Tag Archives: contaminated drug

Contamination found in NIH pharmacy

By Kim Smiley

The National Institutes of Health (NIH) has announced that production of drugs for use in clinical studies has been suspended after fungal contamination was found in two vials of product.  The exact source of the contamination has not been identified, but a recent Food and Drug Administration (FDA) inspection of the facility that prepares the contaminated product found multiple deficiencies, including issues with both the facility and work practices.

This issue can be analyzed by building a Cause Map, a visual root cause analysis that intuitively lays out the cause-and-effect relationships that contribute to an issue. The first step of the Cause Mapping process is to determine how an issue impacted the overall goals.  In this example, the safety goal is impacted because 6 patients were unknowingly given potentially contaminated drugs.  These patients received vials of product from the same batch as the 2 vials found to be contaminated prior to the contamination being identified.  None of the patients have shown signs of illnesses, but they will continue to be monitored. Additionally, the safety goal is impacted because some patients will knowingly be given potentially contaminated drugs.  These patients are due for treatment imminently with no alternative available and the risk of delayed treatment has been determined to be greater than the risk of using the products.  The schedule goal is also impacted as clinical trials are being delayed because the necessary medications aren’t available.

The next step is building the actual Cause Map by starting at one of the impacted goals and asking “why” questions.  So why were the drugs contaminated? It hasn’t been released what specifically lead to the fungal contamination and it may never be known, but the FDA found deficiencies within the facility that could lead to contamination. The inspectors observed workers working with sterile products with protective gear worn inappropriately so that skin and facial hair were exposed.  Issues with the facility itself was also noted, both in the design of sterile work spaces and in the cleanliness of the spaces.  Inspectors determined that the air handling system for the clean rooms wasn’t adequately designed to ensure physical separation from the other spaces.  Additionally, a filter was missing on the air handling system.  The problems with cleanliness of clean rooms included insects found in 2 of 5 clean room ceiling light bays.

The investigation into these issues is ongoing and officials are working to ensure the safety of all products.  As more information becomes available, it can easily be added to the Cause Map.  Once the specific problems with the work processes and facility have been determined, specific solutions can be implemented to address the many issues found by investigators. This problem is one that clearly doesn’t have “one root cause”, but rather many causes that contributed to the problem and more than one solution will be needed to reduce the risk of contamination to an acceptable level.

Non-Sterile Product Administered Intravenously to At Least 40 Patients

By ThinkReliability Staff

A non-sterile product that was meant for clinical simulation (training) only was administered intravenously (via IV) to at least 40 patients, one of whom died and at least 17 of whom became seriously ill. Because the death was in a hospice patient, it was not determined definitively that it was caused by the solution. The Food and Drug Administration (FDA) is taking no chances – after the reports of patient injury, the FDA had released an alert warning medical practitioners not to use the product “for clinical simulation” on patients. The company that manufactured the products later implemented a recall.

Whether or not the patient death can be blamed solely on the IV use of a non-sterile product, administering a non-sterile product to a patient is clearly an impact to the patient safety and patient services goals. At least 17 injuries (which typically were discovered very quickly after use of the non-sterile IV product) have been tied to the error. The recall is a product goal to the manufacturer – which does not produce any sterile products. The investigation by the FDA is an impact to the labor goal. How these goals were impacted and what is being done or recommended to prevent these impacts can be captured in a Cause Map, a visual root cause analysis diagram of cause-and-effect relationships. (To view the Cause Map, please click on the image above.)

Patient safety was impacted because of the administration of a non-sterile IV product to patients. These patients were receiving saline product via IV to treat various medical conditions (dehydration, for example) and the product was not sterile. Because the product was for training purposes only, it was not meant to be sterile. Healthcare facilities that administered the solution said they were unaware that it was a non-sterile product.

The non-sterile product was delivered to the facility, whether by the ordering or delivery of the incorrect product. According to Dr. Alexander J. Kallen, the medical officer at the Centers for Disease Control and Prevention (CDC), “It seems like it’s not just one single mistake. There could have been instances where ordering was done by office staff who didn’t know the difference, as well as instances where the right product was ordered but they received the wrong stuff.” It does appear that the facilities in question (which are located in Florida, Georgia, Idaho, Louisiana, North Carolina, New York, and Colorado) all received the product from the same distributor, indicating a likely issue associated with the distributor’s delivery or ordering process. A nationwide shortage of sterile saline solution may have led to the use of additional suppliers, contributing to the confusion.

Even if the wrong product is delivered to a healthcare facility, there are still multiple opportunities to identify the problem before patient harm results. In this case, had anyone at the healthcare facility looked at the product – which was labeled “For clinical simulation”, the products could have been removed from the facility, as did happen at some facilities, which returned the non-sterile product.

The FDA has requested that all healthcare facilities and product distributors individually inspect saline product to be administered to patients to verify that it is sterile and not intended for training purposes. The manufacturer of the training products has asked its distributors to add language to its advertisements specifying that they are for training, and are not sterile for patient use. In the meantime, the FDA is working with manufacturers of sterile saline to increase the supply, and has provided links to available supply on their website.

What should you do? If you are involved in an IV transfusion, either as a patient or a practitioner, check what’s being delivered and ensure it matches your doctor’s order. Go to the FDA’s site to learn more about the recall, investigation or saline shortage.


FDA Inspections Find Issues at Compounding Pharmacies

By Kim Smiley

Unsafe practices at compounding pharmacies were found during recent Federal Drug Agency (FDA) inspections.  The FDA visited about 30 pharmacies in 18 different states, focusing on the production of sterile drugs which was determined to be the highest risk to patient safety.   The inspection findings include a number of potential contamination issues such as inadequate ventilation, unidentified particles in vials of supposedly sterile medications, cleanliness issues in clean rooms such as rust and mold, and insufficient microbiological testing. Interest in compounding pharmacies was increased after the fall 2012 outbreak of fungal meningitis that killed 50 and sickened hundreds was traced back to compounded injectable steroid medication that had been shipped across the country.

A root cause analysis of the issues at compounding pharmacies can be done by building a Cause Map.  A Cause Map visually lays out the different causes that contribute to an issue and is a way to intuitively illustrate the problem.  Compounding medications are an issue because they can pose both indirect and direct risks to patient safety and patients are using them.   The indirect risk is that patients may inadvertently use an ineffective medication.  Compounded medications are not regulated by the FDA and have not gone through a formal approval process that requires extensive testing.  Medications that are compounded can also be a direct risk to patient safety if they are contaminated or sub- or super-potent.  As the fatal fungal meningitis outbreak unfortunately demonstrated, contamination of supposedly sterile drugs can have deadly consequences. Compounded drugs are receiving more attention than traditionally manufactured drugs because some of the facilities may have less oversight and the recent investigations found more issues with the work processes at the compounding pharmacies than is typically discovered at drug manufacturing facilities.

Many are asking questions about how compounding pharmacies are regulated and overseen.  Compared to drug manufacturers, the FDA’s regulatory authority over compounding pharmacies is limited.  Compounding pharmacies are not generally even required to inform the FDA what drugs they are making or register with the FDA.  State boards of pharmacy regulate the compounding pharmacies and the FDA typically becomes involved only to do for-cause inspections upon receiving reports or complaints or when states have requested assistance.

It’s worth noting that compounding pharmacies do serve an important need.  Some individuals cannot be treated with standard manufactured medication.  An example of this is when somebody is allergic to an inactive ingredient, such as a dye, in an approved medication.  The real concern is that the creation and  use of compounded medications seems to be changing from its traditional function.  According to Ilisa Bernstein, acting director of Center for Drug Evaluation and Research’s Office of Compliance, “Some aspects of these firms’ operations appear more consistent with those of drug manufacturers than with those of traditional pharmacies. Some firms make large amounts of drugs that appear to be copies of FDA-approved, commercially available drugs when it does not appear that there is a medical need for an individual patient to receive a compounded version of the drug.”

There have been a number of voluntarily recalls as a result of the recent inspections.  The FDA and state regulatory boards are working together to address the issues that were uncovered.  Additionally, the FDA is pushing for new legislative authority over the highest-risk compounding pharmacies, but there isn’t agreement on whether changes are necessary and it’s not clear what the outcome will be.

For more information about compounded medications, please visit the FDA website.

Reuse of Insulin Pens May Have Spread Hepatitis

By ThinkReliability Staff

After a similar incident at a Veterans hospital, a hospital in New York reviewed its insulin injection procedures and discovered that insulin pens may have been used for more than one patient.  Re-use of insulin pens for more than a single patient carries a small risk of cross-contamination, which can result in a patient being infected with a communicable disease, such as hepatitis B, hepatitis C, or HIV.

The hospital notified 1,915 patients who had received injections between November  2009 and January 2013 of the possibility for contamination and recommended testing.  Twelve patients have tested positive for Hepatitis C, and one has tested positive for Hepatitis B, though an investigation is ongoing to determine if this is related to the injections.

The use of insulin pens resulted in 30 outbreaks from syringe or needle reuse over ten years, from 2001-2010. So, although the possibility for cross-contamination is considered low, the risk for the spreading of communicable diseases is unacceptably high.

The potential for spreading communicable diseases is an important impact to the patient safety and environmental goals.  We can examine these impacted goals and the cause-and-effect relationships that led to these impacts, in a Cause Map, or visual root cause analysis.

We begin by defining the impacts to the goals.  In addition to the patient safety goal, the compliance goal is impacted because re-using insulin pens is against recommendations by the FDA and CDC.  The organizational goal is  impacted due to a lawsuit from the patients who have tested positive for Hepatitis B and Hepatitis C.  Patient services are impacted due to the improper reuse of the insulin pens, and the labor and property goals are impacted by the additional follow-up, testing and potential treatment for the almost 2,000 patients affected.  Once we have determined the impacts to an organization’s goals, we can ask “Why” questions, which helps develop cause-and-effect relationships that resulted in these impacts.

Insulin pens are designed for multiple injections, meaning that there is stored insulin within the cartridge after a single injection is given.  Backflow of blood into the pen can result in the remaining insulin being contaminated.  This can result in the spread of communicable disease if the pen is then used on a different patient for subsequent injections.

Because it is known that insulin pens should not be used on multiple patients, it is evident that there was an issue with the procedure or policy regarding use of insulin pens.  It is unclear what the specific issues were relating to this incident, but the hospital involved has reviewed and reinforced policies and procedures related to insulin injection.

Many facilities, including the hospital discussed here, which discovered the potential for re-use during a review after a similar incident at a Veteran’s hospital, have discontinued the use of insulin pens due to the potential for cross-contamination.

To view the Outline and Cause Map, please click “Download PDF” above.  Or click here to read the hospital’s press release.

Click here to visit our previous blog about about hepatitis B and C.

Click here to visit our previous blog about a different contamination issue involving hepatitis C.


Update: Contaminated Injections Have Now Killed 29

By ThinkReliability Staff

In a previous blog, we discussed deaths related to fungal meningitis believed to have resulted from fungal contamination of a compounded drug used as an injection for back pain.  Sadly, since our last post, the numbers of deaths and injuries has risen.  So far, 29 patients have been killed and more than 360 have been sickened by the infected injections.  Because drugs from the three affected lots were injected for pain relief to approximately 14,000 patients, investigators expect to see many more cases in the coming months.  Some of these patients received injections in other joints, so they are suffering from peripheral joint infection, which is less severe and less likely to lead to death than fungal meningitis.

We can update the Cause Map, or visual root cause analysis, which was started in our previous blog.  Specifically, as investigators are able to provide more detail about the case, we can update causes and validate them with evidence.  We are also able to update the outline as more patient deaths and sickness are discovered.

Investigators have verified that the source of the fungal contamination was the compounding company.  They noted in investigations that the clean room was contaminated due to lack of control of the humidity and temperature.  It appears that the air conditioning was shut down at night, resulting in environmental issues. Additionally, sterilization at the company was found to be inadequate.  Sterilization procedures were not followed, and sterilization equipment was found to be contaminated, possibly because it was not properly tested.  Once the contamination made it into the drug, the drug was shipped without the company knowing of the contamination, because shipping on some lots took place before the results of sterility testing were received.

The Massachusetts Department of Health has announced increased oversight of compounding companies, including annual inspections.  A bill has been introduced in Congress for FDA regulation of compounding companies that produce larger quantities of drugs for mass distribution, as appears to be the case in this instance.  It also recommends requiring compounded drugs to contain a label stating they have not been FDA-approved.  Although the compounding company responsible for the contamination has been closed down, it is hoped that a higher level of regulation will reduce the possibility of similar deaths in the future.

To view the updated Outline and Cause Map, please click “Download PDF” above.  Or click here to read more.

Contaminated Injections Kill 5

By ThinkReliability Staff

At least 35 patients have come down with rare fungal meningitis after an injection they received for back pain was contaminated with fungus. Five have died so far. Because of the severity of the disease and the long incubation period, more cases – and more deaths – are expected in the coming months.

We can examine the issues related to the fungal meningitis in a Cause Map, or visual root cause analysis. Documenting the causes visually can make a complex medical issue easier to understand. We begin with the impacts to the goals. The deaths and severe sickness are an impact to the patient safety goal. While we begin with the known cases, these numbers can be updated if more cases are discovered. The compounding company which prepared the injections has voluntarily surrendered its license, an impact to the compliance goal and has recalled 3 lots of the drug used in the injection (methylprednisolone acetate), which can be considered an impact to both the organizational and property goal. The extremely difficult treatment ahead of these patients (estimated to take months) is an impact to the patient services and labor goal. The contamination of the injection itself can be considered an environmental goal.

Once we have captured these impacted goals, we can begin with the focus of our investigation – the patient safety goal – and ask “why” questions to develop the cause-and-effect relationships that resulted in the disease. The patient deaths and sickness are due to contraction of fungal meningitis. These patients came down with fungal meningitis because fungus was introduced to their nervous system. The injections that the patients received for back pain were injected epidurally, which allows access to the nervous system, and were infected with aspergillus, a common fungi. More testing is being done to determine whether the contamination was in the drug within the injection, or the numbing agent or antiseptic wipes being used. Due to the widespread (across several states) outbreak, it is believed that the drug within the injection is to blame, but because of the seriousness of this issue, all potential causes are being carefully tested.

Because the drug used in the injection was compounded, the contamination could have occurred within a raw ingredient used in the compounding, or it could have become contaminated during the compounding process. The source of the outbreak is not yet known, but because compounded drugs and compounding companies receive less oversight than drug manufacturers, it is suspected that the contaminant was introduced during the compounding process.

Initial symptoms of fungal meningitis are subtle, including headache, fever, dizziness, nausea and slurred speech. The symptoms can take up to a month from introduction of the fungus to appear. If patients have received a shot for back pain, they should contact their doctor to see if it was from the infected lot. Early and immediate treatment is important.

To view the Outline and Cause Map, please click “Download PDF” above. Or click here to read more.


Skin Death Associated with Contaminated Cocaine

By Kim Smiley

Recently, increasing amounts of information has been released regarding patients suffering from tissue death (purpura) associated with use of cocaine “cut” (contaminated) with levamisole.  Levamisole is a veterinary anti-worming drug no longer used in humans because of adverse side effects (such as the tissue death described above and also its interference with the blood marrow’s ability to produce white blood cells, known as agranulocytosis).  The US Drug Enforcement Agency (DEA) reported in 2009 that 69% of cocaine was contaminated, a significant increase from previous years.

This issue can be examined within a root cause analysis captured in visual form.  To begin, we capture the impacts to the goals.  The patient safety goal is impacted because of the tissue death.  Additionally, employees and patient services are impacted because many healthcare organizations are unable to diagnose the issue.  We begin with these goals and ask “Why” questions to continue the analysis.

Why is the tissue death occurring? Tissue death is resulting from levamisole toxicity and ineffective treatment.  The levamisole toxicity occurs from the use of cocaine contaminated with levamisole.  It’s possible that the levamisole is added to the cocaine to increase the effect of the drug.  Additionally, levamisole is cheap, so it increases the volume of the cocaine, which increases profits.  Because cocaine is an illegal drug, it’s not regulated by any government agency.  This means no quality control is in place that would detect the contamination before use.

Ineffective treatment is generally occurring because of the previously discussed inability to diagnose the issue.  Before these reports were made widely available, most practitioners would not think to look at a no-longer-used drug as a cause of toxicity, especially when a patient is not honest about cocaine usage.  As a possible solution to improve treatment of this issue, the reports are suggesting that practitioners look to cocaine abuse when faced with tissue death, which should increase the effectiveness of the treatment for both the tissue death, and other associated issues with contaminated cocaine.  Also, increased public awareness is being attempted to try and reduce the use of cocaine.  Although previous public awareness drug use programs have been less successful than desired, perhaps the risk of skin death will get some users to quit.

For more information, click here.

Over-the-counter Medications Recalled

By ThinkReliability Staff

On April 30, 2010, following a 10-day FDA inspection of a U.S. manufacturing facility, 43 name-brand over-the-counter (OTC) children’s’ liquid medications were voluntarily recalled.  Although there have not yet been any reported adverse events associated with the recalled medication, the impact of the issue has been far-reaching.

There is the potential (although believed to be remote) for an impact to consumer health, which is an impact to the safety goal.  Additionally, the drugs were recalled for not meeting required quality standards, which can also be  considered an impact to the safety goal.  The product recall, which encompassed 1,500 lots of 43 products, is an impact to both the customer service and property goal.  The cost of this recall has not yet been estimated.  The  manufacturing facility is on hold, which is an impact to the production goal.  Lastly, the time and costs associated with the investigation to determine what went wrong is an impact to the labor goal.  We can record these impacts to the goals in the outline (Step 1).

Once we’ve completed the first step, we move on to the root cause analysis, or Step 2.  We begin the analysis with the impacts to the goals and ask “Why” questions to complete the Cause Map.  Because the FDA’s investigation report has not yet been released, the Cause Map we have so far is very basic.  Essentially, the recalls occurred because unacceptable product was released to consumers.  It was released because the finished product met testing requirements.  However, it was unacceptable because it did not meet quality standards, because of contamination in the raw materials that were used.  At this point in the map, we run into more questions.  More detail can be added to this Cause Map as the analysis continues and more information is released. As with any investigation the level of detail in the analysis is based on the impact of the incident on the organization’s overall goals.

A thorough root cause analysis built as a Cause Map can capture all of the causes in a simple, intuitive format that fits on one page.  View the investigation by clicking on “Download PDF” above.

What’s in YOUR heparin?

By ThinkReliability Staff

In 2008, contamination of the U.S. supply of heparin was brought to light. A significant portion of the U.S. supply of heparin was recalled, and the death toll potentially associated with the contamination has now climbed to 81, with hundreds of adverse events also reported. Additionally, prior to the recall there was concern for deaths and injuries associated with the contaminated drug not fulfilling its expected purpose – preventing blood clots during surgeries and kidney dialysis – because the contaminant has no blood thinning properties. So far, the contaminated drug has been found in 10 countries thus far, increasing concern about the drug supply chain.

Researchers have verified that the contaminant in the recalled heparin is oversulfated chondroitin sulfate (OSCS) and that they have discovered a mechanism by which the contaminant can cause the adverse effects (falling blood pressure and severe allergic reactions). Additionally, the researchers have provided a test for regulators to screen heparin for this contaminant.

They have determined that the OSCS was present at the active ingredient supplier plant in China. Because OSCS does not occur in nature and mimics the chemical structure of heparin so closely, it is believed that the (mostly unregulated) crude heparin suppliers in China added OSCS to increase their profit, as OSCS is many times less expensive than heparin. The OSCS was not detected by standard impurity tests, due to its similarity with heparin. In Congressional hearings since the event, the Food and Drug Adminstration (FDA) has said that the inspections of the Chinese plant (as well as those of most foreign plants) were inadequate due to lack of funding for the FDA mission.

The Cause Map shows that the heparin got into the drug supply after being placed in the raw ingredients. It was not discovered by regulators, due to the lack of a commonly used, effective test. A thorough root cause analysis built as a Cause Map can capture all of the causes in a simple, intuitive format that fits on one page. As more information is released about the failings of the supply chain in this instance, we can add more details to the Cause Map.

Click on “Download PDF” above to download a PDF showing the Cause Map.

See a more detailed root cause analysis of the heparin contamination.