FDA Inspection Program Under Scrutiny

Pharmaceutical manufacturing has become a global business and transformed the way drugs are produced, regulated, and marketed. This development has resulted in many challenges that were recently illustrated by the long investigation into the cause of serious adverse events related to Baxter International's (Deerfield, IL) heparin products. Following reports of as many as 20 deaths and hundreds of allergic reactions associated with this blood thinner, which is widely used in surgery and kidney dialysis patients, the company recalled thousands of vials and shut down production earlier this year.

Jill Wechsler

Although the cause of product contamination was not readily apparent, the fact that the active pharmaceutical ingredient (API) came from a Chinese facility captured national attention. With unsafe Chinese food, toothpaste, and drugs making headlines, itnot surprising that the media focused on Baxter's Chinese API producer and had a field day running stories on small Chinese operators that obtain an extract from pig's intestines for processing into crude heparin. In fact, the problem has become global. Soon after Baxter reported increased adverse events, a similar situation emerged in Germany.

Compounding the problem in the US was the surprising discovery that the US Food and Drug Administration never inspected the manufacturer, Changzhou Scientific Protein Laboratories, nor did Chinese regulators. This debacle highlighted inadequacies in FDAtracking of drug production at home and abroad. FDA officials admit that their system is so obsolete that they have only a vague idea of what drugs are manufactured where and which overseas facilities have been inspected. The case also focused attention on the limits of FDA's preapproval inspection program. And it emphasized the reality that manufacturers bear the ultimate responsibility for ensuring the quality of all ingredients in a drug product.

More imports

The enormous expansion in drug substance imports in recent years has stressed FDA's oversight capacity considerably. At a contentious hearing in Feb. 2008 before the House Appropriations subcommittee that approves FDA funding, Janet Woodcock, then acting director of the Center for Drug Evaluation and Research (CDER), reported that about 80% of APIs come from foreign manufacturers. Committee Chair Rosa DeLauro (D-CT) termed FDA's heparin inspection error as one more example of "FDA's myriad failures" in dealing with multiple drug-safety issues.

Woodcock predicted similar problems in the future with drug products. Although imports of finished drugs now are much lower than those of APIs, she said that this situation "is going to change" because operators in "many regions of the world have indicated that they want to take over drug manufacturing."

This trend will demand further changes in FDA's current good manufacturing practice (CGMP) compliance activities. The agency has been inspecting only about 10% of foreign drug producers each year because field-inspection operations are inadequately funded, Woodcock explained. And because FDA faces deadlines for conducting preapproval inspections (PAIs) of suppliers and producers of new drugs, many low-priority facilities seldom see an FDA agent.

"We have raised red flags for years," Woodcock said, noting that FDA staffers are well aware that drug manufacturing and clinical trials have been moving overseas. Agency experts have created various plans for improving the safety and oversight of imported food and drugs, she noted, and have repeatedly urged an expansion in FDA's field force. But these proposals have been low on the agency's priority list. FDA needs hundreds of additional inspectors and an updated data system to better control drug imports into the US and better ensure drug quality, Woodcock commented, acknowledging that resources to support that kind of expansion are not included in the agency's 2009 budget proposal.

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Missed inspection

The import of heparin API from China is a prime example of the challenges pharmaceutical globalization creates. Baxter's supplier of heparin, Scientific Protein Laboratories (SPL, Waunakee, WI), is an established API producer and contract manufacturer of drugs and biologics. Until four years ago, SPL's Changzhou SPL facility near Shanghai supplied its parent company with crude heparin. This activity did not require FDA inspection. In 2004, SPL expanded Changzhou's operations to produce heparin sodium, which required Baxter to file a manufacturing supplement with FDA to add the Chinese plant as an alternate API supplier.

FDA should have inspected the Changzhou facility in 2004, but did not because of an error in identifying the facility. When a new drug application (NDA), abbreviated application for a generic drug or manufacturing supplement adds a new production site, FDA reviews the inspection records and history for the manufacturing sites listed, explained Joseph Famulare, deputy director of CDER's Office of Compliance (OC). If a site has been inspected recently and is in compliance with GMPs, a PAI may not be necessary.

It was not until Jan. 2008, when FDA and Baxter started receiving hundreds of adverse event reports, that the agency looked more closely at the facilities producing this product and discovered the inspection omission. FDA found that it had approved Baxter's supplement in 2004 without inspecting the Changzhou facility. "We evaluated another firm with a similar name for its inspection history," Famulare explained. This other firm, which had been inspected, was entered into the record, so the Changzhou plant was not followed up for inspection. Famulare termed this error an "isolated situation" that OC was moving quickly to correct.

In addition, China's State Food and Drug Administration (SFDA) did not inspect the facility because it classified Changzhou SPL as a chemicals manufacturer and not a pharmaceutical company. In addition, SFDA does not inspect plants that produce drugs for foreign use.

Seeking causes

As these discoveries unfolded, all parties scrambled to uncover the root cause of the adverse events. FDA inspectors swarmed over SPL, its Chinese facility, and Baxter's New Jersey plant. "We go back to the original raw material and to every production step," explained Michael Rogers, director of the Division of Field Investigation in FDA's Office of Regulatory Affairs (ORA), at a Feb. 2008 press briefing. "We identify the manufacturing process and the raw materials used to make the product."

SPL describes its Chinese plant a "state-of-the art, fully validated CGMP compliant heparin API manufacturing facility" that was "approved by FDA in 2004 under a US NDA for import and use in the United States."

A Feb. 2008 inspection of Changzhou SPL by FDA experts, however, uncovered several "potential deficiencies" in procedures for removing impurities, ensuring proper cleaning of equipment, and process validation. Experts observed signs of improper waste handling, inadequate product testing, and the use of crude heparin from an unacceptable vendor. Baxter says it found similar problems at Changzhou during its own audit in Sept. 2007; evidently, the deficiencies were not addressed expeditiously.

FDA officials emphasized that they could not link the adverse events to these preliminary findings cited in a 483 inspection report and that Baxter had been using this product since 2004 without any problems. To uncover the cause of the adverse reactions, FDA inspectors expanded their investigation to upstream raw-material suppliers, including Chinese consolidators that purchase heparin extract from village pig processors. One possibility was that widespread pig disease in China prompted consolidators to accept products from small, untested operators, and that material from sick pigs were entering the supply chain.

At the same time, Baxter re-examined testing and inspection records from its Cherry Hill, NJ, facility that produces a broad spectrum of generic injectible products, including Baxter's heparin line. This line generates some $30 million in annual revenue, or about 1% of the company's total sales. An FDA inspection in Feb. 2008 found no problems in Baxter's product components or packaging.

Baxter also routinely conducts tests on all incoming APIs. When the company started receiving an unusual volume of adverse-event reports, it began the hunt withFDA for the source of product contamination. Baxter's usual battery of API tests provided no clues. But more sophisticated nuclear magnetic resonance spectroscopy and capillary electrophoresis revealed the presence of a heparin-like substance in API from both Wisconsin and China. FDA hesitated to directly link this contaminant to patient allergic reactions, but offered no other explanations.

FDA officials say that Chinese regulators facilitated broader inspection of the supply chain, which goes beyond the cooperative efforts covered by a memorandum of agreement (MOA) negotiated in Dec. 2007 by US and Chinese officials. The MOA calls for information sharing and regulatory cooperation to facilitate oversight of food, drugs, and medical products. Meanwhile, Chinese SFDA officials insist that they are enforcing regulations on chemicals used in pharmaceutical products. The Chinese authorities also point out that importing countries and companies are ultimately responsible for ensuring product safety and quality.

FDA officials agree that government agencies are not solely responsible for ensuring the quality of APIs. Although FDA inspects many ingredient manufacturers, the agency still relies on pharmaceutical companies to test API quality. This approach is standard overseas, where many foreign regulators leave API oversight entirely to manufacturers.

At a Feb. 2008 conference on FDA enforcement sponsored by the Food and Drug Law Institute, David Elder, director of ORA's Office of Enforcement, emphasized that the finished-product manufacturer must take responsibility for problems with drug quality or safety. Too often, he said, manufacturers blame suppliers for product failures. But he specifically pointed to drug companies in asserting that FDA "will continue to hold them accountable" for such problems.

Additional oversight

Even though an earlier FDA inspection of Changzhou might not have prevented these problems, the inspection error raised questions about how well FDA can track drug manufacturers around the world and ensure that all drug ingredient suppliers fully meet GMPs. Rep. Frank Pallone (D-NJ), chairman of the House Energy and Commerce (EC) Health subcommittee, termed the inspection failure that resulted from confusion over the facility's name an "egregious mistake." It has nothing to do with lack of resources, he stated, but reflects "sloppy work" and "carelessness that seriously jeopardized the health of American patients." The EC panel held a hearing in Nov. 2007 to address FDA's capacity for overseeing the vast increase in drugs and APIs imported from abroad (see "Limited Resources, Expanding Imports Challenge Regulators," Pharmaceutical Technology, Feb. 2008). The heparin debacle provides more fuel for this ongoing investigation.

An important FDA initiative is to establish an electronic system for registering all drug manufacturing and labeling facilities and for listing all regulated products. The agency's current tracking system is not integrated with other FDA databases, making it difficult to detect errors and avoid confusion. The FDA Amendments Act of 2007 provides additional funding to build an integrated drug registration and listing system, and FDA's Bioinformatics Board is working to establish uniform tracking of all regulated products and for adverse event reporting in all product areas. FDA hopes to move forward on this program this year, but first the agency must finalize a proposed regulation for modifying current national drug codes to create a common coding system.

The Bush administration recently signaled its support for legislation that would clarify FDA's authority to investigate foreign firms that violate the Food, Drug, and Cosmetic Act. This power is not explicit under current law, which can make it difficult for US regulators to access foreign manufacturing facilities. Although this legal change might help US officials oversee foreign operators, it would do little to address the international difficulties facing FDA and industry.

Limiting preapproval inspections

The heparin debacle has raised questions from Congressional leaders about the adequacy of the US Food and Drug Administration's preapproval inspection program for medical products. In a letter to FDA Commissioner Andrew von Eschenbach, House Energy and Commerce Committee Chairman John Dingell (D-MI) and Oversight and Investigations Subcommittee Chairman Bart Stupak (D-MI) said they assume that FDA is required to "approve each step of drug manufacturing, including all ingredient sources" before approving any drug for market. If that is not the case, Stupak added, Congress may "prohibit the marketing of any drug from a plant that has not been properly inspected."

FDA officials explain that the agency must ensure that all marketed drugs comply with good manufacturing practices (GMPs) and meet quality standards, but that an on-site field inspection is only one way to verify regulatory compliance. If a manufacturer has a good GMP compliance history and the product under review has relatively low risk, FDA may forego a preapproval inspection (PAI) of a plant that has been inspected within two years. Normally, however, a new active-ingredient supplier that has never been inspected would warrant a visit from FDA staff.

A statutory requirement that FDA conduct a PAI for every new drug coming to market would undermine agency efforts during the last decade to eliminate redundant inspections and better target its depleted field force to the most critical products and facilities. FDA expanded PAIs for drugs about 20 years ago, following an investigation led by Rep. Dingell into fraud and data falsification in the burgeoning generic drug industry. The aim of the PAI policy was to ensure that all drug manufacturers comply with GMPs and provide accurate and authentic data to the agency about manufacturing capabilities and product testing.

Throughout the 1990s, FDA conducted thousands of PAIs covering all new chemical entities, widely used generics, and narrow therapeutic drugs, as well as new manufacturers and new plants. This high PAI volume became unsustainable as agency resources for field inspections became tighter and tighter. And as the generic-drug regulatory program became firmly established by the late 1990s, the agency concluded that recently inspected plants and common products might not warrant a full PAI for every new drug or generic coming to market.

This approach fits FDA's efforts to modernize and streamline oversight of drug manufacturing under its GMPs for the 21st Century initiative. One component of this program is to further target field inspections to products and plants that warrant high risk designations. Along those lines, Office of Compliance (OC) staffers now divide PAI inspection requests to the field into those that would "regularly" lead to an inspection and those that can be decided by district offices. The first category includes new molecular entities, priority new drug applications (NDAs), new dosage forms of priority products, and initial generic-drug applications, explained Edwin Rivera-Martinez, chief of OC's manufacturing assessment and preapproval compliance branch, at the Food and Drug Law Institute compliance conference in Feb. 2008.

Field investigators have discretion to conduct PAIs for most other drugs, Rivera-Martinez emphasized, an approach that fits efforts to give district offices greater flexibility in determining when a PAI is necessary. The Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) also can request a "for cause" inspection separate from the PAI and GMP inspection programs. This will most likely occur when a CDER review division notices something troubling in an application, when a specific inspection request comes from a foreign regulatory body, or when competitors or informants provide information about a company's violative behavior. FDA is working to further refine the categories that would prompt a PAI request from CDER to the field.

Interestingly enough, FDA projects that in 2009 it will conduct more PAIs overseas (nearly 400) than at home (about 300) for brand drugs and generics. The numbers are significantly different for GMP inspections: 1400 domestic inspections are anticipated, compared with less than 300 abroad. Capitol Hill shows considerable interest in boosting the foreign inspection numbers, but it will take a sizeable budget increase to expand this high-cost activity to a significant degree.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com