different specialties, especially in ophthalmology,” she said. “Every specialty should not be regulated the same way. There should be some provisions that could be made so that we can provide medications for patients in the most optimal fashion using the safest drug possible.”

Kim said that patients sometimes need drugs in emergency situations.

“When a patient comes in with endophthalmitis and needs an injection right away, I have the luxury of contacting my in-house pharmacy; they make it ready in half an hour, and I have it ready to administer,” she said. “Hours and minutes count in certain cases of endophthalmitis and endophthalmitis prophylaxis in intraocular foreign bodies. In addition to certain intravitreal antibiotics, it would be impractical to require patient-specific prescriptions for medications such as Avastin.”

Leiter echoed Kim’s statement about access.

“The doctors have to have access to drugs that are for office use,” he said. “Because if somebody comes in with fungal keratitis or endophthalmitis, you need to give him a shot now.”

State enforcement

Compounding pharmacies are largely untracked, unregulated and underinspected, according to a report by Congressman Edward Markey (D-5, Mass.) released in April.

The report stated that because of states’ failure to oversee and regulate compounding pharmacies, the FDA must be authorized to set and enforce safety standards.

“Government’s first duty is to protect its citizens and right now, most states are not doing their duty when it comes to regulating and policing compounders,” the report said.

The report said that the websites of most state pharmacy boards do not allow keyword searches, hindering public access to enforcement records related to specific pharmacies or medications.

To cut through regulatory confusion and redundancy, the FDA should work with state Boards of Pharmacy to regulate compounding pharmacies, according to Leiter.

Current state requirements do not regulate manufacturing practices, he said.

Leiter said his home state of California has instituted separate licensure for sterility.

“California is the only state so far,” he said. “Leiter’s Compounding Pharmacy has a state board of pharmacy license and a separate sterile compounding license.”

Proposed legislation

The Senate bill would give the FDA authority to regulate compounding pharmacies.

According to a news release from the International Academy of Compounding Pharmacists (IACP), Senate bill 959, the Pharmaceutical Compounding Quality and Accountability Act, would give the FDA authority to oversee a new class of compounding pharmacies that ship products across state lines for in-office use.

The new class of pharmacies would not need prescriptions with patient names, Leiter said.

“I’m all for that because, while the state Board of Pharmacy, the FDA and the [Drug Enforcement Agency] are standing outside a pharmacy arguing over who has jurisdiction and who can do what … people are dying,” he said. “Let the FDA do it. [The FDA] should go with the state Board of Pharmacy and work as a team.”

The bill would exempt hospital and health system pharmacies from being considered compounding manufacturers, even if they ship products to affiliates across state lines, the IACP release said.

In a news release, David G. Miller, RPh, IACP executive vice president and chief executive officer, voiced opposition to the exemption of health system pharmacies from rules preventing batch preparation.

“The exemption is especially questionable in light of the volume and types of compounding done in hospital pharmacies, a substantial amount of which includes sterile compounded preparations,” Miller said in the release.

In 2013, 25 bills or resolutions have been introduced in 16 states, and seven of those measures have been adopted or enacted into law, according to the National Conference of State Legislatures.

Legislation introduced in Massachusetts would require pharmacists to take continuing education classes and provide patients with a staffed hotline number to report problems related to compounded agents.

The Massachusetts law would also require the state’s health department to develop and maintain a website that enables the public to search state records of enforcement actions against problem pharmacies and to search records about adverse reactions reported by patients who have used drugs from licensed pharmacies in the state.

Donnenfeld suggested that compounding pharmacies be regulated like surgery centers.

“Surgery centers are all evaluated on a routine basis to make certain that we meet stringent criteria. I think the same thing could be applied to these pharmacies, as well,” Donnenfeld said.

While waiting for who and how they should be regulated, Kim called for compounding pharmacies to meet and exceed regulatory standards and regulate themselves to some extent.

“The pharmacies should feel the need to perform self-quality measures and testing, internal and external auditing to improve their practices,” Kim said. “These compounding pharmacies can seek independent accreditation to show that they meet some of the regulatory standards that are already out there … Compounding pharmacies themselves should try to adhere to and go beyond regulations to ensure safety of the patients. Physicians can reward those companies by purchasing from them while not using others.”

Statements, guidelines

After the fungal meningitis outbreak, the FDA warned health care professionals to be aware that repackaging sterile drugs without taking aseptic measures may reduce drug sterility and increase patients’ risk of infection.

The FDA joined forces with state authorities to inspect compounding pharmacies suspected of not complying with current standards, according to Stephen King, spokesman for the FDA Center for Drug Evaluation and Research.

“While the current FDA oversight over compounding pharmacies is limited, the agency continues to use its existing authorities to protect consumers,” King said in an email interview. “The agency is particularly concerned about the large-scale distribution of compounded sterile drugs to health care facilities nationwide when compliance with appropriate standards for large-scale sterile production may not have been met, potentially putting patients at risk.”

King stated that legislation is necessary to help the FDA regulate compounding facilities that distribute products across state lines.

“There should be appropriate federal standards for these products that are consistently enforced across all 50 states,” King said.

Matthew D. Bennett, senior vice president of communications and public affairs at Pharmaceutical Research and Manufacturers of America, stated the organization’s position on compounding pharmacies.

“Patient safety is the priority for America’s innovative biopharmaceutical companies. Safety should always be at the forefront of the development, manufacturing and delivery of medicines, and biopharmaceutical research and manufacturing companies are rightly subject to rigorous pre- and post-approval safety standards set by the FDA,” Bennett said via email. “The compounding company identified in the recent meningitis outbreak is not an FDA-regulated manufacturer, although the scope of this company’s distribution of compounded products would seem to require consistent regulation to allow for the best possible care and safety of patients.”

American Society of Hospital Pharmacists guidelines include reviewing documentation of a drug’s safety and efficacy, and considering basic parameters such as sterility, toxicity, pH, buffering, stability, labeling and packaging. – by Matt Hasson