heparin and intentional adulteration of drugs
TRANSCRIPT
Heparin and Intentional Adulteration of Drugs Rx360 Fighting Fakes – June 2-3, 2015
Gabrielle Cosel, Manager, Drug Safety The Pew Charitable Trusts
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About the Pew Charitable Trusts Pew is a national non-profit organization that studies and promotes nonpartisan solutions for pressing and emerging problems affecting the American public and the global community. Part of our work is to advance policies that reduce potentially dangerous health risks in consumer, medical and food products and services.
2011 white paper on pharmaceutical supply chain Interviews with more than 75 supply-chain experts including FDA, pharmaceutical manufacturers, distributors and pharmacies.
About The Pew Charitable Trusts
2013 report on drug traceability Cross-sector stakeholder perspectives on anticipated implementation of a national traceability system
Case study: Heparin
Other examples of API falsification and adulteration Solutions
Outline
Heparin
The first clue: unexpected serious allergic reactions at a children’s hospital in Missouri
Heparin
CDC is notified, solicits reports of similar incidents. Identifies over 50 in 48 hours.
Missouri Department of Health and Senior Services
Heparin
Adverse event reports in patients receiving heparin and exhibiting allergic-type symptoms, Jan 2007–Sept 2008
Source: FDA Adverse Event Reporting System. Includes reports that did not specify a month and were assigned to January of that calendar year.
API: Scientific Protein Labs – Wisconsin
Changzhou SPL
China
US
Raw material processing workshops
Raw material consolidators Slaughterhouses
7 Baxter Hospitals and
Pharmacies
OVERVIEW Heparin
US sources
Heparin
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• Heparin adulterant: oversulfated chondroitin sulfate (OSCS).
• OSCS: synthetic material, costs nearly 100 times less to produce than actual heparin
• One estimate: this adulteration yielded $1 million to $3 million in profit.
• Heparin compendial tests outdated, insufficient to catch OSCS due to chemical similarities to heparin.
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Heparin
Heparin
Lessons learned, and changes in the law
A perfect storm? Several issues were revealed by the heparin tragedy:
• Neither FDA nor Baxter inspected/audited SPL Changzhou before Baxter’s use
• Systems and testing in place failed to detect a dangerous adulterant
• Both FDA and Baxter encountered challenges accessing upstream suppliers after the adulteration
Food and Drug Administration Safety and Innovation Act, Supply Chain provisions
• Supports increased FDA inspections overseas
• Clarifies that companies must ensure ingredient quality, back to raw materials, as part of cGMP
Heparin
Monthly Chinese export prices for crude and refined heparin, 2006 and 2007
Source: Beijing Orientbit Technology Co., Ltd.
API falsification and adulteration
Other examples of API falsification and adulteration
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Empty drums conceal “vast warehouse” of uncertified active ingredient at a Chinese plant exporting to the US and Europe. Zhejiang, China.
Image courtesy of Philippe André. pharmacist, industry auditor and Associate Professor at the School of Pharmaceutical Science and Technology at Tianjin University, China (2008)
COMPLEX AND GLOBAL SUPPLY CHAINS
Plant auditor in China estimates 1/3rd of his drug company clients are unaware or misled about the identity or location of their suppliers.
API falsification and adulteration
Show / Shadow factories
Fujisawa USA Generic Drug Manufacturer
Flavine falsifies importation documents so it appears that gentamicin API is made at Long March Pharmaceutical Plant
Flavine International
API broker
Long March Pharmaceutical(Approved API Manufacturer)
Unapproved API Manufacturers
ESI Lederle Generic Drug Manufacturer
Flavine repackages API from unapproved source to more closely resemble Long March products
A few years later, Gentamicin sold by Fujisawa found to contain high levels of endotoxin, causing shaking, chills, and blood pressure drops in patients receiving concentrated doses.
API falsification and adulteration
Gentamicin and Flavine International: False labeling conceals unapproved manufacturing plants – 1990s
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• Chinese factory claimed to make heparin, but actually received it from two unreported suppliers and repackaged the product with their own label.
• This heparin was shipped to the U.S. as far back as 2001, discovered in 2008. Some found to contain OSCS
API falsification and adulteration
Heparin sodium falsification, 2001-2008
API falsification and adulteration
• API manufacturer Zhejiang Jiuzhou allegedly purchased gabapentin API from an outside supplier and relabeled them to identify themselves as the manufacturer.
• “The information from the original certificate of analysis, generated by the actual manufacturer, was transferred to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer… In addition, a new label identifying Zhejiang Jiuzhou Pharmaceutical Co. as the manufacturer was added to drums. In doing so, your firm essentially obscured the supply chain of these APIs.”
• “…in at least one instance of a lot of gabapentin shipped to the U.S., the retest date from the original manufacturer’s certificate of analysis (November 2013) was changed to an expiration date listed as eleven months later.”
Gabapentin API falsification, 2013
– FDA Warning Letter to Zhejiang Jiuzhou Pharmaceutical Co., Ltd., July 2014
Looking ahead
Continue to bolster FDA presence in countries with less-developed oversight systems
Continue to advance industry supply chain management Better information-sharing, both industry and FDA
THANK YOU Gabrielle Cosel, Manager, Drug Safety The Pew Charitable Trusts [email protected]
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