Overseas inspections strain FDA resources

Inspections come under the microscope

28 January 2008 00:00  [Source: ICB]

The manufacture of active pharmaceutical ingredients is moving out of the US, so why aren't FDA inspections?
Cynthia Challener/Vermont

IF YOU buy many generic drugs or over-the-counter (OTC) medicines in the US, you might be interested to know that more than 60% of the active ingredients in those products are produced outside the country, mainly at facilities in China and India. You might also like to know that the US Food and Drug Administration (FDA) inspects only a handful of those manufacturers each year.

Congress held hearings last November on the disparity between overseas and domestic inspections conducted by the FDA. Prior to the hearings, a bipartisan staff delegation from the House Energy and Commerce Committee traveled to China and India to investigate the situation firsthand.

In a letter to the FDA, committee chairman John Dingell (Democrat, Michigan) recommended that a permanent FDA office be established in each country. While India welcomes a more extensive relationship with FDA, China did not have a clear position on the proposal.

All of this activity might suggest that the problem is new. In fact, the Government Accounting Office (GAO) found in a 1998 study that not only the number but the quality of FDA inspections of overseas producers was inadequate. The GAO is updating that research and early results indicate that the magnitude of the problem has grown.

GAO sees little progress

In her testimony before the House Committee on Energy and Commerce Subcommittee on Oversight and Investigations, Marcia Crosse, director of health care at the GAO, indicated that "fundamental flaws that we identified in the management of this program in 1998 continue to persist."

According to the GAO, while the FDA has taken steps to improve its management of the foreign drug inspection program, "systemic weaknesses" remain, and these must be addressed before it can "provide the needed assurance that the drug supply reaching our citizens is appropriately scrutinized and safe."

Insiders speak out

Several ex-FDA officials also testified to the shortcomings of the FDA's overseas inspections. William Hubbard, a senior advisor with the Coalition for a Stronger FDA and a retired FDA associate commissioner, said: "The massive increase in pharmaceuticals being imported into the US [comes] at a time in which the FDA's capacity to oversee those foreign producers is in serious doubt."

For OTC products, the FDA is "virtually absent in the foreign market," and relies upon results obtained from finished-product testing, which "cannot predict, measure, assess, or assure drug safety," said Benjamin England, former regulatory counsel to the FDA's associate commissioner for regulatory affairs. The agency's current system is based on "too many false presumptions," he testified, and "a drastic internal change is needed."

Because the exposure is greater, the OTC industry may actually have a greater impact on public health and safety than the prescription industry, noted Carl Nielsen, retired director of the FDA's Division of Import Operations, Office of Regulatory Affairs. "The current FDA organization, IT systems and regulatory paradigm have not, and cannot effectively manage the foreign industries or mitigate the related risks."

The US generics industry has its own concerns about the impact of the imbalance between domestic and foreign inspections. The disparity creates a "potential competitive advantage for manufacturers operating overseas, where inspections are less frequent and liability less risky," testified Bruce Downey, chairman and CEO of US-based Barr Pharmaceuticals, and chairman of the Generic Pharmaceutical Association (GPA).

The Synthetic Organic Chemical Manufacturers Association (SOCMA), which represents custom manufacturers of active pharmaceutical ingredients (APIs) and other pharma intermediates, would like to see the FDA implement a risk-based approach to determining what facilities should be inspected.

In particular, SOCMA would like to see this approach applied to all manufacturers, with domestic and foreign producers considered together rather than in separate groups. SOCMA's Bulk Pharmaceutical Task Force (BPTF) believes "foreign facility" should be considered a significant risk factor.

One of the difficulties the FDA faces with regard to inspections of international manufacturers is the need for the agency to be invited onto foreign soil. The targeted company typically gets weeks or months of advance notice as well. In the US, inspections are required every two years, are typically unannounced and may last for weeks.

Owing to limited resources, the FDA allows just three to five days for each overseas inspection and cannot extend the dates if any problems are identified. It has no dedicated foreign inspectors and those that do travel often do not speak the language of the countries they are visiting and must rely on company officials for translation.

Measuring and managing risk

Even though the FDA conducts few overseas inspections, available statistics indicate that both good manufacturing practice and preapproval inspections of foreign firms reveal significantly more violations - and more serious ones - than seen in domestic firms, according to John Dubeck, a partner with Keller and Heckman, a law firm specializing in regulatory affairs, and SOCMA's spokesman, at the November hearing.

"These numbers cry out for the FDA to conduct more frequent inspections of foreign facilities," Dubeck asserts. "The manufacturing side of the pharmaceutical industry has changed substantially in recent years, yet the FDA's allocation of inspection resources remains unchanged from an earlier era."

To address the issue of equal access to foreign firms, the BPTF proposes that the FDA refuse the importation of any product that appears to the agency to be adulterated.

"It is arguably within the FDA's discretion to determine that a refusal to allow an inspection of a foreign facility creates the appearance of noncompliance, and that therefore it is permissible to refuse imports from the facility until an inspection is allowed," Dubeck testified.

Resources and authorities

FDA Commissioner Andrew von Eschenbach told the subcommittee that the FDA is "working diligently to efficiently and effectively use the resources and authorities provided by Congress to protect the public health of the US, and to help ensure that imported products are safe for American consumers."

The agency is pursuing several courses of action, including the upgrade of its IT systems and trade negotiations with Chinese officials to establish agreements relating to many FDA-regulated products, including APIs and finished-dosage drugs.

Some success in this area was announced in mid-December. In exchange for increasing the numbers of Chinese tour groups permitted to enter the US, Chinese manufacturers of certain APIs exported to the US will be required to register with China's State Food and Drug Administration (SFDA).

The information will enable both the SFDA and the FDA to monitor and inspect these manufacturers. Agreements on standards for drugs, medical devices, food and animal feed were also established. While a positive step, only a handful of the APIs imported into the US are on the list, so most manufacturers will remain unaffected.

Out of India

Earlier this month, as part of a presidential task force directed at improving the safety of imported goods, including drugs, US Health Secretary Michael Leavitt visited a manufacturing facility owned by Dr. Reddy's Laboratories, the largest pharmaceutical producer in India. The visit was part of a tour of India to review current practices and initiate collaboration on science and research, according to a department spokesperson.

The FDA insists that the drugs available to US consumers remain safe, but such moves tacitly acknowledge significant doubts within the industry and among the public. The pharmaceutical manufacturing base is rapidly shifting with the rise in exports from emerging economies such as China and India, but the FDA's scant resources are not shifting with it. How, when or whether the agency will achieve that feat remain open questions.

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