A Compound Immune System
Global sourcing of active ingredients is challenging regulators
FDA is, in effect, the immune system for the US market, protecting consumers from goods that don't meet safety standards.
The heparin recall of 2008 made it clear that the agency is now overwhelmed by foreign imports. But the trend isn't limited
to FDA—it's crunch time for all drug regulatory agencies.
In early 2008, Baxter Healthcare began recalling nine lots of its heparin sodium injection vials after receiving reports of
allergic reactions. In the ensuing weeks, the recall snowballed to include heparin products from over a dozen companies in
11 countries. Eventually, 149 deaths involved an allergic reaction to heparin.
The recalled product was found to contain over-sulfated chondroitin sulfate (OSCS), a chemically modified, heparin-like molecule
that does not occur in nature. The active pharmaceutical ingredient (API) originated in rural workshops in China. The material
was subsequently handled by several consolidators and then processed by Changzhou SPL. An investigation into FDA's oversight
of the plant revealed that due to a mixup in facility names, the agency had not conducted a preapproval inspection of the
Changzhou plant. When it did so in February 2008, it found "significant deviations" from FDA Good Manufacturing Practices
Twenty years ago, American and European manufacturers furnished 90 percent of the API needs of the US market. Today, that
percentage has dwindled to less than 20 percent, and FDA can't keep up with inspections for GMP. By law, the agency must inspect
US manufacturing plants every two years, but no inspection frequency is specified for foreign sites. Currently, the agency
is not equipped to conduct overseas inspections with the same frequency as domestic inspections and therefore uses a risk-based
process to prioritize. The agency manages to inspect only a fraction of the overseas plants each year.
Who should be responsible for ensuring the integrity of the supply chain for products manufactured in other countries? The
API manufacturing facility? The regulatory authorities in the API's originating country? Regulators in the importing country?
The manufacturer that imports the API for its product? Manufacturers must accept that:
» FDA cannot meet needed inspections.
» The Chinese government maintains that the responsibility for the quality and safety of exported products rests with the importing
» Receiving FDA marketing approval for a drug is no shield from liability in US courts.
Congress recently voted to provide FDA with additional funds that would allow the agency to conduct 120 more foreign medical
product facility inspections each year. Other remedies in the works include a heightened scrutiny of the supply chain during
preapproval and GMP inspections, as well as relying on non-governmental organizations to verify the registration data of foreign
In today's global market, and in light of the accelerating pressure on pharmaceutical manufacturers to reduce costs, this
issue will intensify. Regulators and pharmaceutical manufacturers must build better partnerships to enforce GMP standards
and ensure the safety of the drug supply. Data management capabilities are a key element in this.