The PI training and certification process is a joint ORA–CDER undertaking that exposes candidates to risk-management concepts,
manufacturing innovations, and the importance of an integrated review and inspection process, explained Doug Ellsworth, director
of ORA's New Jersey District Office. A fully trained PI member should be able to identify critical control variables and strategies
and whether a manufacturer has established a sound state of control over its production process. PI training includes quality
by design (QbD), sophisticated statistical analysis, and advanced concepts in change control, corrective and preventive action
plans, and continuous improvement programs.
The development of the PI program supports FDA's PAT Team, another group of investigators trained in advanced PAT concepts.
All PI members now have general training in PAT technology. As these inspectors gain more in-depth PAT knowledge, they most
likely will absorb the PAT team, Ellsworth noted.
FDA also has improved the operations of Team Biologics as part of its GMP modernization effort, with an eye to implementing
quality-management systems approaches. This includes establishing standards to better assess team performance and to determine
the need for improved training and qualification of team members. FDA is working with the Pharmaceutical Quality Research
Institute to evaluate Team Biologics operations and their impact on manufacturers.
A main approach for using FDA resources more efficiently is to target inspections and oversight to industry operations most
in need of FDA scrutiny. CDER has established a risk-based site-selection program for identifying those drug-manufacturing
facilities to schedule for GMP inspection each year. This system uses a model for setting inspection priorities according
to various risk factors associated with products, processes, and facility characteristics. Of some 1500 drug GMP inspections
FDA conducts each year, about 500 are selected based on risk calculations, and 50 are identified as warranting review by the
Unfortunately, the program's current risk-analysis model does not consider how well a company establishes control strategies
based on QbD and risk-management principles. The agency's evaluation system can tap only information in FDA data systems such
as type of product (e.g., sterile, biotechnology), mode of operation, and production volume. FDA analysts can factor in past GMP-compliance history,
which may reflect a manufacturer's state of control, but not whether an advanced PAT system can manage product variability.
Despite these limitations, ORA is extending this risk-based model to better target Team Biologics inspections to high-priority
situations. The agency also plans to use risk factors to select veterinary-medicine plants for inspection. The long-term goals,
says Horowitz, are to develop more outcomes-oriented standards for evaluating risk and to use science and data-driven targeting
to determine inspection frequency and intensity, as well as FDA response to the inspectional findings.
In addition to using risk analysis to schedule inspections, FDA also wants to apply risk-based approaches to the plant-inspection
process. A firm's ability to establish design space and control strategies may limit an inspection's scope. For firms with
strong quality systems, preapproval inspections would be linked closely to the review process and targeted to answer specific
questions related to the accuracy of underlying data. Postapproval inspections would focus on whether a firm's quality system
can manage production so it stays within an approved design space. Ultimately, FDA and a manufacturer may negotiate a regulatory
agreement at the time of approval that describes several acceptable postapproval changes that do not require supplements or
Integrating field and centers
Another important component of FDA's more science-based inspection process requires field staff to collaborate more closely
with Center product specialists and technical experts in evaluating a firm's risk-management programs, product and process
knowledge, process capability, and quality-system robustness, Ellsworth explained. Under an integrated review and inspection
approach, says Joe Famulare, deputy director of CDER's Office of Compliance, inspectors would address key areas suggested
by Center staff, verify process implementation and state of control, assess product life-cycle improvements, and ensure adequate
change control. A PI Quality System Workgroup under FDA's Council on Pharmaceutical Quality is working to define a process
for greater interaction of investigators and reviewers. The group is reviewing current operations to make recommendations
about policies, procedures, and information-technology systems that will facilitate collaboration between these entities.
This move toward the increased integration of inspection and review for drugs builds on long-standing procedures in the Center
for Biologics Evaluation and Research (CBER). Postapproval GMP inspections of biotechnology manufacturers has been performed
by Team Biologics together with CBER product specialists for the past decade, commented Mary Malarkey, director of CBER's
Office of Compliance and Biologics Quality. Such integration begins as early as the investigational new drug application stage
and is particularly important for dealing with complex and innovative technologies.
Ironically, while ORA seeks to streamline its oversight responsibilities, other FDA regulatory initiatives require field inspections
to play a larger role in ensuring industry compliance with standards. FDA is considering policy changes to permit manufacturers
to describe more manufacturing changes in annual reports as one way to reduce the number of postapproval manufacturing changes
that require prior approval by reviewers. These change reports would be available to inspectors at the plant to be evaluated
as part of an inspection. At the pharmaceutical-quality workshop, attendees agreed that changes in current postapproval policies
should not shift burdens from the Centers to the field, a concern likely to surface as FDA continues to seek new approaches
for overseeing manufacturing compliance.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org