FDA Funding Increase in Wake of New Head for Agency

The below story from the AP about Obama's pick for the FDA is good news for all Heparin advocates because it signals a shift from a corporate friendly FDA to one based on science and consumer safety. Nominated for head of the FDA, Dr. Margaret Hamburg has received little opposition in committee and her confirmation is expected soon. More significant is the Obama administration intent to substantially increase the FDA's budget and to stop political appointees from silencing the scientists at the FDA.

More money and independence is absolutely needed at the agency. Swine flu is only a small part of the agenda. Food and drug contamination are bigger threats. The FDA can simply not allow a thirty-year backlog on inspections of overseas drug plants. The FDA cannot do its job with a regulatory structure that allows the new plants to produce until the FDA finds something out of compliance. The law must require inspection and compliance, before drugs are shipped to the U.S. The conditions found by the FDA at Chanzghou SPL where Heparin was contaminated, cannot be allowed to exist in facilities making pharmaceuticals.

Attorney Gordon Johnson
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WASHINGTON (AP) — President Barack Obama's pick to oversee food and drug safety pledged on Thursday to revamp protection of the nation's food supply to help prevent future disease outbreaks.

Dr. Margaret Hamburg, a bioterrorism expert who once served as New York City health commissioner, breezed through her confirmation hearing before the Senate Health, Education, Labor and Pensions committee, with no senators expressing opposition.

Hamburg, 53, said she wants to restore public confidence in the Food and Drug Administration by putting science first and running an open and accountable operation.

The full Senate is expected to vote on her nomination before Memorial Day. If confirmed, Hamburg's most immediate task will be to oversee development of a vaccine for the new swine flu. But she said food safety will be her major ongoing project.

"The agency is facing a range of new and daunting challenges," Hamburg told senators. "These include the globalization of food and drug production, the emergence of new and complex medical technologies, and the risk of adulteration or deliberate terror attacks on our food and drug supplies."

The FDA oversees products ranging from peanut butter to cancer drugs to medical imaging machines — a portfolio that represents about a quarter of consumer products. A few years ago, it was shaken by the withdrawal from the market of Vioxx, a painkiller that turned out to have serious heart risks. More recently, outbreaks of foodborne illness have exposed haphazard oversight of the nation's far-flung food supply chain. Within the agency, scientists in the medical devices center are in revolt over what they say is management interference. And a federal judge recently ruled that the FDA improperly politicized a decision on emergency birth control during the Bush administration.

On top of all that, the FDA must play a critical role in developing a vaccine for the new swine flu virus and ensuring that enough vaccine can be made to protect the public.

Hamburg, as an assistant health secretary under President Bill Clinton, helped lay the groundwork for the government's bioterrorism and flu pandemic preparations.

The swine flu vaccine will be her first task. "I look forward to being actively involved in discussion on such critical issues as how much vaccine to make, whether to alter seasonal vaccine manufacturing, and, ultimately, whether to recommend vaccination for the American people," Hamburg said.

Vaccinating the entire population for swine flu would be a huge undertaking, and might require more than one shot. It would also have to be coordinated with preparations for the regular flu season. But such a large scale effort may not be needed if the virus turns out to be mild.

Turning to food safety, Hamburg said it will require sustained effort, more money, and stronger laws to improve the situation. She wants to shift from chasing outbreaks after they have broken out to preventing them first. That would require all food companies to follow written safety plans, overseen by federal and state inspectors. Traceability and import safety — weak links in the system — would have to be strengthened.

Obama's budget, released Thursday, calls for a $260-million increase for the FDA's food safety program. Past budget cuts have hit the food inspection program hard, and part of the new funding would go to rebuild the ranks of inspectors.

Hamburg said she supports FDA regulation of tobacco and allowing Americans to import low-cost brand name prescription drugs from abroad, positions consistent with Obama's.

Hamburg's professional career has centered on public health. She is the daughter of two doctors, and her family background includes African-American and Jewish heritage. Her mother was the first black woman to earn a medical degree from Yale University. She credits her father's side of the family for imbuing in her a passion for social concerns.

___

Associated Press writer Erica Werner contributed to this report.

Rep. Barton Demands Answers about Heparin Contamination

Finally someone in Washington has remembered that there are still consequences to what they called a “catastrophe” last year.

According to the Dow Jones Newswire, Rep. Joe Barton, R.-Texas, "is pressuring the U.S. Food and Drug Administration for more information about contaminated heparin from China amid concerns that the agency doesn't know what caused U.S. patients to get sick or die while taking the blood thinner last year."

Barton is a member of the House Energy and Commerce Committee which held hearings last year. He has written a letter to the FDA demanding the agency turnover databases on the Heparin contamination. According to Dow Jones:

Barton is trying to determine whether anyone in China has been held responsible for contaminating heparin that ultimately sickened and killed U.S. citizens.

"We don't seem to be any further along a year later from understanding" this issue, said an Republican staffer for the committee, who asked not to be named. "What are they doing about it? Is this an acceptable practice in China?"

It is time that the FDA went public with all it knows about the Heparin Catastrophe. Freedom of Information Requests have been pending before the agency for more than a year now. What does the FDA know? Why are they not telling the American public about the full breadth of this poisoning?

Attorney Gordon Johnson
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©Attorney Gordon S. Johnson, Jr. 2009

FDA Warns Qingdao Heparin Company, conclusion

The FDA warning letter to Qingdao Jiulong Biopharmaceuticals Co. Ltd. concluded as follows:

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

Maybe you should write the FDA and tell them what you think about importing dangerous drugs from China?

Attorney Gordon Johnson
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©Attorney Gordon S. Johnson, Jr. 2009

FDA Warns Qingdao Heparin Company, continued

In the third part of the FDA warning letter to Qingdao Jiulong Biopharmaceuticals Co. Ltd. the focus was on the presence of the OSCS contamination:

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.

Only one inference is possible from these detailed complaints by the FDA: The Chinese don't seem to care about the safety of a drug intended for IV use with the sickest of Americans. Such complete failure could not have slipped by even the most cursory of investigation.

Attorney Gordon Johnson
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©Attorney Gordon S. Johnson, Jr. 2009

FDA Heparin Warning Letter, continued

A different wrongdoer, but so many similar complaints to what the FDA found wrong with Baxter/SPL's production of Heparin. Here is the second part of the FDA warning letter to Qingdao Jiulong Biopharmaceuticals Co. Ltd. Like Chanzghou SPL, insufficient quality review was pervasive.

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).

OSCS again. Is there a common thread here?

Attorney Gordon Johnson
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©Attorney Gordon S. Johnson, Jr. 2009

FDA Warning Letter for Bad Chinese Heparin

The problem of bad Chinese Heparin, and even OSCS, has continued into 2009. Yesterday we outlined the problems the FDA cited with Qingdao Jiulong Biopharmaceuticals Co. Ltd. manufacture. Here is the first part of the FDA warning letter to Qingdao.

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.

In our next blog, we will continue with the warnings given to Qingdao with respect to its failure to conduct regular product quality reviews. 

Attorney Gordon Johnson
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©Attorney Gordon S. Johnson, Jr. 2009

FDA Cites Chinese Heparin Makers

The FDA on April 14 issued a warning letter to two Chinese companies for shipping Heparin after the FDA closed Chinese imports of the drug- Qingdao Jiulong Biopharmaceuticals Co. Ltd. and Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd. The Warning letter to Qingdao Jiulong Biopharmaceuticals Co. Ltd. (Qingdao) highlights similar problems in production as were found in the Inspection of Chanzghou SPL, discussed recently on this blog. Those problems included:

• 1. Qingdao's quality unit failed to have the appropriate system and procedures to provide confidence that the drugs manufactured at the facility met the intended specifications for identity, strength, quality and purity.
• 2. Qingdao failed to conduct and document regular product quality reviews for the drugs produced that would include at a minimum, a review of 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 the product remains within specifications and that corrective actions had been implemented.
  
• 3. Qingdao failed to investigate specific discrepancies related to the lots of impure drugs supplied to its customers. The FDA learned that heparin sodium lots manufactured at Qingdao's 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.
  

We will look at each specific issue on these warning letters in our subsequent blogs. However, that these problems are now occurring at other Chinese suppliers shows how perilous it was for Baxter to import Heparin from a place so seemingly incapable of controlling quality, purity and standards.


Attorney Gordon Johnson
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g@gordonjohnson.com
800-992-9447
©Attorney Gordon S. Johnson, Jr. 2009