Jill Wechsler
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Food and Drug Administration officials have been establishing a host of initiatives to use increasingly limited resources
more effectively to monitor drug and biotech manufacturing facilities in the US and abroad. A main FDA strategy is to use
risk models to determine which manufacturing operations and which products are more risky and require closer scrutiny. Agency
officials look to further integrate preapproval (PAI) and GMP (good manufacturing practices) inspections to reduce redundant
site visits. To clarify when a PAI is or is not necessary, FDA is updating preapproval inspection procedures for drugs and
biologics. The agency also aims to expand systems-based inspections and to cooperate more with international regulatory agencies
to better identify those foreign facilities that merit closer scrutiny.
EVALUATING RISKS
One important effort has been to establish a risk-based approach for identifying top priority drug manufacturing sites for
GMP inspections. FDA also is applying risk models to selecting drug samples for laboratory testing as well as companies that
warrant review of their adverse-event reporting systems.
Of some 1,200 to 1,400 drug manufacturing sites that FDA inspected in 2006, about 500 were categorized as high-risk based
on plant size and operations, product types, process control, and contamination potential. The Office of Compliance in the
Center for Drug Evaluation and Research (CDER) is issuing an updated white paper that describes the program's first year of
operation and, based on this experience, has refined its methods for making priority inspection assignments for 2007. FDA
hopes to inspect high-risk facilities every two years. Low-risk plants, the agency concedes, may be visited only every five
or six years unless the manufacturer experiences production problems or runs into difficulties maintaining product quality.
BIOLOGICS TOO RISKY
While risk-based models are proving useful in identifying manufacturers and products that warrant closer and more frequent
regulatory scrutiny, this approach may be less appropriate for many biotech products, according to Mary Malarkey, director
of the Office of Compliance and Biologics Quality in the Center for Biologics Evaluation and Research (CBER). She pointed
out at the PDA/FDA Joint Regulatory Conference in Washington in September that almost all therapies regulated by CBER are
fairly high risk, so "there's not much wiggle room." In fact, CBER recently decided to inspect vaccine makers annually—instead
of every two years— due to recent concerns about vaccine quality and supply, and CBER continues to review its production inventory
on a biannual basis.
At the same time, Malarkey is looking to make CBER's compliance program more efficient. The agency is continuing efforts to
better integrate preapproval and GMP inspections and to implement a systems-based inspection approach for biological drugs
and blood and source plasma establishments; Malarkey's office plans to update this program in 2007.
CBER has 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 have evolved into a major new industry. This approach
is part of a formal compliance and inspection program established in 2005 as part of a broader FDA Tissue Action Plan. However,
FDA is likely to ramp up its oversight of HCT/P operations due to a number of serious incidents involving falsified records
and manufacturing deficiencies. FDA issued a guidance in September clarifying that tissue establishments are responsible for
ensuring that contractors comply with good tissue practices, and a Task Force on Human Tissue Safety is evaluating the need
for increased inspection and regulation of human tissue firms.
KEEPING THE TEAM
Another initiative involves updating the Team Biologics program. FDA conducted a broad reassessment of Team Biologics two
years ago as part of its GMP modernization initiative. The basic conclusion was to make some changes while continuing this
program for overseeing biotech manufacturers, including blood facilities, vaccine makers, and biotech therapies now regulated
by CDER.
A Team Biologics Operations Group, which includes officials from CBER, CDER, and the Office of Regulatory Affairs, has developed
a Quality Management System to improve Team Biologics operations and revise standard operating procedures and quality assurance
programs for inspection and compliance activities. A main initiative has been to develop metrics to assess the impact of the
Team Biologics program on industry. To this end, the Pharmaceutical Quality Research Institute conducted an online survey
of manufacturer opinions on Team Biologics' effectiveness; the results are being evaluated, even though industry response
has been sparse, Malarkey pointed out.
