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

WARNING LETTER 

WL 320-09-01

VIA Federal Express

April 14, 2009

 

Dr. Mao Jian Yi

General Manager

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

 

Sincerely,

/s/

Richard L. Friedman

Director

Division of Manufacturing and Product Quality

Center for Drug Evaluation and Research-Office of

Compliance

 

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Qingdao Jiulong Biopharmaceuticals Co. Ltd. 4-14-2009

Department of Health and Human Services	Public Health Service Food and Drug Administration
	10903 New Hampshire Avenue Silver Spring, Maryland 20993

WARNING LETTER

WL NO. 320-09-02

April 14, 2009

VIA FEDERAL EXPRESS


Ms. Wang Weiru

President

Qingdao Jiulong Biopharmaceuticals Co. Ltd.

Jiulong Industrial Garden,

Jiaoshou City

Qingdao, People's Republic of China (PRC) 266319

Dear Ms. Weiru:

This is regarding an inspection of your pharmaceutical manufacturing facility, Qingdao Jiulong Biopharmaceutical Co., Ltd. (QJBC) located at Jiulong Industrial Garden Jiaoz, Qingdao, Shangdon Providence 266319, People's Republic of China, conducted by Investigator Carl Lee and Compliance Officer Zi-Qiang Gu, Ph.D., during the period of July 28 to August 1, 2008. The inspection and other information revealed significant deviations from U.S. current good manufacturing practices (CGMP) requirements in the manufacture of drugs.

Deviations were listed on an Inspectional Observations Form (FDA-483) issued to you at the close of the inspection. These and other CGMP deviations cause your 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)]. Section 501(a)(2)(B) of the Act requires that all drugs, as defined in the Act, be manufactured, processed, packed, and held according to CGMP.

We have reviewed your August 13, 2008 written response to the FDA-483 observations and subsequent response of November 7, 2008 to our Request for Additional Information Letter of September 29, 2008. We note that you assert that some corrections have been completed or will soon be implemented. However, your response does not adequately address some of the deficiencies. Our review of the information revealed the following CGMP violations:

1. Your firm's quality unit fails to have the appropriate system and procedures to provide confidence that the drugs manufactured at your facility meet the intended specifications for identity, strength, quality and purity.

In April 2008, FDA learned that 19 lots of heparin sodium were contaminated with Over-Sulfated Chondroitin Sulfate (OSCS), and these lots were later determined to have been manufactured at your facility. Although this heparin sodium did not ultimately reach U.S. patients, your firm has not demonstrated that it has conducted an investigation of these contaminated lots, identified the source of this contamination, and taken appropriate corrective actions to ensure the quality of heparin sodium produced at this site. There is no assurance that your quality unit has systems in place to prevent manufacture and distribution of heparin sodium that has been contaminated with OSCS or other hazardous contaminants. These lots were supplied to Shanghai No. 1 Biochemical Pharmaceutical Co., Ltd. (Shanghai) over an extended period, spanning 2007 and 2008, for distribution under their name.

We are concerned that your firm lacked adequate systems to ensure the safety of raw materials used in your manufacturing, particularly to prevent the substitution of an unsafe substance (OSCS) in place of heparin sodium. It is essential that strict controls over your suppliers be established to prevent any such supply chain breach.

Your firm also failed to ensure that manufacturing and testing procedures apparently transferred to your facility provided for acceptable drug identity, strength, quality, and purity. It is critical for a firm to assess the impact of a change in manufacturing facility, including determining how production and control practices and conditions at the new facility may affect the identity, strength, quality, and purity of a drug.

During the August 2008 inspection, our investigators learned that your current manufacturing process for Heparin Sodium USP was apparently transferred in 2005 from Qingdao Kangyuan, which you assert is a related business entity, to your site and that Qingdao Kangyuan no longer manufactures heparin sodium. However, no information regarding the procedures, protocols and reports related to this technology transfer were available for review. Only estimated dates of when Qingdao Kangyuan ceased manufacturing heparin sodium and when your firm initiated production were provided.

2. Failure to conduct and document regular product quality reviews for the drugs produced that would include at a minimum, a review of your critical in-process controls and test results; review of all batches that failed to meet the established specifications; and investigation of process deviations and complaints to ensure your product remains within specifications and that corrective actions have been implemented.

In a letter sent to your attention on September 29, 2008, we informed you that your written response to the FDA-483 of August 13, 2008 was found deficient and lacked specific information related to the responsibilities of your quality control unit. In your letter of November 07, 2008, you acknowledge our concerns regarding the failure to perform product quality reviews by committing to perform Annual Product Reviews. You indicate that most of the product review activities were documented as part of your annual internal auditing reports. However, during the inspection, the investigators noted that your annual internal reviews involved only completing a check box document. This product quality review is inadequate in that it lacks adequate content or information, such as explanation of all deviations from established procedures and outcome of investigations of critical deviations.

Although in your response of November 7, 2008 you include a new SOP specifying that “Annually, QA shall perform annual quality review on all products manufactured, distributed and marketed by the Company, the corrective action implemented is inadequate. We are concerned that you have only committed to conduct an “annual product review for product lots produced during 2008.  As you are aware, 19 lots of heparin sodium manufactured at your facility during 2007 and shipped to the U.S. were found contaminated with OSCS.

Please include in your response a copy of complete product quality review reports covering the manufacturing of heparin sodium for all lots that remain within expiration. Include the following:

• A review of all critical in-process controls and critical test results.

• A review of all batches that failed to meet established specifications. 
• A review of all critical deviations or non-conformances and related investigations.
• A review of any changes carried out to the process or analytical methods.
• A review of the stability monitoring program.
• A review of all quality-related returns, complaints (formal or informal from all customers) and complaints.
• A review of adequacy of corrective actions implemented (also include the conclusions). 

3. Your firm failed to investigate specific discrepancies related to the lots of impure drugs supplied to your customers. We learned that heparin sodium lots manufactured at your facility were determined to be contaminated with OSCS. At the time of the inspection, no investigation had been conducted into this repeated and unacceptable contamination.

From our investigation, it appears that your customer requested that your firm investigate the OSCS contamination. Although the contamination of these lots was discussed during the inspection, you apparently had not initiated an investigation to determine the root cause of the contamination, identified whether other lots were implicated, or taken appropriate corrective actions to prevent recurrence of this contamination.

Your firm’s failure to investigate these significant customer complaints is a serious deviation from CGMP. It is your firm’s responsibility to ensure that drugs manufactured at your facility are produced in compliance with CGMP. This includes establishing adequate systems to detect such quality issues before an adulterated product is distributed, and promptly implementing corrective measures to prevent recurrence.

No information was provided to assure that any of your firm’s internal practices or upstream sources (e.g., suppliers) that may have been involved in the contamination of the 19 lots produced has been identified and removed from your supply chain. Please include in your written response to this letter a copy of all investigations regarding OSCS that may have been conducted after the inspection, the root cause of the contamination, and the corrective actions implemented to prevent recurrence. Also include the list of the crude and other upstream suppliers for all of the contaminated lots.

The investigators were informed during the inspection that all lots of heparin sodium produced at your facility would be tested using the CE and NMR methods beginning in September 2008. Please state in your response whether your firm has begun to test the heparin sodium using these methods or if these analyses are being outsourced, and when this testing commenced. If your firm has decided to outsource these tests, include in your response the identity of the contract laboratory, their physical address and the qualification report.

Please also address in your response to this letter the following issues:

During the inspection, the investigators were informed that your firm does not distribute heparin sodium directly to the U.S. and that the product manufactured was shipped to Shanghai. During an inspection conducted at a U.S. facility, we found purchase orders and information indicating that since 2005, heparin sodium manufactured at your facility was being shipped into the U.S. Please clarify whether you shipped drugs directly to the U.S. and provide a list of all lots of heparin sodium (intended for experimental or commercial use) shipped to the U.S. since your firm started to manufacture heparin sodium. Please also identify whether you shipped drugs that you understood were ordered by or ultimately destined for the U.S., even if you did not ship them directly to the U.S. yourself. Also include a list of any other customers to whom you have supplied heparin sodium or other substances intended for the U.S. market. Include the amounts shipped and dates of all

shipments.

Please also explain the relationship between your firm and (b)(4). Please provide information regarding any lots of heparin sodium that were shipped by (b)(4) on your firm’s behalf, including lot numbers, dates of shipments and amounts.

In light of the above and the fact that your predecessor (Qingdao Kangyuan) was never inspected by FDA and apparently no longer manufactures heparin sodium, we expect you to address the reliability of any information generated regarding the manufacture, processing, testing, packaging, and labeling of heparin sodium shipped to the U.S. and used to support your DMF 22222.

One way you can do this is by employing a third party auditor to conduct a validity assessment of the information you have provided or intend to provide to support your DMF regarding the production of heparin sodium. Conducting such an audit could expedite the process of re-qualifying your facility.

The listed deficiencies are not to be considered an all inclusive list of deficiencies at your facility. FDA inspections are audits, which are not intended to address all deviations from CGMP or all violations which may exist at a firm. If you wish to ship your products to the U.S., you are responsible for ensuring compliance with all U.S. standards for CGMP and all other applicable U.S. laws and regulations.

Until FDA has confirmed corrections of the deficiencies and compliance with CGMP, this office may recommend withholding approval of any new applications listing your firm as the drug manufacturer. In addition, shipments of articles manufactured at Qingdao Jiulong Biopharmaceutical Co., Ltd located at Jiulong Indusrial Garden Jiaozhou, Qingdao, Shangdon Providence 266319, People’s Republic of China facility and shipped 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. Please identify your response with FEI 3006745882. 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 5110903 New Hampshire Avenue

Silver Spring, Maryland 20993

Tel: (301) 796-3667

Fax: (301) 301-847-8741
Sincerely,
/s/
Richard L. Friedman

Director

Division of Manufacturing and

Product Quality

Office of Compliance

Center for Drug Evaluation and Research

Office of Compliance

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