System-based inspections (SBIs) are risk-based, shifting the regulatory focus from specific products and processes to assessing
the strength of the systems that are meant to prevent and resolve manufacturing difficulties. This risk-based systems approach
affords a broader scope to inspections, with the potential for significant business impact not only to individual products
at a site but to all products that fall under the relevant quality systems.
Within FDA, definitions differ somewhat when applied to system-based inspection technique. The Center for Radiological Health
(CDRH) was the first center to formalize a system-based inspection program through its quality system inspection technique
(QSIT) compliance program, implemented in August 1999. CDER began a similar pilot program of the same name in January 2001,
which has since been formalized as the Compliance Program Guidance Manual 7356.002. This manual is currently in use for inspections
of all human drug facilities. The Center for Biologics Evaluation and Research (CBER) also is implementing system-based inspections
for blood products under a new compliance program.
The CDRH QSIT approach is based on seven major quality sub-systems: management controls; design controls; corrective and preventive
actions; facility and equipment controls; material controls; records, documents, and change controls; and production and process
controls. The CDER program is based upon six major sub-systems: facilities and equipment, materials, production, packaging
and labeling, laboratory control, and the Quality System itself. The CBER blood product system-based inspection will be based
on five sub-systems: quality assurance, product testing, donor eligibility, production and processing, and quarantine and
The CDER QSIT approach consists of dividing entire plant systems into the six distinct sub-systems mentioned above, following
21 CFR Parts 210 and 211. Although QSIT and the new draft guidance document are specific to drug and biological drug product
manufacturers, they can easily and effectively be applied to active pharmaceutical ingredient (API) manufacturers. Each of
the six quality sub-system categories identified by CDER may contain several subordinate systems. These six major quality
sub-systems are the foundation for both full and abbreviated inspections. A full inspection requires evaluation of at least
four of the QSIT-defined sub-systems, whereas abbreviated inspections require review of only two sub-systems. Companies that
are new to FDA, have previously demonstrated noncompliance, or have a pending PAI usually undergo the full inspection. Firms
with compliant histories and those that have recently been inspected (such as contract manufacturers who were recently inspected
for different clients) may receive abbreviated inspections. The Quality System itself is part of every inspection.
CDER's QSIT inspection may focus on the following key areas within the Quality System:
- management review
- complaint reviews
- discrepancy and failure investigations
- change control
- product improvement projects
- reprocess and rework
- returns and salvages
- stability failures
- corrective and preventive action
- quarantine products
- training and qualification.
The other five CDER identified quality sub-system headings are systems that typically are the responsibility of functions
other than the quality assurance (QA) department. However, to be effective and under control, these sub-systems require QA
oversight, review, and approval.
FDA compliance investigators have latitude, with concurrence from the district office, to reduce a full inspection to an abbreviated
inspection. This may sound like good news, but it usually indicates that the firm has failed early in the inspection process
or that one or more of the QSIT systems is significantly out of control, and FDA does not intend to expend the time and resources
to complete an inspection of the remaining systems. Whenever the quality systems portion of the inspection fails, the inspection
is terminated, and the agency contemplates regulatory action.
Quality systems are designed to be proactive and preventative. Companies should conduct internal audits periodically to ensure
that proper processes and practices are being followed. When properly designed, monitored, and followed, quality systems can
reduce waste and rejected material, improve personnel efficiencies, empower employees, and place appropriate accountability
on those responsible for the production, quality, and review of those systems. Moreover, they can prevent major manufacturing
problems, resulting in fewer and shorter inspections, and ultimately a more efficient industry and government.