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FDA must monitor a growing number of facilities and complex drugs despite "resource challenges."
US Food and Drug Administration officials have been establishing a host of initiatives that efficiently use increasingly limited resources to ensure the regulatory compliance of drug manufacturing facilities in the United States and abroad. During the past year, the agency implemented a risk-based approach for determining which facilities to inspect first. The agency long ago abandoned hopes of meeting its goal of visiting every drug-production site within two years. Instead, it now seeks to identify the manufacturers and processes most likely to raise safety and product-quality concerns and, thus, merit more frequent oversight.
Both FDA and industry must "change their whole way of thinking" about future manufacturing and compliance operations, noted Joe Famulare, acting deputy director of the Office of Compliance (OC) in the Center for Drug Evaluation and Research (CDER). FDA wants to give "ownership of quality" to industry, he explained at the PDA–FDA Joint Regulatory Conference in Washington last September. Instead of worrying about what data and operations FDA wants, manufacturers should examine what they must do to demonstrate process understanding of their products.
To this end, FDA's risk-based approach to compliance aims to adjust the level of regulatory scrutiny to the public health risk of a drug. FDA's pharmaceutical inspection program has been stressed by the need to monitor a growing number of manufacturing facilities, including more foreign establishments, that are producing more diverse and complex drugs. The fulfillment of these responsibilities, however, is complicated by "resource challenges," commented John Gardner, director of OC's Division of Compliance Risk Management and Surveillance.
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In addition to determining which operations and which products are riskier and require closer scrutiny, FDA has implemented a number of initiatives to make inspections and drug-quality monitoring more efficient, including:
Risky plants get priority
The risk-based approach for selecting sites for GMP inspections was launched this year under a program developed by Gardner's compliance division. Of roughly 1400 sites that FDA inspected this year, about 500 appeared on CDER's tier-one list for priority inspection during fiscal year 2006. OC is issuing an updated white paper that describes the program's first year of operation and refines the methods for making priority inspection assignments for 2007, based on the office's 2006 experiences. FDA will inspect high-risk facilities every two years. The agency concedes that low-risk plants may be visited only every five or six years unless a manufacturer experiences production problems or difficulties in maintaining product quality.
The 500 facilities in the 2006 tier-one group included those that had not been inspected in the past six years and were long overdue for a visit. The others were plants that had earned high risk scores because of facility characteristics (e.g., size, operations, inspection history), product (e.g., drugs or packaging), process control, and contamination potential. Manufacturers continue to maintain that large, high-volume plants are not necessarily riskier and that facilities' age and operations are more valid risk measures. But FDA officials maintain that a quality problem at a plant producing blockbuster drugs would put more patients at risk and therefore warrants more frequent inspections. Although FDA currently calculates facility size based on product sales, the agency acknowledges that production-volume data for each drug product would be a more valid measure, but says it does not have access to that information.
CDER also is using risk models to select some 1000 product samples to test annually in FDA field laboratories. During the past year, the list included all transdermal patches, the top 100 drugs, the top 30 generics, and products from companies with past compliance problems, field alerts, and difficult manufacturing processes. As in most years, only a very small percentage of samples indicated quality problems.
In addition, OC has begun using risk factors to identify those company adverse drug event (ADE) reporting systems it should inspect. These include firms producing drugs that pose a potentially significant health risk to consumers such as newly approved drugs, new indications, products with a narrow therapeutic range, and treatments for vulnerable patients. ADE inspections assess the quality of the firm's reporting program as evidenced by its written procedures, data processing, and overall performance.
Challenges for biologics
Although risk-based models are proving useful in identifying those drug manufacturers and products that warrant closer and more frequent regulatory scrutiny, this approach may be less useful for biotechnology products because almost all therapies regulated by CBER are fairly high risk, explained Mary Malarkey, director of CBER's Office of Compliance and Biologics Quality, at the PDA–FDA conference. In fact, CBER recently decided to inspect vaccine makers annually (instead of every two years) because of recent concerns about vaccine quality and supply. CBER also is continuing its practice of integrating preapproval and GMP inspections and using a systems-based approach for blood and source plasma establishments, which is a program that Malarkey's office plans to update during the coming year.
CBER developed a risk model to set inspection priorities for the large number of facilities involved in processing human cells, tissues, and cellular and tissue-based products (HCT/Ps) that recently have become the center of a major new industry. This approach is part of a formal compliance and inspection program that was established in 2005 as part of a broader FDA Tissue Action Plan. The agency, however, is likely to ramp up its oversight of HCT/P operations following several serious incidents involving falsified records and manufacturing deficiencies. A Task Force on Human Tissue Safety is evaluating the need for increased inspection and regulation of HCT/P firms.
A major drain on FDA's resources is the need to inspect a growing number of foreign manufacturing facilities for drugs and biologics. Last year, FDA inspected 236 foreign drug manufacturers, more than half of whom were producers of active pharmaceutical ingredients (APIs), reported Edwin Rivera Martinez. He heads an OC Foreign Inspection Team that reviews data about foreign inspections, inspection reports, and warning letters (see sidebar, "Documenting deficiencies").
Martinez's analysis reveals some important differences between US and foreign inspections. For one thing, preapproval inspections accounted for 90% of foreign inspections, but are a program in decline domestically. Overseas inspections of API producers are rising, but FDA visits to foreign manufacturers of drug dosage forms dropped from 69 in 2004 to 55 last year. FDA tries to set priorities for foreign inspections but so far is not using the formal risk-based approach that has been adopted for prioritizing domestic inspections.
This is a mistake, according to some US API manufacturers that claim that less frequent inspection of foreign facilities creates an uneven playing field in the drug-manufacturing market. The Synthetic Organic Chemical Manufacturers Association (SOCMA) recently filed a citizens' petition with FDA requesting an increase in foreign drug-manufacturing inspections to ensure comparable oversight of all operations. SOCMA also proposes that the foreign location of a plant be considered a significant risk factor in setting inspection priorities, a practice that could increase scrutiny of overseas facilities.
At the same time, FDA is working more closely with foreign regulatory agencies to keep abreast of pharmaceutical quality issues related to drug and vaccine makers abroad and to identify those facilities that most warrant inspections. Following the Chiron debacle two years ago, FDA signed a formal confidentiality agreement with the United Kingdom's medicines agency that allows the sharing of regulatory information. FDA also has agreements in place with Canada and the European Medicines Agency for quality-information sharing and is pursuing additional agreements in this area.
FDA intends to expand its access to GMP information around the world by joining the 29 other nations in the Pharmaceutical Inspection Cooperation Scheme (PIC/S). Most European regulatory authorities plus inspection officials from Australia, Canada, Malaysia, and Singapore are members of this networking organization that seeks to build consensus on manufacturing standards and inspection procedures.
Initially established in 1970, PIC/S began as a legal treaty for mutual recognition of pharmaceutical inspections largely among European regulators. Today, it provides a less formal forum for representatives of regulatory agencies to exchange information and experiences related to GMPs, quality inspection systems, and inspector training. Members share inspection reports with one another but are not obliged to accept other authorities' findings. The group develops guidances on a broad range of manufacturing and compliance issues, organizes training seminars, and operates a rapid alert system to quickly inform other nations of product recalls. A main goal is to promote international harmonization of GMPs.
FDA has long been an observer of PIC/S activities involving drugs and biologics and last year applied for formal membership, as did Argentina, Israel, South Africa, and several other nations. This launched a multiyear review process for PIC/S to assess FDA's internal system for conducting quality inspections, for training investigators, and for assuring industry compliance with GMPs.
PIC/S officials recently asked FDA for additional information to answer various questions. A primary concern is that, unlike the European agencies, FDA does not issue any kind of manufacturing site authorization, explained PIC/S chairman Jacques Morenos at the PDA–FDA conference. Even CBER no longer requires biologics licenses for biotechnology production facilities. PIC/S officials would like FDA to explain more fully how its GMP inspection program can ensure that a manufacturer meets regulatory requirements comparable with those of the European authorization process.
FDA officials recognize that the PIC/S approval process may take some time, but anticipate expanded opportunities for sharing compliance information that can inform the agency's inspection decisions. FDA also hopes to be more active in developing recommendations and guidelines on API inspections, oversight of solid dosage forms, and good distribution practices, which relate to the prevention of drug counterfeiting. The International Conference on Harmonization primarily addresses research and review issues, and PIC/S provides a similar forum for inspectors to discuss many compliance principles and establish more-consistent inspection methods, Famulare points out. The group has been helping the World Health Organization (WHO) develop its prequalification list of essential drugs and programs for assessing national regulatory authorities. PIC/S aims to work more closely with WHO and international health organizations in Asia and other regions, with an eye to ensuring the competence of inspectorates around the world.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org