A barrage of inspections by FDA and state pharmacy board investigators has uncovered numerous safety violations at compounding pharmacies that supply hospitals and practitioners across the country with batch quantities of customized sterile solutions.

Most of the investigators’ on-site reports have focused on incidents of failure to maintain optimal-quality conditions and procedures for safe sterile compounding, a reflection of lax adherence to U.S. Pharmacopeia Chapter <797> standards. But some inspections also have uncovered evidence of product contamination, and several recent highly publicized cases have led to large-scale product recalls.

On May 8, for example, the FDA announced that it had concerns about a lack of sterility for drugs manufactured and distributed by The Compounding Shop of St. Petersburg, Fla., following inspections of the company's manufacturing facilities. The FDA requested that the company withdraw all of its sterile products from the market, and that any existing products not be administered to patients.

On April 17, Balanced Solutions Compounding Pharmacy, of Lake Mary, Fla., initiated a total sterile products recall “due to concerns associated with quality control processes” that led to “a lack of sterility assurance.” The recall came as a result of an earlier FDA inspection of the facility, which uncovered gram-negative bacteria in samples of the firm’s chromium chloride formulation for injection.

Kasey Thompson, PharmD

And on March 20, Clinical Specialties, of Augusta, Ga., recalled all of its sterile products, also due to a lack of sterility assurance. The action grew out of an earlier investigation into the company’s repackaged injectable bevacizumab (Avastin, Genentech) following reports of five serious eye infections linked to physicians’ off-label use of the cancer drug for patients with macular edema.

Except for the injectable bevacizumab, none of the recalled products have yet been linked to known adverse events. But coming on top of more than 50 deaths from fungal meningitis and other infections associated with injections of tainted methylprednisolone made by the New England Compounding Center (NECC), the inspection reports and recalls have raised apprehension levels among hospitals and other health care providers that rely on outsourcers to fill at least part of their sterile compounding needs.

“There is a legitimate heightened concern out there,” said Kasey Thompson, PharmD, the vice president of policy, planning and communications at the American Society of Health-System Pharmacists (ASHP). “We could say that as the months have passed, perhaps it has gotten worse.”

Allen J. Vaida, PharmD

The concern may even be having an effect on hospital pharmacy ordering practices, noted Allen Vaida, PharmD, the executive vice president of the Institute for Safe Medication Practices. “A big issue that we’ve been hearing out there,” he said, “is that many hospital administrators are telling their directors of pharmacy, ‘No more outsourcing. We’re scared of this. We want you to do it all in-house.’ And many of these pharmacies may not be equipped to do it.”

Dr. Vaida further explained that many hospitals are not equipped environmentally to carry out compounding activities internally. “They may not be set up or have the staff to follow USP <797> standards,” he said. “I’m not even talking about non-sterile to sterile [compounding]. Very few hospitals are even looking at that. I’m talking about making parenteral nutrition, cardioplegic solutions, and about doing some repackaging into unit-dose sizes.”

In such cases, Dr. Vaida noted, a safer option may be to partner with an established, vetted compounder that has a solid track record of following safe manufacturing practices and has documented proof that they have been adhering to USP Chapter <797> policies and procedures. “The ASHP’s guidelines on outsourcing sterile compounding services [Am J Health Syst Pharm 2010;67:757-765] can really be a big help in evaluating a vendor based on these types of determinations,” he added.

A ‘Wake-up Call’ for More Action

Dr. Thompson noted that the NECC tragedy “was a real wake-up call about how the regulatory system worked as it related to large-scale compounding.” He said one area that has proven to be murky is the degree to which site inspections are done for FDA-registered compounders. “Many of these entities were, and still are, registered with the FDA,” he said. “I think most practitioners thought that this meant that the FDA did routine inspections and regulated those entities. It turned out not to have been the case.”

Dr. Vaida echoed Dr. Thompson’s point that being registered with the FDA is no guarantee that routine inspections will occur. “Many of the [cited compounders] said they were registered with the FDA, and a lot of pharmacies who purchased from them relied on that,” he said. “But now the FDA is basically saying that doesn’t mean anything—it doesn’t mean the FDA inspects them. [The agency is] only called in when something happens.”

Tom Rasnic, MBA, the vice president of Quality Assurance and Regulatory at PharMEDium Services LLC, one of several large-scale pharmacy compounders to undergo federal and state inspections in recent months, took issue with the idea that such inspections are an infrequent and haphazard affair. “Our experience has been that having [been] registered with the FDA resulted in frequent and routine inspections,” Mr. Rasnic noted in an email to Pharmacy Practice News.

The lack of a consistently implemented policy on inspections is only one challenge facing the industry. A larger issue, experts note, is the lack of federal oversight of compounding pharmacies that produce large batches of often high-risk injectable medications without patient-specific prescriptions. This practice has opened a huge medication safety gap that the FDA, Congress and state pharmacy boards are now scrambling to address. “This is something that has fallen into a big black hole,” Dr. Vaida said. “From a regulation standpoint, there needs to be changes,” and federal and state governments “need to get together and define who has authority for what.”

In late March, Margaret Hamburg, MD, the commissioner of the FDA, issued a new call for federal legislation giving the agency clear authority to regulate large compounding pharmacies that operate in the murky zone between traditional compounding for individual patients and manufacturing for anticipated population needs. “The magnitude and complexity of these operations have outpaced the current patchwork of state laws that differ in prescription requirements and quality control rules,” Dr. Hamburg wrote in an FDA Voice blog posting. In mid-April, during a congressional hearing on the compounding crisis, Ms. Hamburg reiterated her call that the FDA should be given more defined enforcement authority over compounding facilities (see related article, page 36).

The commissioner’s call for clarifying legislation was quickly endorsed by PharMEDium. “We support the passage of federal legislation to establish a new FDA category for sterile compounders governed by applicable current Good Manufacturing Practices [GMP],” Mr. Rasnic noted in a statement issued by the company. “We believe FDA oversight of interstate shipments of sterile compounders is necessary.”

Mr. Rasnic added that PharMEDium “supports ... that there be a new FDA category” containing the applicable GMP standards for sterile compounders. Such a category, he noted, would “provide FDA with clear oversight.”

ASHP, along with the National Association of Boards of Pharmacy and other pharmacy organizations, has been an outspoken advocate for new laws that clearly define federal and state roles in regulating the entire continuum of pharmacy compounding practice. “It’s a very delicate, careful set of discussions that we need to have here,” ASHP’s Dr. Thompson said. “You can’t have situations where these entities are preparing copies of commercially available brand-name products. Or situations where you’ve created a regulatory pathway to allow an entity to produce a generic drug without submitting an abbreviated new drug application.”

On the other hand, he said, hospitals have come to depend on these large-scale compounders to supply customized dosage forms and fill voids due to drug shortages. “We can’t just shut down the compounding industry. That would not be good for patient care,” he said. “But at the same time, we have to make sure that the right things are happening and bad things are not. We’re hoping Congress will take action sooner than later and get some draft legislation out there that the communities of interest can respond to.”

Mr. Rasnic commented that drug shortages are not the primary reason why pharmacies choose to outsource. In most cases, he said, hospitals buy from PharMEDium and other established, responsible compounders “to fill voids due to required anticipatory premixed drugs for IV and epidural therapies that are not commercially available.” In partnering with potential outsourcers, he added, it’s important to choose companies “who play by the rules and adhere to USP <Chapter> 797” to ensure the safety of the purchased products.

Concerns Over Liability

Another concern that has emerged is the question of liability. Without new laws establishing clear authority for large compounding pharmacies to produce batch quantities of products in anticipation of patient needs, hospitals that dispense medications ordered from them may find themselves in legal jeopardy if another public health crisis were to occur, like the meningitis outbreak tied to NECC, according to Dan Ross, PharmD, the president of D Ross Consulting, in Glendale, Calif. “If you’re still buying without performing the necessary due diligence,” he said, “you’re putting your hospital at some risk.”

Bonnie Kirschenbaum, MS, a health care consultant based in Boulder, Colo., said that Dr. Ross’ stated concerns over liability are legitimate. But she said they are most relevant for a compounding pharmacy that has gone beyond compounding and into manufacturing from raw non-sterile ingredients, without exerting the same controls that a manufacturer would be subject to, or if the company does not follow strict compounding technique with appropriate quality control measures. Some of these concerns over safety and liability “can be mitigated by carefully vetting any sterile compounding pharmacy that the facility considers doing business with,” noted Ms. Kirschenbaum, a member of the editorial advisory board of Pharmacy Practice News.

Dr. Ross, formerly the director of pharmacy and medication safety at Catholic Healthcare West (now California-based Dignity Health), said it can be hard to determine, at least initially, whether a given manufacturer is in fact exceeding guidelines for safe compounding. The ongoing problem of drug shortages adds further pressure and complications. “If you’re a hospital pharmacy director and there’s a shortage of succinylcholine, you may be tempted to buy anything you can,” he said. “But I’d caution against any rash purchasing decisions.”

In fact, there are several precautions pharmacy directors can take to mitigate the risks of partnering with a third-party compounder. first, Dr. Ross said, they should review ASHP’s resources for vetting outside compounders. What’s more, they also should make their own firsthand inspections of prospective compounding pharmacies, if possible. Additionally, he said, they should consult with hospital administration and legal “to make sure that you and your organization are going into it with your eyes wide open, because your pharmacy directors are going to get hung out to dry” if things go wrong in the end.

One effective strategy for reducing both legal and drug safety risks is to limit the number of “special concoctions” ordered by ophthalmologists, surgeons and other practitioners to when they are medically necessary, Dr. Vaida noted. “This is an opportunity to sit down at pharmacy and therapeutics committee meetings and say that, hey, there is not a lot of evidence for [having so many formulations].”

The time to do that, Dr. Vaida stressed, is right now. “If you have [that conversation] a year from now, people may forget,” he said, “and if you say, “Look at what happened last year,’ they might respond, ‘Oh, that was something that happened in Tennessee, wasn’t it?’”

Putting It all in Perspective

Ernest R. Anderson Jr., MS, RPh

Ernest R. Anderson Jr., MS, RPh, former system vice president of pharmacy at Steward Health Care System, in Boston, and a member of the editorial advisory board of Pharmacy Practice News, said these are all difficult issues—especially when drug shortages are thrown into the mix. “On one hand, patients need drugs that are often in short supply, but when seeking those solutions one has to be certain of the integrity of the repackager that you are purchasing from,” he said. “PharMEDium, as one example, is manufacturing from sterile, commercially available products and not compounding from unsterile powders as the base to manufacture the sterile product. We need to steer clear of those products made in compounding pharmacies from non-sterile powders.”

In his experience doing site inspections of reputable, established, FDA-registered compounding facilities, Mr. Anderson added, he has found that those facilities “far exceed most hospital pharmacies” in their environmental control practices and adherence to compounding guidelines. “But if your administrators still want the in-house pharmacy to do all the compounding in lieu of outsourcing,” he noted, “then the administrators had better supply the capital dollars to make the pharmacy USP <797>–compliant and the staff to do so as well.”

—Bruce Buckley, with additional reporting by David Bronstein