Qualifying Analytical Instruments:
General Chapter <1058> Clarifies
Terminology, Classifies Instruments
Lori Valigra
Instrument qualification is a frequently cited
deviation in regulatory observation and warn-
ing letters. A serious violation could even shut
down a production line. One of the main
reasons for noncompliance is that qualifying
instruments and validating the related software
is a complex specialty area that has lacked clear
guidelines and terminology.
“Historically, qualification of lab instru-
ments was seen as a barrier,” said Paul Smith,
European validation program manager at
PerkinElmer Life and Analytical Sciences. “Be-
cause qualification is a specialist subject, that
made it mysterious, and people didn’t know
what to do to qualify an instrument. It was
something that had to be done and that was
specialized and that delayed the introduction of
a product.”
Efforts to change the situation are underway,
including the release in 2008 of the United
States Pharmacopoeia (USP) General Chapter
<1058> guidelines on analytical instrument
qualification (AIQ). USP <1058> originated at
a 2003 conference of the American Association
of Pharmaceutical Scientists (AAPS).
A USP committee took recommendations,
for example, to more strictly define use of the
Lori Valigra is a science journalist based in Cambridge,
Mass. Reach her at lvaligra@gmail.com.
This article was previously published in June/July 2010 in
Pharmaceutical Formulation & Quality.
Copyright © 2011 John Wiley & Sons, Ltd.
terms “validation” (for manufacturing process-
es, analytical procedures, and software proce-
dures) and “qualification” (for instruments), as
well as to classify instruments into three major
groups based on their complexity. They were
careful to complement existing and widely used
good automated manufacturing practice
(GAMP) principles and procedures set by the
International Society for Pharmaceutical Engi-
neering (ISPE). GAMP covers all aspects of
production and is more complex than USP
<1058>, which is suited to instrument qualifi-
cation but not software validation.
“When we were developing this chapter
[<1058>], our committee was concerned with
the GAMP guidance,” said Horacio Pappa,
PhD, senior scientific liaison in USP’s Docu-
mentary Standards/General Chapters Division.
“We made it easy to perform but did not
contradict what is in the GAMP guidance.”
Dr. Pappa explained that GAMP is for more
sophisticated instruments used with a comput-
er or on a network. USP <1058> applies easily
to commercial off‐the‐shelf instruments.
In addition, GAMP is a voluntary standard
and contains specific steps, while USP <1058>
is guidance. “There are not too many details on
how to qualify [instruments],” Dr. Pappa said
of USP <1058>. “There is no intent to make it a
standard. No one certifies you for <1058>.”
Neither is it meant to verify software.
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68
There is room within USP <1058> for more
specifics, however, and analytical chemists,
contract research organizations, and others
who perform qualification testing must be
aware of them. While the USP general chapters
from <1000> through <1999> are informational,
allowing alternative approaches to be used, the
general chapters from <1> through <999> are
requirements that must be met in order for
equipment to pass inspection. And <1058> refers
to other USP chapters that designate specific
techniques that are requirements, such as <21>,
which addresses thermometers.
USP is mandatory by law under the Food,
Drug, and Cosmetic Act, Dr. Pappa said. “If it
[the applicable chapter] is under <1000>, [it is]
more likely the Food and Drug Administration
[FDA] will enforce it,” he said. “Instrument
guidance is one piece of the whole in terms of
the government assuring any drug or drug
product manufactured in the United States and
Europe meets certain standards of safety, purity,
and quality.”
Instrument Classification
One of the biggest benefits of USP <1058> is its
classification of instruments, said Bob McDowall,
PhD, principal of McDowall Consulting, whose
consulting company outsources service, writes
testing documentation, and trains staff to
qualify equipment. USP <1058> goes further
to qualify analytical equipment than an earlier
proposal by the Pharmaceutical Analytical
Sciences Group (PASG), Dr. McDowall said.
“PASG was a forerunner of <1058>, but
<1058> goes further in trying to classify
instruments into various groups,” he said.
“There is more system suitability testing and
method validation in <1058>.”
USP <1058> classifies systems and opera-
tions into three groups: A, B, and C. Category
A includes standard equipment set to the
vendor’s specifications and with no measure-
ment capability; inspectors can check it by
observation. Such equipment includes centri-
fuges, sonic baths, vortex mixers, and magnetic
Copyright © 2011 John Wiley & Sons, Ltd.
L. Valigra
stirrers, Dr. McDowall said. Category B
includes standard instruments that have mea-
surement values requiring calibration. Such
instruments include balances, pH meters,
thermometers, and pumps. Category C in-
cludes more complex instruments and com-
puterized or networked systems that require
full qualification and specific function and
performance tests. Examples include dissolu-
tion, high‐performance liquid chromatography,
and spectrometers.
Where the categories become unclear, Dr.
McDowall said, is in how the instruments are
used. When a sonic bath from the A group is
used to dissolve material, simply observing that
the material has dissolved keeps it in group A.
But if a method requires a specific temperature
and flasks with materials that are located in
specific areas of the bath, the use is different, and
the sonic bath moves into the more stringent
group B requirements needing calibration.
The Four Q’s
USP <1058> describes the AIQ process for
assuring an instrument is suited to its
intended use and serves as the underpinning
of a USP data quality triangle (see Figure 1)
for all other phases of analytical work. The
three activities layered on top of AIQ are
analytical method validation, system suitabil-
ity tests, and, at the top, quality control
checks. Each layer is intended to add to
overall quality. Analytical method validation
is documented evidence that an analytical
procedure is suitable for its intended use.
System suitability tests verify that the system
will perform to the criteria for a given
procedure, and the tests are performed along
with sample analysis. Other chapters have
more details. USP general chapter <621>
Chromatography, for example, has more
information on system suitability tests related
to chromatographic systems.
The AIQ process is broken down into four
stages known as the “4Qs” (see Table 1). They
are design qualification (DQ), installation
Qual Assur J 2010; 13, 67–71
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Figure 1. USP data quality triangle
qualification (IQ), operational qualification
(OQ), and performance qualification (PQ). DQ,
which defines the functional and operational
specifications of the instrument and associated
software, is performed before buying a new
instrument. Dr. McDowall said that it is typically
either done poorly or not at all. IQ, which is
performed upon installation of a new system as
well as on existing unqualified systems, estab-
lishes that the instrument is delivered as designed
and is specified and installed properly. OQ, which
is done after installation or major repair, docu-
ments that the instrument will run according to its
operational specification in the intended applica-
tion. And PQ documents that the instrument
performs consistently to specification and its
intended use and is performed at specified
intervals for each instrument.
Table 1. The Four Qs
Copyright © 2011 John Wiley & Sons, Ltd.
69
In September 2009, the FDA tightened the
regulations by which it handles a 483 inspec-
tion report, narrowing the time for a complete
response to within 15 working days before it
elevates a problem to a warning letter. Once
issues are resolved, the letter is closed out.
The whole process—from warning letter to
resolution—is posted on the FDA’s website,
Dr. McDowall explained.
“Standards are done by internal audit, contract
manufacturing organization or contract research
organization external audit, or inspection by the
FDA. If you are not in compliance, your company
proposes corrective actions and a time period to
do them. It’s up to the inspector to approve it,” he
said. Depending on how serious the violation is, a
whole lab could not be qualified or a piece of
equipment needing cleaning could put the entire
manufacturing line into question, he said. “It
potentially could shut down a production line.”
Software Gap
Dr. McDowall said one weakness of USP
<1058> is that it isn’t good for validating
software. “At pharmaceutical companies, ana-
lytical chemists or quality control people do this
under good manufacturing practices,” he said.
“The instrument is qualified by the vendor, but
software isn’t validated.” He said he gets called
into labs sometimes to link a qualified instru-
ment and software validation. One problem
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70 L. Valigra

with vendor documentation, he said, is there is terminology, it does largely ignore software,
no place for a company to customize it. an area that is one of GAMP’s strengths.
While AIQ has strengths in its simplicity, PerkinElmer’s Smith, for one, would like to
classification of instruments, and clarity of see the two guidances come closer together.

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DOI: 10.1002/qaj

“Top‐tier pharmaceutical companies strongly
align instrument qualification with GAMP,”
Smith said. “USP <1058> is an opportunity to
take advantage of that to drive harmonization.
I’m starting to see evidence of it.” Users
typically drive harmonization, he said, adding
that it would benefit different parts of pharma-
ceutical companies that may be using different
criteria. Companies now using the structure of
GAMP are also going to <1058>, he said, and
in the short term they are willing to bear the
extra cost of adding documentation and over-
qualifying equipment.
“If <1058> were more prescriptive, you’d
expand it a lot and lose the benefits of its
simplicity,” Smith said. “What I’d like to see
Copyright © 2011 John Wiley & Sons, Ltd.
71
is the people who wrote <1058> and GAMP
get together.” He added that an organization
that decides to use <1058> needs to harmo-
nize around it. “The benefits of a similar
structure are beneficial in an audit,” Smith
said.
“If a procedure is outlined in a general
chapter, it is easier for a manufacturer to follow
that,” added Dr. Pappa. “The FDA is familiar
with it, so it is a ‘known currency.’” Although
Dr. Pappa said there is no current effort at USP
to harmonize with GAMP, he didn’t rule out the
possibility when a new expert committee
overseeing the chapter takes over at the end of
June 2010. “It’s a five‐year cycle, so they could
look at GAMP,” he said.
Qual Assur J 2010; 13, 67–71
DOI: 10.1002/qaj