Heparin, Its Production, Effects And Counterfeit Problems
Heparin, a commonly used anticoagulant drug in the world, which is an animal derived product which comes with the risks of adulteration and contamination. An injectable anticoagulant, Heparin is used to prevent thromboembolic complications. Anticoagulants work by decreasing the clotting ability of the blood, helping to prevent the formation of clots as well as stopping the further expansion of any existing clots. Although heparin does not break down existing blood clots, it does enhance the body’s natural mechanism involved in clot lysis. It is used by patients who are undergoing specific medical procedures that increase the chances of blood clotting such as open-heart surgery, bypass, kidney dialysis, and blood transfusions. Other than that it can be used to diagnose and treat a serious blood condition known as intravascular coagulation. The most negatively charged biological molecule, Heparin is a naturally occurring polysaccharide, belonging to the family of glycosaminoglycan’s. Processed from natural GAG which is produced by the purification of animal tissue. It was introduced to clinical medicine in the 1930’s yet after decades of research, its structure and mechanism are still not understood properly. In May 1935, the first human trials of heparin were conducted and Connaught’s heparin was confirmed as a safe, easily-available and effective blood anticoagulant.
Yet further research has contributed to low molecular weight heparins by the 1970s. This medication is available in the form on injections given directly into a vein by a professional. It should not be injected into a muscle directly. Heparin should be used according to a doctor’s prescription. This medication is sometimes used together with other drugs that have "blood thinning" or anti-platelet effects such as aspirin, clopidogrel, or warfarin. If your doctor prescribes a combination of these drugs, he or she will monitor you closely to minimize your risk of bleeding. Keep all medical and laboratory appointments.
When deciding to use Heparin physicians must take necessary precautions, as there are risks associated with the drug. Common side effects associated with Heparin are bleeding, decreased platelets, injection site irritation, allergic reaction or hair loss. Some patients can have certain bad reactions to heparin (heparin-induced thrombocytopenia-HIT or heparin-induced thrombocytopenia and thrombosis-HITT). This can occur during treatment and up to several weeks after treatment with heparin has stopped.
The FDA has divided medications that are based on safety to use during pregnancy in five categories that are A, B, C, D and X. Heparin is in category C, as this medication should only be used when it is desperately needed. Although it is not excreted in human milk, caution should be shown while a nursing mother is using Heparin.
Production of Heparin
Various injuries have been related to the use of Heparin, which consisted of an active pharmaceutical ingredient API from China which has become the largest Heparin API producer and exporter. The U. S. Food and Drug Administration (FDA) estimates that 40 percent of the finished drugs used by U. S. patients, and 80 percent of their active ingredients, are manufactured abroad. Most of these drugs have proven to be safe however, relying on global sources have created new risks which include tampering and poor quality control that take place outside the jurisdiction of FDA.
Effects of Heparin
In early 2008, ‘fake’ heparin-based medicines caused deaths in the US and other parts of the world. In a bid to realize cost-saving opportunities, Chinese producers had added a potentially toxic substance called ‘over-sulfated chondroitin sulfate’ to pharmaceutical grade heparin. A handful of batches were made which made their way around the globe in 2007, patients started to report of various awful side-effects and in some cases the side effects were so bad that the patients died. In late 2008 the US center for Disease Control and Prevention (CDC) started their investigation of an outbreak of allergic-type reactions that were dating back to November 2007 in patients who has been receiving dialysis treatment by Baxter healthcare. Hence the focus shifted to the dialysis machines themselves, but once the CDC was involved they had discovered a set of batches that had come from one pharmaceutical company, and was the common factor amongst all the patients. Adverse reactions included difficulty breathing, nausea or vomiting, excessive sweating and falling blood pressure, which can lead to life-threatening shock. These reactions have been seen with as few as several thousand units per milliliter of heparin, and as much as 50, 000 units per milliliter.
This caused Baxter healthcare the major US manufacturer, alongside other fourteen US companies recalled numerous drug products. Baxter and FDA at that time were unable to point out the exact source of Heparin adulteration but there was evidence to suggest that it was from the Chinese API production site. The problem still persisted, and this time not only in dialysis patients, but patients who were using Heparin in other settings. Hence the same pharmaceutical company recalled their products worldwide. After another manufacturer recalled their products in Germany, the FDA pushed all manufacturers and regulatory authorities to screen their medicines for further contaminants. This lead to the identification of Chondroiyin sulfate, which had been over sulfated and had been causing these negative reactions in patients. The FDA believes that the adulteration was an economically motivated act.
When the FDA had finally investigated the factory in China known as Changzhou Scientific Proteins Laboratories, they came across various impurities, and deficiencies. FDA officials said chemically manipulating chondroitin sulfate, which is widely available from animal sources, would be cheaper than getting raw heparin from pig intestines. China’s drug watchdog confirmed the contaminant had been found in batches of heparin supplied by a China-U. S. joint venture plant in Changzhou to Baxter
It had no operating license from the FDA or any government agency from China, both which are serious violations of the FDAs policies. This led to the investigation of the American company involved in this unregulated, unlicensed and contaminated product. When the Food and Drug Administration got hold of the case, Baxter Healthcare tried everything they could to make sure that the information was kept from the public eye, and the media. However, this did not go as they had anticipated as the death toll that was growing due to the people who had taken doses of the contaminated product. As the product had been properly disposed of, the FDA and Baxter Healthcare worked together to make sure that there was no panic amongst the public. The non-contaminated manufacturers worked together with the FDA to ensure that the gap created by losing the top Heparin manufacturers was filled. This created a sense of safety and numerous customers started to gain back their faith. To ensure safety of heparin products in the United States, FDA asked manufacturers of heparin-containing products to test the heparin active pharmaceutical ingredient (API) used in these products with the two screening methods posted to FDA's website, capillary electrophoresis (CE) and proton nuclear magnetic resonance (H-NMR). FDA wants to extend its appreciation to all companies who expeditiously adopted these methods and provided monthly updates. These methods have been included in the United States Pharmacopeia monograph since June 2008, and are to be used for all products intended for the U. S. market. Adherence to an appropriate testing regimen will be monitored by our inspection program and enforced by FDA.
As a project manager working for the Changzhou Scientific Protein Laboratories, the first and most important thing to do is to push the company to get the license from the Chinese government agency or the respective government agency of the country where I plan to export my product. I would ensure sure the factory is running according to the health codes which should be regulated often. Fixing the problem at the root of the problem is the most important start to creating safe un-contaminated Heparin. Without the repairs and licensing, there is no credibility or trust in that factory. It’s important for the Changzhou Scientific Protein Laboratories to work with the FDA and their local government agency equivalent to make sure there is nothing that is not up to date and the final product and free of impurities and in contamination. It is essential to keep in mind the international code of Occupational Safety, Health and Working Conditions. As a project manager for Baxter Healthcare, and the important thing to do here is set up extensive testing of all the raw materials coming in from not only international factories, but also from local factories. Making sure there is nothing wrong with the materials being brought in is the key piece of creating safe Heparin for patients to receive. Without verification of non-contamination, the production runs the risks of having another incident like this Heparin contamination incident, which gets the FDA involved. On the flipside, if I were a project manager for the FDA, then there would be a lot of push on the supplier and the manufacturer to gain license.
Compliancy is key when it comes to working with the FDA. By following up, doing surprise check ins and possibly threatening the companies with legal action if issues are not resolved, it is the job of the FDA to ensure that what we put in our bodies is safe and comes from verifiable, legal, and safe places. Prevention is the key in today’s age. This is a scenario that can very much happen in 2018. With the United States importing so many products from China, the understaffed FDA cannot keep tabs on the factories and their supplies. The materials being brought in are easily slipped under the radar due to lack of testing. Having unverifiable sources for their medicines, a company has a greater chance of failure and fallout, depending on the scenario. A recall like this over a widely used product is not uncommon is today’s society. With the need for producers to speed up production for economic gains, rather than ensure safety of product. By pushing companies to put quality over quantity, as there are certain standards to maintain. In the case of Heparin, it was costs that were the driving factor for Baxter Healthcare and that lead to some very unsafe choices in materials, leading to the production of unsafe contaminated medicine that resulted in many deaths.
