In April 2012, the FDA issued the following field guidance:
Import Alert Name:
Detention Without Physical Examination of Different Forms of Heparin and Heparin-
Related Products for CGMP Issues
Related Products for CGMP Issues
Reason 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 FDA's 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 firm's 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 firm's 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 firm's quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firm's 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.
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 FDA's 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 firm's 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 firm's 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 firm's quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firm's 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 Administration
Division of Import Operations and Policy (HFC-170)
12420 Parklawn Drive, ELEM-3109
Rockville, MD 20857
Or via email: Importalerts2@fda.hhs.gov
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 Administration
Division of Import Operations and Policy (HFC-170)
12420 Parklawn Drive, ELEM-3109
Rockville, MD 20857
Or via email: Importalerts2@fda.hhs.gov
Product 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 Practices
PROBLEM: Good Manufacturing Practices
Charge:
"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 GMPs
OASIS Charge Code: DRUG GMPs
CHINA
Casing Factory Jintan City
Date Published : 02/22/2012
7 Bei Huan West Road , Jin Chen , Jintan City, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases;Jintan Yongmao Casing Co. LtdJintan Caliber Casing Co. Ltd
Notes:Aliases;Jintan Yongmao Casing Co. LtdJintan Caliber Casing Co. Ltd
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases; Jintan Yongmao Casing Co. Ltd Jintan Caliber Casing Co. Ltd
Notes:Aliases; Jintan Yongmao Casing Co. Ltd Jintan Caliber Casing Co. Ltd
Changsha Wulipai Food Stuff Factory
Date Published : 02/22/2012
"No 8 Bayi Road , Changsha, , Hunan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Changzhou SPL Company, Ltd.
Date Published : 02/22/2012
3 Changhong West Rd., , Hutang Township, Wujin City , Changzhou, Jiangsu Province CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Chongqing Baijie Changhong Casing Co., Ltd
Date Published : 04/04/2012
Baijie, , Chongqing, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
Chongqing Imperial Bio Chem Co
Date Published : 02/22/2012
5 Yanghe Sancun , 19-7 Citic Bank Building, Jiangbei Dist. , Chongqing, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Chongqing Paiquiang Agribyproduct Co., Ltd
Date Published : 02/22/2012
158 Gonglongpo , Yudong , Chongqing, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
HEILONGJIANG YUANGUANG CASING CO., LTD.
Date Published : 02/22/2012
7 Bohai Rd., Jizhong District , Haping Rd. Develop. District , Harbin, CN-23 CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Alias;Heilongjiang Yuanguang Caliber Casing Co.; LtdAlternate Address;No.7 Bohai East Road;Jizhong District HeilongjiangChina
Notes:Alias;Heilongjiang Yuanguang Caliber Casing Co.; LtdAlternate Address;No.7 Bohai East Road;Jizhong District HeilongjiangChina
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Alias; Heilongjiang Yuanguang Caliber Casing Co.; Ltd Alternate Address; No.7 Bohai East Road; Jizhong District Heilongjiang China
Notes:Alias; Heilongjiang Yuanguang Caliber Casing Co.; Ltd Alternate Address; No.7 Bohai East Road; Jizhong District Heilongjiang China
Henan Zhengping Huixin
Date Published : 02/22/2012
Fuzhuang Yangying Town , "Zhengping, , Henan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases;Henan Zhengping Huixin
Notes:Aliases;Henan Zhengping Huixin
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases; Henan Zhengping Huixin
Notes:Aliases; Henan Zhengping Huixin
Hubei Anlu Food Stuff Factory
Date Published : 02/22/2012
Xinli Village, Zhuzhan Town , Xiaogan City, , Hubei, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 K - - -- A-Cholinergic
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Jiangsu Long Life Group
Date Published : 02/22/2012
No. 216 Renshou Rd. , Rucheng Town, Rugao, , Jiangsu, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Junan Hengxing Foodstuff Co., Ltd
Date Published : 02/22/2012
No. 126 Meishan Rd , Ju'nan County, , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Nanjing Maohai Biotech Co.
Date Published : 02/22/2012
8 Developing Zone , Yaxi Town, Gaochun County , Nanjing, Jiangsu Province, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Nantong Jianhua Casing Co. Ltd
Date Published : 02/22/2012
Linjiang Village/Langshan Town, , Nantong, , Jiangsu , CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Qingdao Hualu Foods Co., Ltd
Date Published : 02/22/2012
Industrial Park of Jiaodong Town , Jiaozhou, , Qingdao, CHINA
55 Q - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Shandong Union Food Stuff Qingzhou Branch*
Date Published : 02/22/2012
Mojiacun Subu Town , Qingzhou, , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases;Qingzhou United
Notes:Aliases;Qingzhou United
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Notes:Aliases; Qingzhou United
Notes:Aliases; Qingzhou United
Shanghai Biochemial And Pharmaceutical Co Ltd
Date Published : 02/22/2012
Room A403, No. 494 Zhongxing Road , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.
Date Published : 02/22/2012
387 Shangqui Road , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.
Date Published : 02/22/2012
1317 Jianchuan Road, , Minhang District , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Sichuan Shuangliu Food Stuff Factory
Date Published : 02/22/2012
61 Wujiaba Nort Street , Shuangliu, , Sichuan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Sichuan Zhongjiang Xiongjian Casing Co.
Date Published : 04/04/2012
"Kanjiang, , Zhongjiang, , Sichuan, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
Weifang Legang Food Ltd.
Date Published : 02/22/2012
No. 1 Honghe Street , Honghe Town, Changle County , Weifang , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Xinjiang Lanshanbinggong Food Factory
Date Published : 02/22/2012
No31 QinjianRoad , Gumudi Town, Miquan City, , Xinjiang, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Xuzhou City Mianshang Fengxian Shengda Casing Factory
Date Published : 02/22/2012
Zhangshicheng Village , Zhaozhuang Town , Xuzhou, Jiangsu, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Zhejiang Casing Animal By-Products Co.,Ltd.
Date Published : 02/22/2012
369 Dong Xing Road , Tonglu Economic Developing District , Hangzhou, Zhejiang Province CN-33 CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012
Desc:Heparin and Heparin-related products
Zhengzhou Yuanlong Casing Co., Ltd
Date Published : 04/04/2012
"Renmin Road, , Zhengzhou, , Henan, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012
Desc:Heparin and Heparin-Related Products
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