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
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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.
FYI
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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, jwechsler@advanstar.com
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