FDA Identifies Contaminant In Heparin Batches

A contaminant found in recalled batches of the blood-thinner heparin was deliberately altered in a way that mimicked the real drug, the Food and Drug Administration said, a finding that will add to pressure on U.S. regulators and pharmaceutical companies to step up oversight of burgeoning Chinese drug production.

Yesterday, the FDA said the contaminant, which has surfaced in batches of heparin made from active ingredient sourced in China, appears to be a chemically altered material derived from a cheap and widely available substance found in animals, particularly in cartilage.

The agency said it isn't clear if the contaminant, called over-sulfated chondroitin sulfate, is the cause of allergic reactions, some fatal, that occurred in people who took heparin supplied by Baxter International Inc., which has recalled the drug batches linked to the problem. The contaminant has been found in heparin taken by people who had reactions.

Janet Woodcock, the director of the FDA's drug center, said agency investigators aren't sure how the substance got into the heparin. 'We cannot rule in or out whether this is accidentally or deliberately introduced into the product,' she said.

However, Dr. Woodcock said the contaminant seems to have been deliberately processed by adding more sulfate. She said the 'compound to our knowledge is not naturally occurring' and 'didn't come straight from the pig.' Heparin is derived from pig intestines.

An FDA official noted that chondroitin sulfate is 'abundant and cheap,' and the chemical processing required to add the extra sulfate 'will not be that expensive either.' The agency said the substance is likely to be less expensive than actual heparin, but FDA officials 'do not have any further data to estimate the cost after the sulfation process.' In some samples of Baxter's active ingredient, the contaminant made up between 2% and 50% of the total material, Dr. Woodcock said.

Academic experts said the process of adding sulfate was likely one that would require at least a basic chemical manufacturing facility. The extra sulfate would make the chondroitin sulfate more chemically similar to heparin, and it could have clumped together with the actual heparin in a way that would make it difficult to detect through most standard processing, said Jian Liu, an associate professor at the University of North Carolina, Chapel Hill.

The disclosure immediately drew concern from Congress. Democratic Reps. John Dingell and Bart Stupak of Michigan said they planned a hearing about heparin next month. Democratic Sen. Edward Kennedy of Massachusetts said 'it is unacceptable that Americans have died and been seriously injured by what appears to be deliberate tampering.' Sen. Charles Grassley, an Iowa Republican, said the investigation has 'provided additional evidence of the need for a robust foreign inspection program within the Food and Drug Administration.'

Last year, the FDA blocked all toothpaste from China at the U.S. border for testing after reports that authorities found diethylene glycol, a chemical used in products such as antifreeze, in toothpaste in Panama and other countries. In addition, wheat flour from China that was used in some pet food was found to contain melamine, an industrial chemical. The substance was blamed for pet illnesses and deaths.

The FDA recently announced that it had received permission from the State Department to place eight staffers in China, but its plans were pending authorization from the Chinese government. In fiscal 2007, there were a total of 714 Chinese facilities making drugs or drug ingredients for the U.S. market.

Counterfeit drugs and ingredients have been an increasing worry for the FDA. In fiscal 2007, the FDA opened 31 domestic counterfeit-drug investigations, which can involve products with ingredients made overseas. There were 54 in 2006 and 32 in 2005. In 1997, there were just nine.

In a statement, the trade group Pharmaceutical Research and Manufacturers of America said 'brand-name pharmaceutical companies work closely with foreign and domestic manufacturers of [active pharmaceutical ingredients] to help ensure that extensive regulatory requirements are met to protect patient health.'

Baxter and supplier Scientific Protein Laboratories LLC of Waunakee, Wis., both said yesterday the contaminant seems to have been introduced into the heparin at its crude stage, before it arrived at Scientific Protein's Chinese joint venture Changzhou SPL for processing into active ingredient. Both Baxter and a consultant working with Scientific Protein said the substance appears to be derived from pig tissue.

A Baxter spokeswoman said the company is focusing its investigation on 'consolidators and workshops' in China, and added that 'consolidators are a bit more sophisticated' in chemical expertise. Baxter said Scientific Protein uses three consolidators but won't say whether the adulterant is present in lots from one, or two, or all three of its consolidators.

The FDA has received reports of hundreds of reactions and 19 deaths of patients after taking heparin. Heparin sold in Germany by Rotexmedica GmbH, a unit of the French company Groupe Panpharma, also has been recalled. Baxter and Rotexmedica relied on different Chinese suppliers.

美国食品和药物管理局(FDA)表示，在召回的抗凝血剂药物肝素中发现的一种污染物，是经过假冒处理故意添加进药物中的。这一发现将促使美国监管部门和制药企业进一步加大对日渐增多的中国药品的检查力度。

FDA周三表示，在使用中国产活性成份制造的那批召回肝素中发现了一种污染物，看上去是一种用可以通过多种动物组织，特别是软骨组织提取的廉价化学替代品。

FDA表示，目前仍不清楚是否正是这种名为“多硫酸软骨素”的物质导致有患者使用百特公司(Baxter International Inc.)的肝素后产生不良反应乃至丧命。百特公司已经召回了这批有问题的肝素。在有不良反应的患者所使用的肝素中也发现了此种物质。

FDA药物中心主任珍妮特•伍德考克(Janet Woodcock)表示，调查人员还无法确认这种物质是如何混入肝素中去的，因此无法确认或排除这是一次意外事故，还是蓄意而为。

但伍德考克称，看上去这种物质经过了刻意的处理，加入了较多的硫酸。她表示，“据我们所知，此种化合物既不会在自然条件下生成，也不是直接来自猪的身体组织”。肝素可以从猪肠中提取而来。

FDA官员指出，硫酸软骨素产量大，并且便宜。而且对这种物质进行“硫化”处理的成本并不高。FDA表示，虽然并未掌握处理后的成本数据，但很有可能会比真正的肝素便宜。伍德考克表示，在百特公司的活性成份样品中发现污染物的含量在2%至50%之间。

有学术专家指出，至少要有基本的化工制造设备才能进行此类硫化处理。协助调查的北卡罗来纳大学(University of North Carolina)副教授Jian Liu表示，经硫化后的硫酸软骨素在化学结构上与肝素更相似，并以相似的方式凝聚在一起，用一般的检验方法无法辨别出来。

这项发现立即引起了美国国会的关注。密歇根州民主党众议员约翰•丁革尔(John Dingell)和巴特•斯图派克(Bart Stupak)称，他们打算在下月就肝素事件组织听证会。马萨诸塞州民主党参议员艾德华•肯尼迪(Edward Kennedy)称，美国人因为这种似乎是蓄意的掺假行为而受到严重伤害乃至丧命，这种事情是不可原谅的。爱荷华州共和党参议员查尔斯•格拉斯雷(Charles Grassley)则表示，此次调查为FDA需要建立更有力的外国检查制度提供了新的依据。

FDA最近宣布，已获得美国国务院批准在中国派驻8名人员，但这项计划仍需获得中国政府批准。在2007财政年度，共有714家中国企业生产的药物或药物成份销往美国市场。

伪劣药品及药物成份已逐渐引起FDA重视。在2007财政年度，FDA针对伪劣药品发起了31项调查，其中包括使用了进口成份的药物。在此之前的2006和2005财政年度，类似的调查分别有54起和32起，而1997年只有9起。

百特公司及其原料供应商Scientific Protein Laboratories LLC周三均表示，在后者的在华控股企业常州凯普药业公司(Kaipu Biochemical Co.)将肝素粗品加工成活性成份之前，这些污染物在粗加工阶段就已混入原料中。百特及Scientific Protein Laboratories LLC的一位顾问都表示，此种物质似乎是从猪组织中提取出来的。

百特的一位发言人表示，公司将调查重点放在“原料集中供应商和生产厂”身上。而集中供应商掌握的化学技术要更专业、更全面一些。百特表示，Scientific Protein有3家集中供应商，但没有透露是在其中一家、两家，还是全部三家供应商提供的原料中发现了掺假行为。

此前FDA共接到因使用肝素而引起上百起不良反应和19起患者死亡报告。此外，法国公司Groupe Panpharma的子公司Rotexmedica GmbH在德国销售的肝素也被召回。不过Rotexmedica和百特的中国供应商并不是同一家。

• 6小时掌握学英语的秘诀！——点击看答案
• 专治男女记不住单词的秘密