Contaminant in the Recalled Unfractionated Heparin Preparations
Contaminant in the Recalled Unfractionated Heparin Preparations:
In late January, Baxter Healthcare Corporation voluntarily recalled the following lots of heparin: 107054, 117085, 047056, 097081, 107024, 107064, 107066, 107074, and 107111. These products were labeled as heparin 1000 U/ml in 10 ml vials and heparin 1000 u/ml in 30 ml vials. The reason for this recall was the reported adverse reactions which were associated with the use of these heparin batches. These included abdominal pain, hypotension, burning, chest pain, diarrhea, dizziness, dyspepsia, dyspnea, arrhythmia, flushing, headache, hyperthyroidism, hypoesthesia, increased lacrimation, loss of consciousness, malaise, nausea, palor, palpitation, paraesthesia, pharyngeal edema, restlessness, vomiting, stomach discomfort, tachycardia, thirst, trismus, unresponsiveness to stimuli, and drug ineffectiveness. These adverse reactions were reported in hundreds of patients treated with these heparins in the US. As many as 19 deaths were linked with the use of the recalled heparins. These multiple adverse reactions were later attributed to heparin manufactured by Baxter's suppliers using Chinese raw material from SPL Changzhou. Subsequently, Baxter recalled all of the remaining lots and doses of its heparin sodium injection multidose, single dose vials and Hep-lock, heparin flush product.
In a recently held press conference, the USFDA briefed the press that the potential contaminant in the recalled Baxter product is a heparin-like substance. The USFDA commented that utilizing high tech methods heparin-like molecules have been identified. No specifics regarding these contaminants were given. The manufacturing process of heparin is such that other heparin-like contaminants such as the dermatan sulfate, heparan sulfate, and chondroitin sulfate are removed effectively. These represent the main contaminants in heparin.
However, these contaminants are unlikely to produce any allergic effects, nor the reported adverse reactions, since some of the antithrombotic drugs contain significant amounts of these heparin-like substances. Because of the carbohydrate nature of the contaminants identified by a special method of nuclear magnetic resonance (NMR), it is quite disturbing to note that such contaminants may have inadvertently been added to the recalled heparin. Heparin-like materials have been isolated from the shellfish, marine plants, bones, or the skin of mammalian origin for several therapeutic purposes. While structurally similar these heparin-like substances exhibit different biochemical and pharmacologic effects. There are also various proteins contaminants that can be expected along with the carbohydrates. Thus, it is likely that besides the carbohydrate contaminants, some unknown protein contaminants may also be present in these products.
The statement that a heparin-like material was identified using high tech methods is ambiguous and misleading. Such statements should be specific and clear regarding the methods used and the nature of the contaminants detected. It is very unlikely that such contaminants as dermatan sulfate, heparan sulfate or chondroitin sulfate, which are the most likely contaminants in heparin, are responsible for the reported complex adverse reactions and/or death in patients treated with heparin. It is quite conceivable that excessive amounts of degradation products and chemically modified sugars may be present resulting in unusual signals in some of the methods used to analyze these products.
Glucosamine sulfate is a representative building block of heparin and related agents. It is widely present as a structural component of the products isolated from mammalian tissue and shellfish. Glucosamine sulfate and related sugars constitute the bulk of heparin-like material known as heparinoids which are isolated from natural sources and have been used for various pharmaceutical purposes. These heparinoids are wide spread and are present in almost all animals in varying proportion. Such heparinoids as chondroitin sulfate and chitosan can be chemically modified to exhibit a heparin-like profile. However, these can be differentiated from heparin in chemical and biologic tests.
It is highly unlikely that heparinoids or their chemically modified forms can mediated the complex adverse reactions which have been reported with the use of recalled heparins. Unless some of these heparinoids combine with endogenous proteins to generate antigenic complexes, the direct immunogenic effects are unlikely to occur. However, based on the limited information, and the reported adverse reactions, it is likely that the possibility of bacterial contaminants such as endotoxin and other toxic bacterial products may also have contributed to the observed adverse effects. It would be prudent to test the recalled products for these contaminants.
The inspection by the USFDA has already identified various deficiencies in the plant responsible for producing and processing the related heparins. Heparin is extracted from porcine mucosa, which is obtained primarily from China. The proper processing of mucosa, including the initial cleaning and extraction, represent important steps in the manufacturing process of heparin. It is at this stage that trace amounts of bacterial cellular products, toxins and other undesirable contaminants can be incorporated with the products. The pharmacopeial methods used to determine the potency of heparin such as the sheep blood recalcification time and pyrogen testing of the finalized products are not capable of detecting these contaminants. It is also important that a comprehensive testing for potential trace protein contaminants be considered.
The USFDA has stated that the recalled batches contain somewhere between 5-20% heparin-like contaminants. It is highly unlikely that the standard manufacturing process could produce such a high degree of contamination of heparin-like material during the manufacturing process. The more likely cause may be mixing of batches or intentional mixing of heparin-like substances. This may be an oversight issue and requires further investigation. Such contaminants in high proportion have never before been reported.
While techniques such as capillary electrophoresis and NMR are useful in identifying carbohydrate impurities, these methods do not detect trace protein contaminants, which may be helpful in identifying the source of the contamination, such as marine allergens. This is a reflection of the complexity of the heparin structure and the need for methods to assure the quality of the product. There are no controls at this time except for the pharmacopoieal assay specifications, which are stated, in biologic units
We believe that the public statements from the FDA and Baxter are not clear and that supportive information should be provided. Both have the responsibility to provide clear information on this matter. Moreover, there appears to be a difference of opinion on the origin and nature of contaminants between the regulatory bodies and the suppliers. Because of the magnitude of the severe adverse reactions, it is likely that multiple factors may be responsible for the reported adverse events and deaths related to the use of recalled heparins. Therefore, unless a definitive cause and effect is established, such statements are premature. The assertion that these heparin-like substances may be responsible for the observed toxic to fatal outcomes are not based on facts or data.
Bacterial contamination during the final fabrication of unfractionated heparin has also been reported. This issue may be more complex than what has been stated. Regardless, it has a major public health impact. It is not acceptable that such problems should arise from poor quality assurance at the bulk material supplier level and sub-standard practices at the fabrication sites. These should be addressed. The contamination issue is a recent problem which probably arose because of the increased demand for heparin to manufacture low molecular weight heparins.
Similar allergic reactions and numerous deaths have also been reported recently from Germany, and as a result, the German regulatory agency has recalled the unfractionated heparin from RotexMedica. The source of RotexMedica heparin are also two Chinese suppliers, namely Changzhou Qianhong Bio-Pharma Co. and Yantai Dongcheng Biochemicals Co. suggesting that the problem may be related to the manufacturing of the heparin preparations. As a result, the European Community countries have cautioned responsible parties to monitor more closely, patients anticoagulated with heparin of imported origin. Japanese and south East Asian countries have also alerted the regulatory bodies and clinical community regarding this problem. Therefore, this issue has become a global problem, which should be addressed at the World Health Organization level.
The USFDA's statement that 5-20% of heparin-like substances were found in the recalled heparin only points out the failure of current quality assurance methods in detecting contaminants in heparin preparations. It doesn't provide any information on the relevance of these contaminants to the observed adverse effects. If the USFDA believes that these substances are responsible for the adverse effects, then a concerted effort to isolate these contaminants and test them for the potential adverse effects in animal models may be essential. Retrospective analysis of the biologic fluids from patients who died as a result of the adverse reaction and plasma samples from those who survived these reactions may provide helpful hints on the causative factors mediating the observed adverse effects.
Unfractionated heparin used in the US and European Community represents the most widely used anticoagulant in various indications such as in hemodialysis, apheresis and surgical procedures, and it has been used for these indications for a long time without these current problems. Although isolated incidences of heparin allergy and adverse reactions have been reported in the past, the frequency of recently reported reactions and death are alarming and represent a public health issue. Heparin is a biologic product of complex nature and the presence of bacterial, protein and other contaminants in substandard products may cause various severe adverse reactions.
The currently available heparin in the US and Europe is mostly obtained from the raw material/finished products originated in China. Recently, there have been several reports on the substandard quality of imported heparin preparations. In addition, reports on the health of livestock used in drug and food products have also been published. Recently, the Chinese swine population has suffered from blue ear syndrome. The implication of this disease on heparin production is not known, however, it is possible that this disease may have generated certain mediators which can produce pathogenic responses. The importance of animal health on the quality and safety of food and drug products is of paramount importance.
It must be stressed that unfractionated heparin is the most important anticoagulant drugs which is crucial in the surgical and medical management of thrombosis and cardiovascular disorders. Despite the known adverse reactions such as the bleeding and heparin induced thrombocytopenia this drug represents a life saving blood thinner which is essential to the management of patients with thrombosis. Heparin has been used for nearly 50 years without the pandemic problems which have been recently reported. The reported incidents represent a problem which may have stemmed from some unfortunate non-compliance and lack of oversight. It should be noted that if heparin is manufactured in compliance with the currently accepted guidelines, it is unlikely that the current issues related to substandard product, resulting in the reported safety issues would have occurred. An important consideration is related to the developments of low molecular weight heparins and their expanded indications.
Low molecular weight heparins are manufactured by the depolymerization of porcine mucosal heparin. A large amount of the heparin supply is now diverted for the manufacturing of these agents. Therefore there is a limited supply of this drug available to meet the demand. This may be a factor in the introduction of sub-standard or modified versions of heparin. Based on the limited information it is quite clear that the recalled products represent a heparin preparation which contains sizable amounts of heparin like contaminants that are markedly different than the heparin. These unusual contaminants along with other unidentified substances are responsible for the unfortunate adverse events. Therefore the reported adverse reactions may be due to multiple factors which may possible include the so called heparin-like substances. Additional studies are needed to investigate this problem. However, implementing proper oversight and the use of standard procedures can provide a pharmaceutically acceptable preparation.
The suppliers of heparin, regulatory bodies and pharmacopeial organizations are primarily responsible for quality assurance and oversight in assuring the quality of the heparin we use. Simply stating that the recalled products contain 5-20% heparin-like structures is misleading and non-informative. The ongoing problems with the use of heparin require a comprehensive investigation and may have additional implications on the production of all of the other heparin-related drugs.
Debra A. Hoppensteadt, Ph.D.