INSTRUMENT VALIDATION FOR REGULATED STUDIES - Flow Cytometry in Drug Discovery and Development - page 261

legally obligated to comply with the set of standards as defined by CLIA, and to obtain
licensure from an agency such as the College of American Pathologists (CAP)
through demonstration of their proficiency [2]. Stated another way, CLIA is the law
and CAP is an accrediting agency. The roots of this regulatory oversight can be traced
to the late 1960s when it became apparent that malignancies were sometimes
overlooked due to high error rates in evaluation of Pap smears [3], with the Clinical
Laboratory Improvement Amendments of 1988 (CLIA'88) as an important historical
milestone.
Today's flow cytometry laboratory may rely heavily on demonstration of profi-
ciency through CAP processes, including test method validation and instrument
calibration. A significant number of clinical scientists that utilize flow cytometers
reside in or around the CLIA environment and it is therefore not surprising that many
of the principles and practices of CLIA are leveraged in an effort to introduce quality
into biomarker campaigns. These processes, however, are exclusive of instrument and
system validation as defined under the GLPs and GCPs. Laboratories that perform
immunophenotyping on specimens from persons (or animals) treated with investiga-
tional agents may need to comply with the GLPs and GCPs to support their regulatory
filings and therefore are not subjected to CLIA mandate.
13.2.2 GLP
The Drug Amendments of 1962 were drawn in part from the European drug market
approval of thalidomide, a sedative prescribed to pregnant women to treat morning
sickness that caused severe birth defects [4]. These measures provided more time to
reviewnewdrug applications, more safety and efficacy testing, and authorized records
inspections of the sponsoring company. The FDA later added requirements for the
manufacturer to prove drug effectiveness (in addition to safety) and to present
postapproval reporting to the FDA. This forms the bedrock of GLPs.
The basic contemporary document dealing with international GLPs is the OECD
Principles of Good Laboratory Practice, revised in 1998 [5]. With respect to these
principles, there is no question that GLP studies are the native soils that nourish
the practices and principles of instrument validation. Perhaps, the most important
philosophy that can be provided to those new to instrument validation as governed
underOECD/GLP is that validation exercisesmust followpredicate rule (Figure 13.2),
with execution governed by a variety of systemexperts (Table 13.1). That is, validation
is a carefully orchestrated process where results will either pass or fail predefined
acceptance criteria. A second important point is that those who provide guidance for
instrument validation use the term “computerized systems,” meaning that the flow
cytometer is one component of a process whereby electronic data are generated,
analyzed, and stored. Finally, it is important to know that validated systems must be
“closed systems,” meaning that access is granted to only those who are qualified via
their experience and have received appropriate training.
Many flow cytometry vendors fail to provide technical controls for even the most
basic elements of a validated system. For example, granting entry into a flow
cytometer via a password often provides a user access to the entire set of electronic