FDA警告信再添14家中企 肝素钠出口临二次危机.doc

FDA警告信再添14家中企 肝素钠出口临二次危机2月23日，美国食品药品监督管理局(简称“FDA”)公布了14家为制药公司提供污染肝素钠的中国公司，使得列在进口警告清单上的中国供应商数量达到了22家，这是继2008年百特肝素钠污染事件后，中国供应商再度遭遇出口信任危机。肝素污染扩散新加入名单的14家企业包括金坛市肠衣厂、长沙五里牌食品厂等数家中资企业，基本都是行业知名度不高的小规模生产企业。FDA认为，这些公司为制药企业提供了受污染的肝素原料，这些产品将被排除在供应链之外。这也意味着，清单上的中国供应商产品将禁止进入美国境内，而后者则是全球最大的肝素钠进口市场。这正是2008年“肝素钠污染事件”的发酵。2008年初，美国百特公司生产的肝素系列产品在美国引发多人死亡的严重不良反应，为其提供原料的常州凯普公司随即被禁止向美出口。虽然常州凯普是美国SPL和常州天普共同组建的外商投资企业，但此事仍然引发了中国肝素原料药企业在美国市场的信任危机，国内其他肝素钠企业也受到重大冲击，出口受挫。肝素钠是从猪的小肠粘膜中分离纯化的一种天然抗凝血剂。它广泛用于在外科手术前后防治血栓的形成，输血时预防血液凝固和作为保存新鲜血液的抗凝剂。上海第一生化药业内部人士告诉记者，“出事”前，公司出口肝素钠原料药的量还是挺多的，但是上了“警告信”后，也就等于失去了美国这个市场。目前公司主要生产肝素钠制剂产品，供应国内市场。第一生化2009年出现在美国FDA的警告信名单上。风波之后，FDA发布了指南草案，建议药品生产企业对肝素粗品进行检测，以确保其成分仅来源于猪肠。该草案还表示，广泛使用的抗血凝药物，其制造商应审核其原料供应商。FDA还称，已发现中国供应商故意掺入过硫酸软骨素(OSCS)肝素活性成分的一种掺假形式，因为该成分更便宜。“肝素受OSCS污染，似乎是某种形式的故意掺假，也被称为经济动机掺假。”2009年10月，美国FDA网站正式宣布，由美国药典委员会组成的“肝素钠特别专家小组”已完成对美国药典中有关肝素钠条目的质量标准修改工作。此举对中国肝素钠的出口产生重大影响，迫使中国企业对产品质量进行相应的改进。业内人士指出，现在FDA在华有常设机构，核查更加容易，从事药品原料生产的企业，如果想要让自己的产品打入国际市场，一定要与国际接轨，不能忽略企业的形象和产品质量。美国是目前世界上最大的肝素原料药市场，且美国地区肝素钠原料药销售价格较高，预计2010年美国肝素原料药市场占据全球市场的一半份额。行业利润危机行业内人士告诉记者，由2008年肝素钠污染所引发的行业洗牌，已经使得国内肝素钠生产厂家从原先的几百家锐减至目前的不到50家。而且随着出口国的标准门槛提高，一批作坊式企业正在被淘汰。“行业巨头才更有话语权。”公开资料显示，国内排名第四的肝素钠原料药供应商烟台东诚生化已经通过证监会审核，南京健友生化2011年11月亦公告正式接受上市辅导，此前，海普瑞(002399)、千红制药(002550)、常山药业(300255)都已经成功登陆A股，至此，我国肝素钠原料出口前五大供应商将全部上市。而作为全球肝素钠供应量占比达到75%的军团，国内肝素钠生产企业近两年急速扩张产能。目前，海普瑞肝素钠原料药年产能7万亿单位，千红制药IPO后已将产能从原有的2.2万亿单位扩大到5.5万亿单位，常山药业在IPO后也将肝素钠原料药产能从原来的8500亿单位急速扩产至3.85万亿单位。东诚生化的招股说明书显示，在其成功IPO的16个月后，公司肝素钠原料药的产能将在原来1.2万亿单位的基础上新增2.8万亿单位，达到4万亿单位。而南京健友的IPO募集资金也将用于扩大肝素钠产能。“随着几大巨头的产能相继达产，肝素原料的争夺日趋激烈，并成为企业竞争的核心要素之一。”分析人士指出，目前在各家巨头的竞争下，肝素原料的价格有所上升，也相应提高了企业的生产成本，但成品的价格却有所下降，企业遭遇利润危机。海普瑞2月20日发布的2011年业绩快报显示，预计2011年公司营业总收入将比上年减少35.26%，营业利润同比减少49.12%。主要原因在于，海普瑞支柱产品肝素钠原料药的销售单价和销售量均有下降。百特危机后，海普瑞“零缺陷”通过了当年FDA重新认证，并独家向美国出口，“垄断”概念由此而来，成为那次危机中最大的受益企业，一度风光无限。值得一提的是，美国药品监管部门FDA针对肝素产品的第三次修订标准正在拟定中，新标准对杂质含量、肝素原料来源限制等方面的要求更加严格。测定硫酸软骨素(OSCS)的灵敏度达到0.1%，此前要求的灵敏度是1.0%。出口标准提高无疑也将增加企业的生产成本。(Note: This import alert represents the Agencys current guidance to FDA field personnel regarding the manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person, and does not operate to bind FDA or the public).Import Alert # 55-03Published Date: 02/22/2012Type: DWPEImport Alert Name:Detention Without Physical Examination of Different Forms of Heparin and Heparin-Related Products for CGMP IssuesReason for Alert:Heparin is a widely used anti-coagulant and is commonly used during surgical procedures and for those undergoing dialysis. There are an estimated 12 million Americans that use heparin each year. In 2008, a number of deaths in the United States were associated with either contaminated or adulterated heparin. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, diarrhea, and abdominal pain.The vast majority of crude heparin, heparin intermediates, and heparin API used in finished drug product in the United States is imported from other countries. The phrase different forms of heparin and heparin-related products is used for brevity to refer to articles such as crude heparin, heparin intermediates, heparin active pharmaceutical ingredient (API), heparin products, and heparin-containing products.As part of FDAs activities intended to protect the health and safety of U.S. consumers, FDA often conducts inspections of foreign establishments that produce FDA-regulated articles intended for use in the United States. One basis for detention without physical examination is that the firms quality system is inadequate for the prevention of contamination or otherwise does not conform to CGMP. Heparin contaminated with oversulfated chondroitin sulfate (OSCS) clearly indicates that the methods used in or the controls used for the manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with CGMP. OSCS is not part of the manufacturing process for heparin and its presence suggests that somewhere in the supply chain OSCS has been added intentionally to heparin for financial reasons because it is a very cheap material prepared by a simple synthetic process. In addition, it mimics certain heparin properties so that it would pass then current United States Pharmacopeia (USP) specifications for Heparin Sodium USP. (The USP has since revised in 2009 its monograph for Heparin Sodium USP to incorporate tests that can detect the presence of OSCS).Manufacturers must have adequate traceability, qualification, and testing systems in place in order to satisfy applicable CGMP requirements. Where there is an inspection that identifies an inadequate system in this regard, the firms drug(s) or other products appear to be adulterated and are subject to imports refusal per 801(a)(3).Furthermore, if the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain, then there is an appearance that the firms quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firms drugs or other products may no longer appear to be adulterated.The attachment to this alert identifies firms for which we have information indicating that the different forms of heparin or heparin-related products appear to be adulterated for one of the reasons described above. It appears per 801(a) that the methods used in and controls used for the manufacture, processing, packing, or holding of the drugs or other products from the firms listed in the attachment do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B); therefore such articles are subject to refusal of admission into the United States.Guidance:Districts may detain without physical examination all forms of heparin and heparin-related products from the firm(s) identified on the attachment to this import alert.Since the article appears to be adulterated due to inadequate GMPs and is subject to Refusal of Admission per Section 801(a)(3) of the Act, FDA considers reconditioning or submission of analytical results to be insufficient to overcome the appearance of the violation. Drugs and other products offered for importation from the firm(s) listed on the attachment to this import alert are subject to detention without physical examination until FDA is satisfied that the appearance of a violation has been removed, either by inspection, reinspection, submission of documentation, and/or other actions requested by the FDA.Firms may provide copies of inspection reports for inspections performed by third parties to assist FDA in prioritizing inspection requests. An establishment wishing to schedule an FDA inspection or to provide a copy of an inspection report conducted by a third party, should do so by submitting a request or documentation to the following address:Food and Drug AdministrationDivision of Import Operations and Policy (HFC-170)12420 Parklawn Drive, ELEM-3109Rockville, MD 20857Or via email:IProduct Description:Different Forms of Heparin and Heparin-Related Products (e.g., Crude Heparin, Heparin Intermediates, Heparin Active Pharmaceutical Ingredient (API), Heparin Products, and Heparin-Containing Products) from the firms listed below.PROBLEM: Good Manufacturing PracticesCharge:The article is subject to refusal of admission pursuant to Section 801(a)(3) in that the methods used in and controls used for the manufacture, processing, packing, or holding of drugs and other products do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B).OASIS Charge Code: DRUG GMPsList of firms and their products subject to Detention without Physical Examination (DWPE) under this Import Alert (a.k.a. Red List)CHINACasing Factory Jintan CityDate Published : 02/22/20127 Bei Huan West Road , Jin Chen , Jintan City, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases;Jintan Yongmao Casing Co. LtdJintan Caliber Casing Co. Ltd61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases; Jintan Yongmao Casing Co. Ltd Jintan Caliber Casing Co. LtdChangsha Wulipai Food Stuff FactoryDate Published : 02/22/2012No 8 Bayi Road , Changsha, , Hunan, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsChangzhou SPL Company, Ltd.Date Published : 02/22/20123 Changhong West Rd., , Hutang Township, Wujin City , Changzhou, Jiangsu Province CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsChongqing Imperial Bio Chem CoDate Published : 02/22/20125 Yanghe Sancun , 19-7 Citic Bank Building, Jiangbei Dist. , Chongqing, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsChongqing Paiquiang Agribyproduct Co., LtdDate Published : 02/22/2012158 Gonglongpo , Yudong , Chongqing, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsHEILONGJIANG YUANGUANG CASING CO., LTD.Date Published : 02/22/20127 Bohai Rd., Jizhong District , Haping Rd. Develop. District , Harbin, CN-23 CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Alias;Heilongjiang Yuanguang Caliber Casing Co.; LtdAlternate Address;No.7 Bohai East Road;Jizhong District HeilongjiangChina61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Alias; Heilongjiang Yuanguang Caliber Casing Co.; Ltd Alternate Address; No.7 Bohai East Road; Jizhong District Heilongjiang ChinaHenan Zhengping HuixinDate Published : 02/22/2012Fuzhuang Yangying Town , Zhengping, , Henan, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases;Henan Zhengping Huixin61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases; Henan Zhengping HuixinHubei Anlu Food Stuff FactoryDate Published : 02/22/2012Xinli Village, Zhuzhan Town , Xiaogan City, , Hubei, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 K - - - A-CholinergicDate Published: 02/22/2012Desc:Heparin and Heparin-related productsJiangsu Long Life GroupDate Published : 02/22/2012No. 216 Renshou Rd. , Rucheng Town, Rugao, , Jiangsu, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsJunan Hengxing Foodstuff Co., LtdDate Published : 02/22/2012No. 126 Meishan Rd , Junan County, , Shandong, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNanjing Maohai Biotech Co.Date Published : 02/22/20128 Developing Zone , Yaxi Town, Gaochun County , Nanjing, Jiangsu Province, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNantong Jianhua Casing Co. LtdDate Published : 02/22/2012Linjiang Village/Langshan Town, , Nantong, , Jiangsu , CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsQingdao Hualu Foods Co., LtdDate Published : 02/22/2012Industrial Park of Jiaodong Town , Jiaozhou, , Qingdao, CHINA55 Q - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsShandong Union Food Stuff Qingzhou Branch*Date Published : 02/22/2012Mojiacun Subu Town , Qingzhou, , Shandong, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases;Qingzhou United61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsNotes:Aliases; Qingzhou UnitedShanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.Date Published : 02/22/20121317 Jianchuan Road, , Minhang District , Shanghai, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsShanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.Date Published : 02/22/2012387 Shangqui Road , Shanghai, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsShanhgai No.1 Biochem & Pharma Co., Ltd.Date Published : 02/22/2012494 Zhongxing Road , Room A-403 , Shanhgai, CHINA55 R - - - Pharm Nec (Mfr)Date Published: 02/22/2012Desc:Heparin and Heparin-related products61 L - - - A-CoagulantDate Published: 02/22/2012Desc:Heparin and Heparin-related productsSichuan Shuangliu Food Stuff FactoryDate Published : 02/22/201261 Wujiaba