Contaminated Heparin
Cause Mapping Example:
One of the National Quality Forum's defined "never events" is patient death or serious disability caused by contaminated drugs (or devices or biologics). As an example of one of these incidents, we'll look at the deaths from contaminated heparin in 2007-2008.
Heparin is widely used as an anticoagulant (blood thinner). In early 2008, the Food & Drug Adminstration (FDA) received reports that 19 people had died, and at least 785 had experienced adverse reactions due to contaminated heparin. In April, 2008, the FDA released new numbers that showed that 103 people had died from taking heparin since January 2007 and that 62 of those deaths were from allergic reactions or hypotension (dangerously low blood pressure). These numbers were later updated to 81 deaths associated with (and potentially caused by) the contamination. The heparin in question was found to contain up to 50% oversulfated chondroitin sulfate (OSCS), which mimics heparin so closely it can not be distinguished in basic tests but provides no anticoagulant activity. The adverse effects are caused by severe allergic reactions, including low blood pressure which can occasionally lead to fatal stroke. Additionally, there is a concern (but no documented cases), because the active ingredients contained in a heparin injection could be reduced by up to 50%. Heparin has been recalled in 10 countries, and consumers are very concerned about the potential quality of drugs, especially those imported from overseas. In this case, the raw materials in question were manufactured in China.
This is an example of how the Cause Mapping process can be applied to a specific incident. In this case the heparin contamination is captured as an example of the Cause Mapping method. The three steps are 1) Define the problem, 2) Conduct the analysis and 3) Identify the best solutions. Each step will be discussed below.
Step 1. Define the Problem
The first step of the Cause Mapping approach is to define the problem by asking the four questions: What is the problem? When did it happen? Where did it happen? And how did it impact the goals? One person may say that the problem was the contamination of the heparin. Another person might say that the problem was that people were killed, and a third person could say that the problem was that the heparin entered the drug supply. We write down these three “problems” on the first line. In the Cause Mapping methodology the facilitator anticipates that the group may disagree so all three responses are written down. There is no need to spend time debating the problem. The magnitude of this incident is defined by the impact to the goals. Below is the outline, including impacted goals for this event.
The second question is the "When?" which is the date and time of the incident. When captures the timing of the issue and also has a line for what was different or unusual in this occurrence. The question of what was different is fundamental in any investigation. On the heparin issue we capture the date as 2007-2008 because so many individual deaths and adverse events are involved.
In an investigation there can be several pieces of information that need to be captured when specifying the location. At a minimum the physical/geographic location and the process should be captured. The physical location is is where geographically the incident happened. In this case, researchers have shown that the contaminant was present in the heparin before it left the heparin active ingredient plants in China (there may be more than one involved.) A key difference here is that the problems were only associated with raw materials that were manufactured in China.
The next section is the impact to the overall goals. For the drug supply, one of the overall goals is to have zero deaths and injuries. There were potentially 81 fatalities and 785 adverse effects from the contamination. One of the other goals is to have a drug that is effective. In the case of the heparin contamination, there was the potential that the contaminated drug would not work. These are all impacts to the safety goal. Additionally, the contamination caused extreme customer concern (which I'll consider an impact to the customer service goal), and lots of heparin had to be recalled from 10 countries, an impact to the materials and labor goal not only due to the cost of the recalled heparin but the potential of not having enough of a drug that provides a medically necessary service.
Step 2. Identify the Causes (The Analysis)
The analysis step is where the incident is broken down into causes which are captured on the Cause Map. The Cause Map starts by writing down the goals that were affected as defined in problem outline. For the heparin contamination, the safety goal was impacted because of the 81 lives that were lost, the adverse reactions, and the potential for the contaminated drug to not work. The severe customer concern is an impact to the customer goal, and the recall of lots of heparin is an impact to the material goal. These are the first cause-and-effect relationships in the analysis.
The analysis can continue by asking Why questions and moving to the right of either of the cause-and-effect relationships above. In this example we’ll start with the loss of lives and adverse reactions. The next question is “Why did this occur?” Researchers discovered that the contaminant activates two inflammatory pathways, one which initiates blood clotting and blood vessel dilation, causing a decrease in blood pressure which can lead to fatal shock, and the other produces anaphylactic toxins, which causes the allergic reactions. The pathways were activated because the contaminated heparin was used for medical treatment. (More on this later.)
There is the potential for the contaminated drug not to work because the contaminants do not have anticoagulant (or anti-blood clotting) properties and because the contaminated heparin was used for medical treatment. It was used for medical treatment because heparin is used to prevent blood clots, and for kidney patients undergoing dialysis, and because the contaminated heparin was in the drug supply. This is also the cause for the customer concern, and for the recall of lots of heparin from 10 countries.
The contaminated heparin was in the drug supply because it was contaminated by up to 50% oversulfated chondroitin sulfate (OSCS) and the OSCS was not detected by regulators. It was not detected by regulators because the testing was ineffective. The testing was ineffective because adequate tests for impurities were not performed, because only sophisticated testing can differentiate between OSCS and heparin (because OSCS mimics heparin) and the sophisticated test is not widely used. The heparin was contaminated because the manufacturer used contaminated active ingredient, because the supplier exported contaminated active ingredient, and again, because the testing was ineffective.
The supplier exported contaminated active ingredient because they used contaminated raw ingredients (more on this later), because their processing appears to be unable to remove impurities (because they did not establish specifications for impurities), and because regulatory inspections were ineffective.
Inspections were ineffective for many reasons. First, the FDA did not inspect the plant in question before approving the heparin for sale, which is against FDA policy. Then, when the FDA later went to inspect the plant in China, it inspected the wrong plant, for reasons that are unclear. In general, FDA inspections of foreign plants are few and far between (most estimates are once every 13 years - the FDA has refused comment.) However, the FDA has admitted to having a massive shortage of funding and inspectors to do their job, which has expanded greatly as more and more drugs are being manufactured outside the USA. A recent GAO report raised serious concerns about the FDA's ability to properly regulate foreign-manufactured drugs. In addition to the botched FDA inspections, concerns raised by an earlier inspection by Baxter (the company manufacturing the heparin) appear to have not been addressed, again for reasons that are unclear.
Now, why were the raw ingredients contaminated with OSCS? Because OSCS does not occur in nature, and because it has such a close resemblance to heparin, it is believed that it was intentionally added to save money, as heparin ingredients have been increasing in cost due to a shortage of raw ingredients. This is becaues the raw ingredients are manufactured from pigs, and pig disease sweeping China has decreased the availability. OSCS is a cheap substitute. This is in line with other Chinese contamination issues, such as the dog & cat food contamination and another case involving cold medicine in Panama. In both these cases a cheap (and dangerous) substitute was added to the product to increase the apparent yield. Adding to this is that the raw ingredients were from unregulated suppliers, because most suppliers in China are unregulated.
Even more detail can be added to this Cause Map as the analysis continues. 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. The specific action items from the heparin contamination can be matched to specific causes on the detailed Cause Map.
Step 3. Select the Best Solutions (Reduce the Risk)
Once the Cause Map is build to a sufficient level of detail with supporting evidence the solutions step can be started. The Cause Map is used to identify all the possible solutions for given issue so that the best solutions can be selected. It is easier to identify many possible solutions from the detailed Cause Map than the oversimplified high level analysis of "don't make drugs in China."
Something to note about the solutions: all of them require a LOT of work. Obviously one of the huge problems in this case is the lack of funding and inspectors for the FDA, especially with the expanding drug manufacturing market outside the United States. So, increasing funding and/or redefining the responsibilities for the FDA are solutions. But some of the other solutions also involve the FDA and will therefore require additional funding regardless. For example, a solution to "unsanitary manufacturing" is to increase sanitation requirements. However, increasing requirements without increasing inspections will probably not help. It's also possible that it is not the requirements that are the problem, but rather the lack of inspections. Another solution (one that some companies are frantically working on) is to develop a synthetic source for anticoagulants that does not involve materials derived from pig. But like all other drugs, this would require the approval of the FDA. From the cause map above, it's plain to see that there were several problems that led to this situation. And though all the blame can certainly not be placed on the FDA, it seems pretty clear that the solutions must begin with the FDA.
There are causes to every issue. The contaminated heparin tragedy at a high level has only one cause. At a more detailed level it has 4 causes, 14 causes and 44 causes. All of the levels of the Cause Map are accurate some simply have more detail that others. An issue should be worked to a sufficient level of detail to prevent the incident; meaning to reduce the risk of the incident occurring to an acceptable level. This is why solutions and work processes at a coffee shop are not as thorough or detailed as an airline or nuclear power facility. The risk or impact to the goals dictates how effective the solutions should be. Lower risk incidents will have relatively lower detail investigations while significantly high risk to an organization’s goals requires a much more through analysis.
Cause Mapping Improves Problem Solving Skills
The Cause Mapping method focuses on the basics of the cause-and-effect principle so that it can be applied consistently to day-to-day issues as well as catastrophic, high risk issues. The steps of Cause Mapping are the same, but the level of detail is different. Focusing on the basics of the cause-and-effect principle make the Cause Mapping approach to root cause analysis a simple and effective method for investigating safety, environmental, compliance, customer, production, equipment or service issues.
Click on "Download PDF" above to download a PDF showing the Cause Map.
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