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Allegations in the Lawsuits Filed by Zoll, Kranz &
Borgess, LLC
Baxter is one of the largest producers of heparin in the United States, and its sales of heparin constitute at least a 50% market share. Baxter sells an estimated 35 million units of Heparin per year, with annual sales of approximately $30 million dollars.
Baxter obtained the component ingredients in its recalled heparin, called “active pharmaceutical ingredients” or “API” from Scientific Protein Laboratories, LLC, (“SPL”). Through its joint venture, Changzhou SPL Company, SPL operates a Heparin API manufacturing facility located in Jiangsu Province, China. Changzhou SPL is the sixth largest exporter in China of heparin ingredients by volume for 2007.
Both Baxter and SPL warranted and represented to the public that it was taking great care to assure the safety of its drugs and their raw component ingredients. For example, in its
10-K SEC filing on February 28,
2007.
Baxter warranted and represented the following to the public:
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That it “places a significant emphasis on providing quality products and services to its customers.”
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That in “an effort to manage risks associated with raw materials supply, Baxter works closely with its suppliers to ensure availability and continuity of supply while maintaining high quality and reliability;”
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That “great care is taken in assuring the safety of raw materials;”
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That it “regularly reviews its quality systems to determine their effectiveness and identify areas for improvement.”
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That it “performs assessments of its suppliers of raw materials, components and finished goods.”
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That the “operations of Baxter and many of the products manufactured or sold by the company are subject to extensive regulation by numerous governmental agencies, both within and outside the United States.”
Likewise, as set forth on SPL’s internet website
and company brochures, SPL warranted and represented the following to the public:
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That its “experience and know-how in commercial-scale production of active pharmaceutical ingredients from biological sources, together with its expertise in analytical testing, quality assurance, and regulatory affairs, is the backbone for [its] contract development and cGMP manufacturing services.”
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That its “contract manufacture sector is staffed by knowledgeable and experienced R&D scientists and process engineers, operating in a state-of-the-art cGMP facility with capabilities in natural products extraction, fermentation, and purification.
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That it “is committed to providing high quality contract development and manufacturing services…”
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That it has the capability to “establish specific cGMP process guidelines and control conditions.”
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That it “utilizes both conventional and state-of-the-art methods for recovery and purification of recombinant microbial products as well as extracted natural products.”
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That its “recovery and purification facility includes cGMP compliant, solvent-capable, Class 10,000 clean rooms.”
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That its “quality control and microbiology laboratories are fully validated.”
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That “SPL’s quality control and microbiology laboratories are fully validated. We utilize numerous standard and compendial methods for in-process and release testing of drug products. We also have the capability to develop, qualify, and validate a wide range of non-compendial analytical test methods”
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That its “facilities are operated strictly in accordance with FDA’s cGMP requirements. We have an experienced and dedicated quality assurance and regulatory staff committed to providing complete regulatory support to our customers and maintaining the highest quality standards for our commercial products and contract manufacturing services.”
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That “SPL is regularly inspected by multiple regulatory agencies such as the FDA and USDA and participates in many annual customer audits. We maintain a stellar regulatory inspection record by doing things right the first time and maintain that commitment to excellence every day of the year.”
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That “SPL has gone to great lengths to ensure that consistency in compliance is maintained at both of our global manufacturing sites in Waunakee, WI and Changzhou, China. We rigorously apply the same work processes, documentation requirements and QA/QC regimen at both facilities to provide our customers with the reliability and peace of mind they value no matter where SPL products are sourced around the world. FDA-approved APIs from both sites are supported by an ever-expanding list of Drug Master Files, Import Certificates, EU Certificates of Compliance and other documentation that makes sourcing APIs through SPL simple and worry-free.”
However, despite Baxter and SPL’s representations regarding safety to the public, the lawsuits filed by Zoll, Kranz & Borgess, LLC allege that the companies failed to exercise reasonable care in the manufacture and inspection of their heparin, resulting in a contaminated drug being sold to and injuring the American public. (See
Overview of the Heparin Recall and the Contaminant for information regarding the contaminant, over-sulfated chondroitin sulfate.) For example, despite its warranties, the Changzhou SPL facility in China was never inspected by the U.S. Food and Drug Administration (“FDA”) until after the recall of Baxter’s Heparin in 2008. When the International Compliance Team for the U.S. FDA performed an inspection of the Changzhou SPL facility from February 20 – 26, 2008, multiple violations were found. (See also Testimony of FDA at the U.S. House Commerce Committee on Energy and Commerce, 4/29/08 Hearing entitled, “The Heparin Disaster: Chinese Counterfeits and American Failures.”)
The partially redacted
report of the inspection
establishes severe deficiencies in the companies manufacturing and inspection processes. More specifically, the inspectors made the following observations:
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There have been no critical processing steps identified for the Heparin Sodium USP [Redacted] process, and, the repeated and efficient removal of impurities, such as proteins, nucleotides, virus, endotoxin, bacteria and heavy metals at the appropriate, specified, process steps has not been evaluated. There was no report for annual [Redacted] test results available.
The improvements offered by removal of a raw material [Redacted] test [Redacted] a batch size increase, an added [Redacted] step, a change in [Redacted] for the [Redacted] step and [Redacted] and parameter changes, approved in a 1/05 process validation report for Heparin Sodium USP, were not
demonstrated.
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There has been no impurity profile established for Heparin Sodim USP and no evaluation for degradants during stability program testing.
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The manufacturing instructions for Heparin Sodium USP are incomplete in that they do not include a description of manual manipulations of the [Redacted] during processing steps, they do not include the actual, manually entered [Redacted] set temperatures and times and, operator observations such as level measurements, used in calculations, during the [Redacted] step are not recorded.
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There has been no test method verification performed for the reported USP test methods, Nitrogen Determination, Protein and Total Aerobic Microbial Count, employed in testing of Heparin Sodium USP and Heparin Crude materials, to show that the methods are suitable under actual conditions of use. In addition, there is no routine test for [Redacted] residue amount at the time of release.
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Investigations into failed lots and out of trend lots were approved as complete, but did not identify a cause for the problem. For example,
Heparin Sodium USP batch [Redacted] failed the Nitrogen Determination test and was reprocessed to make [Redacted] without finding the reason for the slightly high, OOS Nitrogen result.
Investigations into [Handwritten #2: cross out a word, added "OOT"] of customer [Redacted] specification [Redacted] for Heparin Sodium USP lots [Handwritten #3: cross out word(s)] [Redacted] and
[Handwritten #4: cross out word.] were performed without knowing what the failed test measurement actually represented.
[Redacted][Handwritten #5: added "and the failure of lot"][Redacted]
Investigations into ROI out of trend results for Heparin Sodium USP lots [Redacted] identified both results inappropriately as outliers.
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Heparin Crude lots [Redacted] received 8/06 from vendor
[Handwritten #6: cross out word(s)] [Redacted] that included material from an unacceptable workshop vendor were used in Herapin Sodium USP
[Redated] marketed to the USA. In addition, prior to 3/06 there are no [Redacted] records from vendor [Redacted] showing the source for their crude materials.
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The inside surface of large, "cleaned" [Redacted] tanks used in the final [Redacted] step, after both [Redacted] were very scratched, with unidentified material adhering to the insides and, the inverted handles held liquid, which spilled to the bottom of the tank when it was uprighted. There was no written procedure showing that the tanks were dedicated to a particular process step. There was no data collected to verify marker and tape volume markings on the outside of the tanks and, the cleaning method was not validated. It was noted that equipment cleaning tags were made of paper and taped to the piece of equipment unprotected from liquids used in the processing room environments.
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Raw material inventory records were incomplete in that samples removed from the containers and the status and amount of materials returned from use by the production processing department were not recorded. For [Redacted] stored in a freezer, the amount, condition and date of return was not recorded.
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Control of material flow in the processing area was inadequate in that waste [Redacted] was carted through a door to the outside in the processing area and not provided for by the material flow written procedure.
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The outer foil bags containing Heparin Sodium USP lot [Redacted] manufactured and held since 5/25/07, are not labeled. The drum lid showed the only indications of the lot number.
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There is no report or data to show that leachables for the [Redacted] bags used to hold Heparin Sodium USP lot, have been evaluated.
As a result, the FDA issued a strong warning letter
to the factory dated April 21, 2008 outlining the “significant deficiencies,” including, but not limited to, Changzhou SPL’s failure to provide any assurances that processing steps used to manufacture heparin are capable of effectively removing impurities. Indeed, the letter indicated that Changzhou had even acknowledged to the FDA that it received and used heparin crude materials from a workshop that Changzhou itself had deemed as “unacceptable” in a “pre-audit.” The FDA gave Changzhou SPL 30 days to respond and has refused to allow shipments of the drug until the violations have been corrected.
A copy of one of the complaints filed by Zoll, Kranz & Borgess, LLC can be accessed by
clicking here.
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