New Law Enhances Safety of Compounded Drugs and Protection of the Drug Supply Chain

By: Margaret A. Hamburg, M.D.

Since last year’s tragic meningitis outbreak and subsequent events involving compounded drugs, Congress has been hard at work to pass new legislation to provide FDA with the appropriate authorities for regulating compounded drugs to help make these products safe for the American public.

Margaret Hamburg, M.D.Over a much longer period of time, efforts have been made in Congress to enhance the security of the drug supply chain and protect consumers from exposure to counterfeit, stolen, contaminated or otherwise harmful drugs.

I am pleased that the Drug Quality and Security Act can help FDA protect public health in both of these critical areas.

One part of the new law offers a step forward in FDA’s oversight of certain entities that prepare compounded drugs. The new law will enable these compounders to register with the FDA to become “outsourcing facilities,” making them subject to certain other requirements including Federal quality standards, known as current good manufacturing practice. These facilities will also be subject to inspection by FDA on a risk-based schedule. If compounders register with FDA as outsourcers, hospitals and other health care providers will be able to provide their patients with drugs that were compounded in facilities that are subject to FDA oversight and federal requirements for current good manufacturing practice, among others. To that end, we will be encouraging healthcare providers and health networks to consider purchasing compounded products from facilities that are registered with FDA and subject to risk based inspections.

Drugs produced by compounders that are not registered as outsourcing facilities must meet certain other conditions described in the law, or they will be regulated by FDA as conventional drug manufacturers.

Generally, the state boards of pharmacy will continue to have primary responsibility for the day-to-day oversight of state licensed pharmacies, including traditional pharmacy compounding. And FDA will continue to cooperate with state authorities to address pharmacy compounding activities that may be in violation of the Federal Food Drug and Cosmetic Act.

Another part of the new law enables certain prescription drugs to be traced as they move through the U.S. drug supply chain. The goal is to protect the public from exposure to counterfeit, stolen, or otherwise harmful drugs. This will require manufacturers, repackagers, wholesale drug distributors, and dispensers (other than most licensed health care practitioners) to provide product and transaction information with each sale and notify the FDA and other stakeholders of illegitimate products, which will result in improved detection and removal of potentially dangerous drugs from the supply chain.

Starting four years after enactment of the law, manufacturers, followed by repackagers, will be required to affix a unique product identifier to each drug package that contains the drug’s national drug code (NDC), serial number, lot number, and expiration date. Starting six years after enactment of the law, wholesale drug distributors, followed by dispensers, may only trade products that  are encoded with product identifiers and will be able to verify the product identifier if they determine that they have  suspect product. Ten years after enactment, supply chain stakeholders and FDA will benefit from an electronic, interoperable system which will facilitate the efficient exchange of product and transaction information for prescription drugs at the individual package level. The system, when fully implemented, will enable verification of the legitimacy of the drug product identifier down to the package level, enhanced detection and notification of illegitimate product, and improved efficiency of recalls.

The Drug Quality and Security Act is a significant step toward having new and stronger drug quality and safety laws. While the law does not provide FDA with all the additional authorities sought, these provisions are a sign of progress.

We are committed and prepared to implement the new law that will help us to further protect public health.

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

Proactive Inspections Further Highlight Need for New Authorities for Pharmacy Compounding

By: Margaret A. Hamburg, M.D.

Ever since the recent fungal meningitis outbreak tragically took so many lives and injured so many others, we have been very clear that we all must act aggressively to help make sure nothing like this ever happens again. Last month I wrote in FDAVoice about the legislation and resources we believe are urgently needed to effectively oversee the evolving compounding pharmacy industry.

Margaret Hamburg, M.D.Above all, patient safety is our greatest priority. In addition to working with Congress and other stakeholders on legislation, we also have been very focused on evaluating our current surveillance and enforcement approach to compounding pharmacies and are using our existing, yet limited, authorities more effectively to protect consumers.

FDA has continued to conduct for-cause inspections upon receiving reports or complaints about serious adverse events related to drugs made by compounding pharmacies, or when states have requested our assistance.

And in coordination with state officials from around the country, we have just recently completed proactive inspections of 31 firms that are known to have produced sterile drugs in the past. We identified these firms using a risk-based model that included factors such as serious adverse event reports, historical inspection data, and reports of product quality problems. The inspections specifically focused on each firm’s processing of sterile drugs to identify firms that may pose a higher risk of producing contaminated sterile products. A summary of these inspections can be found on our website.

During the course of both our proactive and reactive inspections over the past few months, we observed concerning sterility practices, inappropriate conditions for sterile processing and other practices that create risk of contamination. As of this week, we have issued to all but one pharmacy that we inspected an inspection observation report (called an FDA Form 483, or just a “483”) that lists objectionable conditions observed at the facilities. The one firm not receiving a FDA Form 483 was not producing sterile drugs.  

As noted on some of these 483s, select FDA observations during the inspections include:  unidentified black particles floating in vials of supposedly sterile medicine; rust and mold in “clean rooms” where sterile injectable medications were produced; technicians handling supposedly sterile products with bare hands; and employees wearing non-sterile lab coats.

In part, due to FDA’s inspectional observations noted during the inspections, several firms have voluntarily recalled their products, and others temporarily suspended production of their products intended to be sterile while they correct deficiencies found by the investigators.

It may surprise some people to know that, even in light of the recent tragic events, some of the firms we inspect still challenge our authority to conduct full inspections of their facilities. Our inspections have been delayed or the inspectors were denied full access to records at some of these facilities. At least four of our recent inspections were delayed by such resistance; and in two other instances, we had to get administrative warrants from the courts, resulting in U.S. marshals accompanying FDA inspectors back to the firms so FDA could complete the inspection. These challenges and others highlight the need for clearer authorities for FDA to efficiently protect public health.

Additionally, these inspectional observations reveal that there continues to be reason for concern about sterility deficiencies and other problems in some compounding pharmacies across the country – problems that could potentially affect the health of patients. To carry out this proactive inspection effort, FDA had to shift resources from other areas, and this is not a sustainable approach for the longer term. 

We are committed to working with the states, industry and Congress to put the necessary protections in place, but we need to act quickly. And we will continue to work tirelessly on this issue. Patients deserve nothing less.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

FDA Must Have New Authorities to Regulate Pharmacy Compounding

By: Margaret A. Hamburg, M.D.

The deadly outbreak of fungal meningitis associated with a compounded medication was a horrible tragedy, and I’ve asked myself many times if and how it could have been prevented. I speak for everyone at FDA when I say that our hearts go out to the many victims, including those still struggling with this devastating infection, and their loved ones.

Margaret Hamburg, M.D.While our investigation of this deadly outbreak has been a top priority, our responsibility at FDA is also to help make sure this doesn’t happen again. We are currently deploying resources to work with states to inspect certain state-licensed pharmacies that produce sterile drug products that we believe may present the highest risk. Over the past two months, we have inspected over 30 facilities and will continue to work to protect public health. 

But our authorities are limited and not the right fit for FDA to provide appropriate and efficient oversight of this growing industry. There should be legislation that establishes appropriate, minimum federal standards for firms that compound sterile drug products in advance of or without a prescription and ship them interstate.  FDA must have clear authority to proactively inspect pharmacies to determine the scope and nature of their operations.  Even during this time of heightened awareness, our inspectors are being delayed in their work or denied full access to records at some of the facilities we are inspecting.

And serious problems at compounding pharmacies continue to occur. Just this week there have been two recalls of sterile compounded and repackaged drug products. In one recall, the presence of floating particles, later identified to be a fungus, were reported in five bags of magnesium sulfate intravenous solution, resulting in a nationwide recall of all sterile drug products produced by the pharmacy. In the other recall, all sterile drug products from a second pharmacy were recalled as a result of reports that five patients were diagnosed with serious eye infections associated with the use of repackaged Avastin. 

There is a legitimate role for traditional pharmacy compounding. Every day, thousands of pharmacists practice traditional pharmacy compounding—mixing a drug in response to a valid prescription for an individual patient’s need. For example, these drug products could be liquids for patients who can’t swallow pills, or they could be made without certain allergens. These operations are licensed and primarily regulated by the states.

However, a new breed of specialty pharmacy compounding has evolved that has outgrown the law, and can pose a threat to the health of the public.  New legislation is needed that specifically addresses such compounding and the now-established safety concerns.

These pharmacies produce medications in advance of or without obtaining a prescription and distribute them across the country. They make drug products that are intended to be sterile and must be made to exacting standards to prevent dangerous contamination. The magnitude and complexity of these operations have outpaced the current patchwork of state laws that differ in prescription requirements and quality control rules.

I firmly believe that new legislation is necessary to help FDA effectively oversee firms engaged in widespread distribution of sterile compounded drug products in advance of or without receiving a prescription. To that end, FDA is working with Congress, states, industry, and all interested stakeholders to develop a basic framework to protect public health. The Senate committee with jurisdiction over this issue has been working hard on a bipartisan basis to craft such a framework, and we are hopeful that their efforts will yield strong legislation for patients across the nation.

In the new framework, FDA believes that certain high-risk sterile compounding facilities should be subject to federal oversight to ensure that the compounding of sterile drug products at those facilities can be done without putting patients at undue risk, including: 

  • requiring compliance with federal quality standards that are appropriate for the compounding of riskier products and exposure of larger numbers of patients,
  • requiring federal registration of the compounding facilities that will be subject to federal quality standards so FDA knows where they are and what drug products they are making, and
  • requiring these higher-risk compounding pharmacies to report to FDA serious adverse reactions to their drugs of which they become aware so that we can act before potential problems get out of hand. 

And for all pharmacy compounding, FDA believes certain basic protections should be in place. These include: 

  • clear authority to examine a pharmacy’s records to more quickly locate the cause of an outbreak or other violations of the law, and
  • prohibiting compounding of the most complex and highest risk products—drugs and biologics that should only be made for patients by an FDA-registered drug manufacturer under an approved new drug application. The manufacturer will have demonstrated in this application that the product is safe and effective and can be safely made according to the highest quality standards.  

FDA supports and would like to explore with Congress several other ideas, such as requiring compounded drug products to have clear label statements identifying the nature and source of the product. The labeling statements would provide prescribers and consumers with valuable information about the products they are using or taking so that they can make informed judgments about their use. Of course, funding will be necessary to support the inspections and other oversight activities outlined in this framework.  We look forward to working with Congress to explore funding mechanisms, which could include registration or other fees, as Congress has authorized and FDA has successfully implemented in other settings. 

Protecting Americans from unsafe and contaminated drugs is not just an important responsibility for FDA—it is part of our core mission. We must be able to identify dangerous practices before they result in actual harm and, when necessary, intervene to minimize the damage and prevent such tragedies in the future.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

We’re Working to Offset Ameridose Impact

By Margaret A. Hamburg, M.D.

Drug shortages are two words that no one wants to hear—not patients, not health care professionals, and not me.

Margaret Hamburg, M.D.FDA has been working hard to prevent and mitigate drug shortages. In 2011, the number of medications in short supply hit 251. Addressing drug shortages must be a top priority for us at FDA because these are medications that people need to stay healthy, to treat their illnesses, and even, in some cases, to stay alive.

This year, we’ve taken significant steps to expand our efforts and to engage in new ways with industry. Between Jan. 1 and Sept. 30, 2012, FDA worked with drug manufacturers to help avert the shortage of 145 drugs. Many critical medicines used to treat cancer and conditions such as attention deficit hyperactivity disorder (ADHD) are no longer in short supply.

However, drug shortages are still a serious problem, one that may be temporarily impacted by Ameridose LLC’s voluntary recall of all of its unexpired products. Ameridose, located in Westborough, Mass., is managed by some of the same people as the New England Compounding Center—which produced the drug that is implicated in the deadly, multi-state outbreak of fungal meningitis. An inspection of Ameridose was initiated as part of FDA’s ongoing investigation of the outbreak.

FDA recommended that Ameridose recall its sterile drugs because we could not be assured of the sterility of those products. However, this recall may affect supplies of certain life-saving drugs for some health care systems. FDA has identified a number of Ameridose products—including drugs used during surgery and to treat medical conditions that include congestive heart failure—that were on the current drug shortages list before the recall.

We also know that the supply of other drugs may be affected by the Ameridose recall. That’s why FDA is taking proactive steps to minimize the impact this recall may have on current drug shortages, and to prevent other shortages from occurring.

For recalled medications on the current drug shortages list, FDA is taking the same actions it has used successfully to mitigate other shortages.

  • FDA is working with manufacturers of these drugs, requesting that they ramp up production if they are willing and able to do so.
  • For any manufacturers of these drugs that may be experiencing manufacturing or quality problems, FDA is offering assistance to enable them to produce shortage drug products that are safe and high quality.
  •  As with shortages of any critical products, FDA will expedite the reviews of any pending applications that could help with addressing the shortages.
  • FDA is identifying any additional manufacturers willing to initiate or increase production.
  • If manufacturers of critical drugs are not able to meet U.S. patient needs, FDA will explore overseas companies that are willing and able to import foreign drugs to address the shortage. In these instances, FDA evaluates the imported drug to ensure that it is of adequate quality and that the drug does not pose undue risks for U.S. patients.

Since the beginning of the year, the number of advance notifications to FDA of potential shortages has greatly increased. If we know that a problem is on the horizon, we’re able to proactively work with industry, organizations, patients and stakeholders to address it. We have doubled the number of staff members who work in drug shortage prevention and response.

We at FDA are committed to doing everything we can, using all available tools, to prevent or mitigate drug shortages and help keep critically needed products on the market.

Margaret A. Hamburg, M.D., is Commissioner of the U.S. Food and Drug Administration.