Inspections, Compliance, Enforcement, and Criminal Investigations
Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd. 4-14-2009
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Division of Manufacturing and Product Quality
International Compliance Team, HFD-325
10903 New Hampshire Ave
Silver Spring, Maryland 20993
VIA Federal Express
April 14, 2009
Dr. Mao Jian Yi
Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd.
1317 Jianchuan Road
Minhang District, Shanghai 200240
People’s Republic of China
Dear Dr. Jian Yi:
This is regarding an inspection of your pharmaceutical manufacturing facility, Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd. (Shanghai) located at 1317 Jianchuan Road Minhang District, Shanghai 200240, People’s Republic of China, conducted by Investigator Carl Lee and Compliance Officer Zi-Qiang Gu, Ph.D., during the period of August 4-7, 2008. The inspectors identified significant deviations from U.S. current good manufacturing practices (CGMP) requirements in the manufacture of drugs, and we have also determined that you had made untrue statements to FDA relating to the manufacture of Heparin Sodium USP.
The inspection revealed that the facility was not manufacturing, and did not appear to have ever manufactured, Heparin Sodium USP (or heparin sodium) for the U.S. market. The investigators also determined that, contrary to your firm’s claims, manufacturing of heparin sodium was conducted at facilities other than the one identified in your DMF. In addition, our review of information submitted to the Agency in your DMF 12281, as well as documents collected during FDA’s inspections of both your facility and of subcontractor Qingdao Jiulong, along with additional information, uncovered untrue statements and information submitted by your firm to the agency with respect to the actual manufacturer(s) of heparin sodium.
These violations, along with those noted below, cause your drug heparin sodium to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 351(a)(2)(B)].
Our review of information obtained to date has revealed the following:
FDA conducted the inspection of August, 2008, to inspect your facility and review records relating to your ongoing manufacturing and testing operations. However, our inspection found that two other facilities have performed manufacturing and testing of heparin sodium in place of your facility since 2001. These facilities were identified as Qingdao Kangyuan and Qingdao Jiulong (neither listed in the DMF). Since 2001, at least (b)(4) lots of heparin sodium were supplied by you to International Medication Systems, Limited (IMS) in the U.S. There was no information (i.e., no manufacturing batch records) at your site to show that you had ever produced any of this material shipped from your facility to the U.S. Instead, we found during the inspection that heparin sodium was received at your facility packaged in 5 kg (b)(4) bags inside fiber drums, labeled with the name of the manufacturers (Qingdao Kangyuan or Qingdao Jiulong). The investigators also found that the manufacturers’ labels had been removed from the 5 kg bags during the repackaging operation and the bags were placed inside aluminum drums used to ship the heparin sodium to the U.S.; the bags were then sealed and identified with the Shanghai No. 1 label.
Although this heparin sodium ((b)(4) lots) was shipped to the U.S., we note that no drug products made with these lots have been marketed in the U.S. at this time.
During the inspection, we also found, for example:
• Your firm lacked laboratory testing records for the heparin sodium released from your facility to the U.S. to demonstrate that each batch met specifications. Significantly, our inspection found that your firm did not adhere to your DMF commitment to perform tests reported on your Certificates of Analysis (COAs).
• Your firm failed to investigate discrepancies related to lots of the heparin sodium supplied to the U.S. We learned that lots of heparin sodium shipped from your facility were found to be contaminated with Over-Sulfated Chondroitin Sulfate (OSCS). Although your firm quarantined some of the contaminated material apparently produced by Qingdao Jiulong in 2008, you permitted at least 19 lots to be shipped to the U.S. In addition, your firm failed to conduct an investigation into the cause of this repeated, unacceptable contamination. Instead, you requested that Qingdao Jiulong investigate the contamination, although the product was repackaged and relabeled at your facility.
In addition to the above violations, untrue information was submitted by your firm to FDA relating to the manufacture of Heparin Sodium USP. Your firm informed the Agency in writing that heparin sodium was produced at Shanghai. Specifically, your authorized U.S. Agent stated in the “CGMP Certification,” dated March 19, 2004:
“Amphastar Pharmaceuticals, Inc., on behalf of Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd hereby declares that the information submitted with respect to Active Ingredient Heparin Sodium USP manufactured in its plant, SBPC, Minhang 1317 Jianchuan Road, Minhang District, Shanghai, China 200240, is in accordance with GMP and the methods described herein and that each lot of the manufactured product will conform to the specifications and test methods described in this Drug Master File.”
You specifically indicated in DMF 12281, under Section B. of General Information, B.I Drug Establishment Registration that:
“All manufacturing, packaging and control of Heparin Sodium USP, as well as final drug substance and stability testing, are performed at:
Minhang Branch of Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd. 1317 Jianchuan Road Minhang District, Shanghai, China 200240.”
Furthermore, Section C.II.4 of your DMF 12281, Major Amendment of March 2004 includes the following statement:
“No contract firms are involved in the manufacturing of the drug substance, Heparin Sodium USP, that is the subject of this Drug Master File. Additionally, no contract firms are involved in material, component, or stability testing requirements as filed in this Drug Master File.”
Although you made these assertions, FDA has learned that the Heparin Sodium USP shipped to the U.S. was not manufactured by your firm. Your firm lacked evidence that the above-referenced lots of Heparin Sodium USP supplied to the U.S. were manufactured at Shanghai, in contrast to your written statements submitted to FDA.
On June 27, 2008, your U.S. Agent submitted a letter on your behalf identifying Qingdao Jiulong (located at Jiulong Industry Park, Jouzhou, Qingdao, Shandong, China 266364) as an “alternate” manufacturing site of heparin sodium. When FDA inspected the facility in August 2008, we found that Heparin Sodium USP had also apparently been produced by a second site, Qingdao Kangyuan, from approximately 2001 until 2006. This manufacturer of heparin sodium had never been inspected by the FDA, and had not been mentioned in correspondence to FDA by your firm, or your U.S. Agent, dating back to 2001.
During our inspection, your firm indicated that the Qingdao Kangyuan facility transferred the manufacturing of heparin sodium to Qingdao Jiulong in late 2005, and ceased production of heparin sodium. Because of the submission of untrue statements to FDA, the Agency was never given the opportunity to inspect the conditions and practices at the Qingdao Kangyuan manufacturing facility to verify whether heparin sodium was manufactured there and determine whether it was manufactured, processed, packed, and held in compliance with CGMP. We also confirmed that from late 2005 to present, the Heparin Sodium USP you supplied to the U.S. was produced, contrary to your representations to FDA, by Qingdao Jiulong and not at your facility.
In summary, information collected during the August, 2008 inspection and subsequent information obtained by FDA has demonstrated that Shanghai No. 1 Biochemical and Pharmaceutical Co., Ltd., has not produced any of the above-referenced heparin sodium shipped to the U.S. Rather, your firm used two other manufacturers to produce heparin sodium, failed to notify FDA of this manufacturing arrangement, and affirmatively represented that “no contract firms are involved in the manufacturing of the drug substance, Heparin Sodium USP, that is the subject of th[e] Drug Master File.” As noted above, you identified Qingdao Jiulong as an “alternate” manufacturing site only in 2008, many years after submitting your written statements discussed above.
The discrepancies identified above and the listed deficiencies are not an all inclusive list of deficiencies at your facility. FDA inspections are audits, which are not intended to address all deviations from CGMP and all violations that may exist at a firm. If you wish to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Until FDA has confirmed corrections of the deficiencies and compliance with CGMPs, this office may recommend withholding approval of any new applications listing your firm as the drug manufacturer. In addition, shipments of articles manufactured at the Jianchuan Road, Minhang District, Shanghai, China 200240 People’s Republic of China facility into the U.S. are subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C Act [21 U.S.C. 381(a)(3)] in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the FD&C Act [21 U.S.C. 351(a)(2)(B)].
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice. Please respond to this letter within 30 days of receipt and explain why your firm:
• repeatedly departed from your DMF commitments, which explicitly commit to FDA that all manufacturing and testing would be conducted solely at your site and no subcontractors would be used; and
• did not report, until recently, the information regarding contract manufacturers in the DMF that you filed with the Agency.
Please also state whether you notified your U.S. Agent or customers of the above facts. If so, please state when and provide supporting documentation.
Please identify your response with FEI #3004475606. If you have any questions concerning this letter, you may contact Carmelo Rosa, Compliance Officer at the address and telephone numbers shown below.
U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Team
White Oak Building 51, Room 4240
10903 New Hampshire Avenue
Silver Spring, Maryland 20993
Tel: (301) 796-3667 fax: 301-847-8743
FAX: (301) 301-847-8742
Richard L. Friedman
Division of Manufacturing and Product Quality
Center for Drug Evaluation and Research-Office of