CDER’s Efforts to Help Improve the Quality of Drug Compounding Include an Ongoing Focus on Insanitary Conditions

Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.

Although compounded drugs can serve an important medical need for certain people, these drugs also present a risk to patients. In 2012, a contaminated compounded medicine — injections of the anti-inflammatory drug methylprednisolone — prepared by the now-out-of-business New England Compounding Center (NECC) caused a nationwide fungal meningitis outbreak. This outbreak killed 64 people and caused infections in almost 800 others who received this product. Well before this incident and during the years since, FDA has been diligently working to enhance the quality of compounded drugs for the American public.

In this CDER Conversation, Ian F. Deveau, Ph.D., division director within CDER’s Office of Manufacturing Quality, shares his perspectives. Dr. Deveau was a lead compliance officer of the NECC incident.

As a lead compliance officer of the NECC incident, you have a unique perspective on pharmacy compounding issues in the U.S. What has FDA learned since this tragedy?

One key thought I’d like to share is that, unfortunately, the NECC tragedy was not unique. It was by far the most prominent, the most wide-spread, and sadly, the most tragic in terms of deaths and injuries. However, prior to NECC there were others — and even more sadly, we continue to see harm to patients because of poor compounding procedures. For instance, from 1990 to 2005, we know of at least 240 serious illnesses and deaths associated with improperly compounded drugs. We’ve learned that despite many efforts to enhance practices to improve the quality of compounding for patients, there are still challenges and more work needs to be done. But I want to emphasize that while we need to move the needle to enhance the quality of compounded drugs, there are compounding facilities making quality drugs for patients who may need them.

Let’s get to those challenges in a moment, but first, have you seen improvements?

Without a doubt, we have done much to help improve compounding in the U.S. — before and since the NECC tragedy. And we will continue to put patients first in our oversight efforts; I believe compounders and the agency share this goal of protecting patients. Many compounders have stepped up to address our concerns about practices that could result in compounding drugs that cause patient harm. There have been occasions when we have seen fewer problems when we reinspect certain facilities and we hope this continues. But there is still much work to be done to improve the overall quality of compounded drugs to protect patients.

What are some ongoing challenges?

If I had to direct attention to one glaring area that is still in need of improvement, I would definitely focus on insanitary conditions. Under federal law, drugs prepared, packaged or held under insanitary conditions are considered adulterated. Insanitary conditions in the facility could cause a compounded drug to become contaminated or otherwise cause patient harm.

We are concerned that despite our intensified inspection and enforcement efforts, we are still finding insanitary conditions during facility inspections. We strongly urge compounders to heighten their awareness of methods and techniques to make certain no insanitary conditions exist in their compounding areas. Our final guidance on insanitary conditions offers valuable information about the types of insanitary conditions we’ve seen and how compounders can identify these types of conditions within their facilities and implement corrective actions to address these issues.

Following an FDA inspection, our investigators provide facilities with their observations in a Form FDA 483. Facilities in which FDA observes insanitary conditions need to adequately address these concerns or they may face further regulatory or enforcement action. FDA has taken regulatory or enforcement action when insanitary conditions exist. Information about inspections, product recalls and related FDA actions is available on FDA’s website.

With a goal of protecting patients and identifying problems in facilities that need to be addressed, we have conducted hundreds of inspections of compounding facilities, many resulting in warning letters or leading to recalls. Many recalls were for drugs intended or expected to be sterile but recalled due to a lack of sterility assurance. We continue to receive reports of serious adverse events or drug quality issues, such as drugs contaminated with bacteria or fungi.

So, from my point of view, we are still seeing too many pharmacies with insanitary conditions.

Can you give us examples of insanitary conditions? What insanitary conditions are FDA investigators looking for during an inspection?

During an inspection, our investigators are on the lookout for things like filth, dirt, mold, peeling paint, chipped drywall, damaged air filters and so on. Some insanitary conditions are obvious, but others are less so. A wood table, for example, may not seem insanitary. However, it is porous, making it difficult to clean. It also is particle-generating and can collect dust and many other contaminants, no matter how well it might be cleaned.

Also, pets and drug compounding are not a good match. Dog and cat owners love their animals. If you have these animals at home, like I do, you know how much pet hair and dander they generate all over your house. If you work at a compounding facility, leave your pet at home.

Table is laminated wood particle board and therefore porous, making it difficult to clean.

Air cleanliness is another important issue. I’ve seen far too many cases with evidence of visibly dirty air filters in laminar flow hoods where sterile products for injection into the body are prepared.

Visibly dirty HEPA air filters in an outsourcing facility.

It’s also important to make sure lesser-quality air does not enter areas where higher-quality air is needed. For example, a door that is left open between an uncontrolled area and a room where sterile compounding is conducted.

Compounded production took place in a carpeted room where room air was not HEPA-filtered. Carpeting is hard to clean.

Sterile cleaning and disinfecting agents that kill spores, a type of very resilient bacteria, should be used with enough “dwell time,” or time in which the surface is kept “wet” with the cleaning and disinfecting agents. Think of a child’s toothbrush with a built-in timer that will light up after two to three minutes to indicate that brushing time is over. Any dirty equipment is clearly an insanitary condition.

Visibly dirty equipment used to make injectable drugs is another example of an insanitary condition.

We have found Bacillus sp. and other spores as well as bacteria when we analyzed non-sterile wipes.

Non-sterile wipes being used to disinfect the cleanroom. Sterile wipes should be used.

The most significant liability is the people working in the compounding facilities. That’s why gowning, or covering your body, is so important, including hands, wrists, legs, hair, feet and mouth. Skin is a huge culprit in creating insanitary conditions. There are more than 1,000 known microbial species found on healthy human skin. The average person sheds 37 colony forming units (CFU) per hour. CFU is a microbiology term to quantify how much bacteria exist in a solution. In other words — a lot of bacteria can enter the air from a person’s exposed skin. Also, compounders working in cleanrooms should not wear make-up or have exposed jewelry, as these can shed microorganisms.

Additionally, you cannot imagine what can be spread when saliva enters the air. That’s why I can no longer watch live performers, such as a play, without thinking about the germs they may be emitting. But in all seriousness, when masks are not used in the preparation of drugs intended to be sterile, that represents a major insanitary condition.

Does FDA find these types of insanitary conditions during inspections?

Unfortunately, yes. So many of our findings are the kinds of things most people would look at and not recognize as dangerous. But when you are assessing them in terms of preparing drugs that will be injected into peoples’ bodies, they really matter. For example, a chef at a restaurant isn’t usually concerned about air moving from the dining hall into the kitchen; however, for a compounder producing sterile drugs, air moving from a break room or other non-sterile room into a sterile compounding area can lead to drug contamination and serious health consequences.

As I said earlier, there are now many compounding facilities that appear to appropriately prepare compounded medicines. We have come a long way in our efforts to forge improvements. But we’ve seen multiple times over the years, all it takes are a few bad operators to make compounding a riskier practice than it needs to be.

Any advice for patients to get their compounded medicines from reliable sources?

We work hard to protect patients and help make sure that compounding facilities engage in quality practices. However, patients are their own best advocates, and I encourage people to be informed about the compounded medicines they may be taking. Ask your health care professional about the compounded medicine he or she prescribes. Have them explain the risks and benefits of the medication. Compounded drugs are not FDA-approved, meaning their safety and effectiveness are not evaluated prior to patient use. That being said, these drugs can be an appropriate treatment option for certain people.

I advise individuals to know where your compounded medications are made. Talk to your doctor about any issues other patients may have experienced with the medication. Research the compounding facility. As I mentioned before, we have a list of compounded risk alerts, as well as information about inspections of compounding pharmacies. You can also contact your state’s Board of Pharmacy to ask questions about a pharmacy.

Any advice for pharmacies and physicians to help protect patients?

We have been diligently working to help pharmacies enhance the quality of their compounding practices and comply with regulatory requirements. Much of our work involves the creation of FDA guidance documents, which outline the agency’s thinking about drug compounding.

FDA has created the Compounding Quality Center of Excellence to help improve the overall quality of compounded drugs, primarily those made at outsourcing facilities. Our free online trainings that are a part of the Center of Excellence are a good way for pharmacists to learn more about cleanrooms, sterile processing and much more. Additionally, we urge pharmacists and others who work in compounding facilities to carefully review our final guidance on insanitary conditions.

We urge compounders to proactively work to protect patients from receiving poor quality compounded medicines. When there’s a steadfast commitment to quality vigilance, everyone wins.