FDA Seeks a More Efficient Inspection Program - Pharmaceutical Technology

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FDA Seeks a More Efficient Inspection Program
Agency officials focus on risk-based assessment models and international cooperation to streamline the inspection process.

Pharmaceutical Technology

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.

Going overseas

Documenting deficiencies
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.

More cooperation

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,


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