Article

pubs.acs.org/jchemeduc

Good Laboratory Practice. Part 1. An introduction

Richard C. Wedlich,* Agata E. Libera, Amanda Pires, and Matthew T. Therrien
NSF Pharmalytica. Part of NSF Health Sciences, 719 Middle Street, Bristol, Connecticut 06010, United States
ABSTRACT: The Good Laboratory Practice (GLP) regulations were put into
place in 1978. They establish a standard of practice to ensure that results from
the nonclinical laboratory study reported to the U.S. Food and Drug
Administration (FDA) are valid and that the study report accurately reects
the conduct of the study. While the GLP regulations promulgate standards of
laboratory conduct, for example, use of qualied personnel, instrumentation,
and analytical methods, they also create a need to properly and thoroughly
document such conduct. When this is done, it is easy to reconstruct and audit
the study at a later date. Ultimately, the laboratory conduct in any particular
study is compared to the FDAs expectations, which evolve over time within the
framework of these regulations, thereby moving the entire pharmaceutical
industry forward. Yet, few people learn about these GLP standards before
entering the industry. It is simply a matter of time before American colleges and
universities respond to a pharmaceutical industry need and introduce GLP to
undergraduates.
KEYWORDS: Upper-Division Undergraduate, Graduate Education /Research, Analytical Chemistry,
Problem Solving/Decision Making, Laboratory Management, Drugs/Pharmaceuticals
his article is the rst in a series of three (DOI: 10.1021/
ed3002557 and 10.1021/ed300256a) intended to educate
the chemist so that he or she can intelligently meet many of the
challenges unique to a laboratory operating under the Good
Laboratory Practice (GLP) regulations such as those
laboratories that are ubiquitously present in the pharmaceutical
industry. Ultimately, professional chemists in GLP laboratories
learn certain GLP regulations by heart, as those regulations
apply to the chemists specic lab. For students, however, it is
more important to learn overarching GLP principles instead of
specic regulations and how those principles combine to form a
coherent approach to conducting GLP-compliant experiments.
Many laboratory practices learned in undergraduate lab classes
are actually regulatory requirements in GLP practice, but are
not labeled as such. For example, most students are required to
keep lab notebooks that are suciently detailed and accurate to
allow recreation of the experiments. In GLP regulations, it is
stated that within a lab, the study director shall assure that all
experimental data, including observations of unanticipated
responses of the test system, are accurately recorded and
veried.1 This regulation contains the same sentiment as the
lab notebook rule. Yet, despite GLPs ever-present nature, few
books are written about GLP practices and often go through
the regulations one at a time, are lengthy, and are aimed at
professionals (a short selection is cited)24 making them
relatively inaccessible to university audiences.
The present articles provide a good overview of overarching
themes in GLP regulations, making them accessible to a wider
audience. Most of the topics discussed are, in fact, addressed in
various undergraduate laboratory courses including the
importance of keeping a lab notebook, recording observations

2013 American Chemical Society and

Division of Chemical Education, Inc.

clearly and contemporaneously, calibrating instruments, and

planning experiments.5 These practices take on additional
signicance to students when they understand that (i) GLP
guidelines must be followed for employment in GLP
laboratories and (ii) the Food and Drug Administration
(FDA) and Environmental Protection Agency (EPA) require
that GLP guidelines are followed in all nonclinical lab study
experiments. Yet, there are few degree programs in the United
States that include direct study of GLP. One such program is
the M.S. degree in Quality Assurance and Regulatory Aairs
from the School of Pharmacy of Temple University. In
addition, there are very few academic GLP laboratories in the
United States despite the fact that it is feasible to operate such a
laboratory. Those researchers interested in incorporating GLP
practices into their academic laboratories should consult the
literature.6,7 It is simply a matter of time before American
colleges and universities respond to a pharmaceutical industry
need and introduce GLP to undergraduates.

BACKGROUND
The Good Laboratory Practices constitute the U.S. government regulations found in Title 21, Part 58 of the Code of
Federal Regulations. These were put into place by Congress in
the late 1970s, foremost to ensure the FDA that results from
nonclinical laboratory studies reported to the agency through
new drug applications were valid and accurately reected the
study conduct. Today, all data supporting applications to the
FDA for research or marketing permits of FDA regulated
products and product registrations submitted to the EPA meet
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WHEN DOES GLP APPLY?

The development of a new drug is completed in four distinct
recognized stages, beginning with the discovery of a potential
drug.15 Animal studies, including toxicological and safety
pharmacological studies together with pharmacokinetic and
bioavailability studies, constitute the next stage and are referred
to as nonclinical laboratory studies and this work is
conducted under GLP. Clinical (i.e., human) studies make up
a third stage and are designed to develop an understanding of
the safety and ecacy of the drug in various human populations
and such work is conducted under Good Clinical Practice.18
The postapproval stage is the last and a drug at this stage is
registered with the FDA and available on the market. Such
drugs are monitored through pharmacovigilance procedures
that may prompt further clinical studies.

the GLP regulatory requirements. Products regulated by the

FDA include, but are not limited to, human drugs, medical
devices, combination medical devices, and biological products;
whereas the EPA regulations include pesticides, biocides, and
toxic chemicals. To place this into perspective, the FDA
currently has jurisdiction over approximately 2025% of the
U.S. gross national product.8
Under the Federal Food, Drug and Cosmetics Act, the
sponsor of the regulated product (e.g., the drug manufacturer)
is responsible for establishing the identity, purity, strength,
safety, and ecacy of that product through appropriate
laboratory testing. Amassing these data requires a multifaceted
study that can involve many labs and investigators around the
world. This varied and complex analytical chemistry support is
conducted under GLP regulations to provide data used to
decide whether approval for clinical (human) trials is received.

THE ESSENTIALS TO LAB COMPLIANCE

Essentially, laboratory work in support of a GLP study is
conducted by a qualied analyst, using a qualied instrument,
and following a validated or veried analytical method or
standard operating procedure (SOP). The procedure to
qualify the analyst involves documenting in their training
le proof of their qualication based upon a combination of
their education, prior job experience, and specic on-the-job
training. The goal of qualifying the instrument is to show the
instrument is t for its intended use and can be as simple as
calibrating the instrument against a reference standard traceable
to the National Institute of Standards and Technology (NIST).
Quoting the regulations, Equipment used for the generation,
measurement, or assessment of data shall be adequately tested,
calibrated and/or standardized.19 Similarly, the procedure to
validate or verify the analytical method may only require
verifying that expected results are obtained when following the
method as applied, for example, to a reference standard, or it
may be more involved such as demonstrating that the method
passes predened acceptance criteria (such as those set on
linearity, range, limit of detection, accuracy, and precision)
when following a validation protocol in conformance with the
appropriate International Conference on Harmonization (ICH)
Guidance to industry.20 All such qualications of either
instruments or analysts must be thoroughly documented and
the documents properly archived so that, even years later, it will
be possible to demonstrate to the FDA the qualication status
at the time of the study. Doing these essential steps puts the
laboratory on its way to becoming GLP-compliant.

ORIGINS OF GLP
Although the original Food and Drug Act was passed by
Congress in 1906, the next serious piece of drug regulation was
passed in 1938 after the 1937 Elixir of Sulfanilamide tragedy.
The S.E. Massengill Company sold a drug called Elixir of
Sulfanilimide that contained sulfanilamide dissolved in
diethylene glycol for treatment of Streptococcus infections.
Although diethylene glycol itself is nontoxic, it is metabolized in
the liver and kidneys into toxic metabolites.9 If diethylene
glycol is consumed in a high enough dose, similar to that found
in Elixir of Sulfanilimide, the results are kidney failure and
cardiac arrest.9 Ultimately, the drug claimed the lives of
approximately 100 people before it was recalled through a
tremendous eort by the FDA.8,10 However, as there was a lack
of drug regulation before 1938, the court had to limit the ruling
to misbranding the drug as an elixir, which implied an
alcoholic solvent, not diethylene glycol. The next year, in 1938,
congress passed a regulation requiring drugs to be shown as
safe prior to marketing.8 Further, it was not until 1962, after an
additional drug tragedy involving Thalidomide, that the FDA
law was amended (by the KefauverHarris Drug Amendment)
and required drug manufacturers to prove the ecacy of a new
drug in addition to its safety.8
Soon thereafter in the early 1970s, a scandal arose involving a
company named Industrial Bio-Test, which held contracts on
approximately 40% of all safety testing on products regulated by
the FDA or EPA including drug, pesticide, and food additive
products.11,12 In April of 1976 the FDA, specically Dr. Adrian
Gross, an FDA pathologist, uncovered a massive fraud that
included data falsication on an unprecedented scale and
resulted, after a ve-year investigation, in jail and probation
time for three of the leaders of the company.13 In response to
this scandal, the government put together the U.S. Toxicology
Monitoring Task Force to ensure the validity of the nonclinical
laboratory studies. This task force was the origin of the GLPs.
Now, a new drug for human use cannot be marketed without
FDA approval of a new drug application, which is submitted by
the drug manufacturer and must include safety and ecacy data
developed in nonclinical and clinical GLP studies.1417
Furthermore, to transport such a drug across state lines, either
a new drug application or an investigational new drug
application must have been accepted by the FDA.8 As such,
drug manufacturing is more highly regulated by the government than previously.

ROLES AND RESPONSIBILITIES

All aspects of a GLP study are regulated, from the experimental
design, through sampling and performing chemical analyses, to
recording, reporting, and archiving experimental results and
conclusions. Conduct of the study necessarily involves many
people each playing a variety of roles and it is important to
single out from the start who is responsible for what. Those
persons who have the power and responsibility to direct
resources (e.g., facilities, personnel, money, equipment, etc.)
and to ensure that the study conduct is in compliance with GLP
regulations are collectively called management. Management
establishes a document control unit that ensures that any and
all records used or generated in the conduct of the study and
deemed necessary for its evaluation and (later) reconstruction
are controlled, meaning that such documents are not lost,
damaged, destroyed, altered, or revised without proper approval
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ately available laboratory manuals and standard operating

procedures relative to the laboratory procedures being
performed. Published literature may be used as a supplement
to standard operating procedures.24 However, methods change
over time and such changes must be documented. Changes are
annotated on the change control page of the method along
with the justication for each change. Because it is required to
document in the raw data the activities (e.g., steps taken in
the analysis) taken by the lab to support the study, methods
oer some relief to the analyst from continually writing these
steps in their lab notebook or workbook. Rather, they simply
reference the method document control number in their lab
notebook or workbook. A contract research organization that
has been operating for some time will typically have developed
and validated (or veried) hundreds of analytical methods, but,
not all methods are developed in-house. They can be
transferred from another lab. Analytical test methods are also
available through a number of organizations including, but not
limited to, NSF International, USP (United States Pharmacopeia), ASTM (American Society for Testing and Materials),
OECD (Organization for Economic Co-Operation and
Development), and EPA (Environmental Protection Agency).

and documentation. Management also establishes a quality

assurance unit to monitor the study at appropriate intervals and
report back on a timely basis any and all noncompliances to
management and the study director, which management assigns
to each study.21 The study director serves as the single point of
study control and is responsible for the study design, technical
conduct of the study, interpretation, analysis, documentation,
reporting of the study results, and archiving of study materials.
Each person or group involved in the study has a specic job
that helps regulate and document the study in a controlled way.

WRITTEN PROCEDURES
The importance of having approved written procedures in place
cannot be overemphasized. It goes back to the familiar
accountability rule-of-thumb, say what you are going to do
and then do what you say. They provide instruction to the user
and are reviewed and approved by management and quality
assurance. A periodic schedule of review and revision is
established for all procedures. The document control unit sees
to it that only the recent version of the approved document is
available for use. Quoting the regulations, A testing facility
shall have standard operating procedures in writing setting forth
nonclinical laboratory study methods that management is
satised are adequate to insure the quality and integrity of the
data generated in the course of a study.22 Furthermore, written
procedures facilitate a quality audit that takes place after the
study is complete. Auditors ascertain from the selection and the
organization of these procedures if the laboratory clearly
understands the GLP regulations that apply to the work that
they do. Typically, auditors want to see the index of the
laboratorys standard operating procedures (SOPs) and
scrutinize key procedures. Key SOPs include (i) document
control, (ii) training and qualication of analysts, (iii)
procedures for recording raw data, (iv) corrective and
preventative actions, (v) change control, and (vi) quality
assurance monitoring of GLP studies. Auditors check for
documented evidence that SOPs are being followed and any
deviation from an SOP is reported to the study director and
study management.
Written procedures are also found in the study protocols.
The study director obtains control over the study by writing the
study protocol and then using it to communicate with the
laboratory how the study will be conducted. The protocol is
nalized and approved before the start of the study. Studyspecic material that is generally not included in the SOPs is
found in this document, including but not limited to the details
of the experimental design, clear statements of the study
objectives, details of the methods to be used in the conduct of
the study (including methods for the control of bias) and the
records to be maintained. Quoting the regulations, Each study
shall have an approved written protocol that clearly indicates
the objectives and all methods for the conduct of the study.23
Additionally, highly specic lab instructions are written into
analytical test methods. Unlike SOPs, these laboratory
procedures are specic to a certain analysis. Like SOPs and
protocols, they are controlled documents, reviewed and
approved by lab management and quality assurance. An
analytical test method (simply called method) will often be
used in a number of very dierent studies that require the same
specic analysis be performed. The study protocol need only
refer to the method by document number (and usually, the
method is then relegated to an appendix of the protocol).
Quoting the regulations, Each laboratory shall have immedi-

THE STUDY FINAL REPORT

It is a regulatory requirement that the study director prepare
and submit a study nal report providing the reviewing agency,
for example, the FDA, with the what, where, how and when of
the study.25 The study nal report includes among other things:
(a) a statement of the objectives of the study, (b) a description
of all methods employed, (c) all of the experimental data and
results generated in the conduct of the study, (d) descriptions
of all calculations, and (e) all conclusions drawn. Attached to
the study nal report is the compliance statement, written by
the study director, that provides a description of any and all
circumstances that may have aected the quality and integrity
of the study and attests to any and all noncompliances that
occurred in the study.

RECONSTRUCTING THE STUDY

So much success in the GLP arena depends upon being able to
reconstruct the study. Reconstructing the study means
putting together a complete picture from the documented
(largely, written) records of how the study was conducted: who
worked on it, what were their qualications, what instruments
were used and were they properly qualied throughout the
study, what reference standards were used, were they within
their expiration dates, were they properly stored, and how were
the samples prepared. These records must be written by
persons who understand that the records will be used by others
at a later date (perhaps, a much later date) and must support
any claims made in the nal study report. It helps to have good
written procedures (protocol, SOPs, and methods) in place
throughout the study and to be able to call them up at any time.
The account of how the analysis was performed must be
permanent and readily retrievable. The data to be captured are
dened in the protocol. One strives to present a complete set of
data. Having good lab notebooks and workbooks and
instrument logbooks in place helps. Should some or all of the
data be suspected as being in error or awed in some way they
may be invalidated (but still kept and not obscured in any way)
following a predened and management-approved procedure
called an investigation. Investigations are treated in the third
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(6) Hancock, S. Qual. Assur. J. 2002, 6 (1), 1521.

(7) Abad, X.; Bosch, A.; Navarro, C. Qual. Assur. J. 2005, 9 (4), 304
311.
(8) Kennedy, W. United States Regulations. In Principles and Practice
of Pharmaceutical Medicine; Fletcher, A. J., Edwards, L. D., Fox, A. W.,
Stonier, P., Eds.; John Wiley & Sons, Ltd.: Chichester, U.K., 2002.
(9) Vale, J. A.; Widdop, B.; Bluett, N. H. Ethylene Glycol Poisoning.
Postgrad. Med. J. 1976, 52, 598602.
(10) Hutt, P. B.; Merrill, R. A. Food and Drug Law: Cases and
Materials, 2nd ed.; Foundation Press: New York, NY, 1991; p 476.
(11) Novak, R. A. Todays Chemist 2001, 10 (11), 4546.
(12) Culliton, B. J. Science 1976, 193, 3235.
(13) Taylor, J. M.; Stein, G. C. Historical Perspective. In Good
Laboratory Practice Regulations, 4th ed.; Weinberg, S., Ed.; Informa
Healthcare USA, Inc.: New York, NY, 2007.
(14) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.1 (a), Title 21, 1978.
(15) Mathieu, M. New Drug Development: A Regulatory Overview, 5th
ed.; PAREXEL International Corporation: Waltham, MA, 2000; p 186.
(16) Hutt, P. B.; Merrill, R. A. Food and Drug Law: Cases and
Materials, 2nd ed.; Foundation Press: New York, NY, 1991; pp 513
544.
(17) New Drugs. Code of Federal Regulations, Part 310, Title 21, 1978.
(18) Bohaychuk, W.; Ball, G. Good Clinical Practices. In Principles
and Practice of Pharmaceutical Medicine; Fletcher, A. J., Edwards, L. D.,
Fox, A. W., Stonier, P., Eds.; John Wiley & Sons, Ltd.: Chichester,
U.K., 2002.
(19) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.63 (a), Title 21, 1978.
(20) ICH Q2B Validation of Analytical Procedures: Text and
Methodology, adopted in 1996, Geneva Q2B, in 2005 incorporated in
Q2(R1).
(21) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.35 (a), Title 21, 1978.
(22) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.81 (a), Title 21, 1978.
(23) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.120 (a), Title 21, 1978.
(24) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.81 (c), Title 21, 1978.
(25) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.185 (a), Title 21, 1978.

article of the present series. Failing to reproduce an analysis can

come about even though the original analyst was scrupulous.
Even a study that generated data that were not very
reproducible, can be reconstructed provided that the problems
with reproducibility in the analytical results were properly
investigated and documented. As one might expect, good
science aids in good compliance, but does not guarantee it. First
and foremost, the scientist must be honest and not bias the
analysis. Scientic integrity rules the day, always.
Hand-in-hand with making the study easy to reconstruct, is
making it easy to audit. A professional auditor possessing an
appropriate level of experience in and knowledge of the type of
work being performed in the lab must be able to quickly
evaluate whether the study was conducted in compliance with
GLP. Because the audit of the study may well be conducted by
an EPA or FDA investigator months or even years after
completion of the study, the snap-shot in time concept is
important. This involves linking the study to a study le that is
maintained by the document control unit and designated via a
unique study identication number. Relevant information is
simply added to the study le at the time it is generated. When
this is all done correctly, it is easy to follow this audit trail
from the study nal report right back to experimental details
such as the lot number of the solvent or reagent used to prepare
the standard solution and to be able to say almost in the same
breadth, what instruments (if any) had performance issues at
the time of the study and what version of such-and-such an
SOP was in place at the time. A good test of study integrity is
the coherence and completeness of its records and the amount
of time it takes to retrieve the study to the satisfaction of an
FDA eld investigator, say, 5 years after the study was
completed.

CONCLUSION
One would anticipate that in a competent pharmaceutical
analysis laboratory, reliable analytical results would be
generated by trained, capable scientists, using instrumentation
and equipment that are t for their intended use and following
accepted analytical methodology. Meeting the GLP regulations
adds yet another dimension to this: to quote Taylor and Stein,
The proposed regulations placed a heavy emphasis on data
recording and record and specimen retention to ensure that a
study could be reconstructed at a later time if the need arose.13
Study reconstructability remains a central pillar of the GLPs.

AUTHOR INFORMATION

Corresponding Author

*E-mail: rwedlich@nsf.org.
Notes

The authors declare no competing nancial interest.

REFERENCES

(1) Good Laboratory Practice (GLP) for Nonclinical Laboratory

Studies. Code of Federal Regulations, Part 58.1 (b), Title 21, 1978.
(2) Seiler, J. P.; Good Laboratory PracticeThe Why and the How,
2nd ed.; Springer-Verlag: Berlin, Germany, 2005.
(3) Good Laboratory Practice Regulations, 4th ed.; Weinberg, S., Ed.;
Informa Healthcare USA, Inc.: New York, NY, 2007.
(4) Handbook Good Laboratory Practice (GLP), 2nd ed., Kioy, D.,
Long, D., Bhalla, S., Seiler, J. P., Eds.; World Health Organization:
Geneva, Switzerland, 2009.
(5) Wilson, E. B., Jr. An Introduction to Scientic Research; Dover
Publications, Inc.: New York, NY, 1990.
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Good Laboratory Practice. Part 2. Recording and Retaining Raw Data

Richard C. Wedlich,* Agata E. Libera, Amanda Pires, and Cassandra Tellarini
NSF Pharmalytica. Part of NSF Health Sciences, 719 Middle Street, Bristol, Connecticut 06010, United States
ABSTRACT: A clear understanding of how raw data is dened, recorded,
and retained in the laboratory record is essential to the chemist employed in
the laboratory compliant with the Good Laboratory Practices regulations. This
article is intended to provide an understanding by drawing upon examples
taken from the modern pharmaceutical analysis laboratory.

KEYWORDS: Upper-Division Undergraduate, Graduate/Research, Analytical Chemistry, Problem Solving/Decision Making,

Laboratory Management, Drugs/Pharmaceuticals
industry will nd having read and understood the present article
will provide them a leg-up on the job interview. Good
documentation practices as discussed here are encountered
by the chemist on his or her rst day in the professional lab
and in the specic case of the pharmaceutical analysis lab, the
expectation is furthermore that the chemist will follow these
practices before generating any data to support a GLP study.
The instructor responsible for preparing the undergraduate for
graduate research or a career in the pharmaceutical lab can draw
upon the concrete examples provided here to educate, provide
additional motivation, and show that the subject, As with
Wagner, its not so bad as it sounds.1

t is absolutely critical to operating a laboratory under the

Good Laboratory Practice (GLP) regulatory requirements
for proper identication, recording, and retention of raw data
to ensure it is readily available and at the same time protected
from corruption or loss. Nonclinical laboratory studies can be
invalidated and marketed products that are regulated by the
Food and Drug Administration (FDA) and consumed by humans
can be deemed adulterated and recalled based solely on the
deciency of the laboratory to adequately and honestly document the conduct of their experimental studies done to support
these products. The GLP regulations that apply to the testing
laboratory apply equally to all supporting laboratories, academic
and nonacademic.
This article is intended to provide guidance on what should
be recorded and retained in a GLP complaint lab. The old rule
of thumb, that if you did not write it down, you cannot claim
to have measured it applies, but how should you write it down,
where should you write it, and what must you claim to have
measured? The GLP regulations described in Title 21 of the
Code of Federal Regulations, Part 58 provide answers.2 They
are, however, left intentionally vague. The subject is raw data
and has a clear place in the laboratory. Many of the concepts
involved and strategies devised for dealing with this issue are
already familiar to experienced researchers and some are taught
in the undergraduate chemical laboratory. All students learn early
on the importance of keeping a good lab notebook, without
knowing this is a GLP regulatory requirement. Similarly, students
in instrumental analysis class learn how to build a calibration
curve but are probably not aware that retaining all the weights
and volumes of the reference standards prepared and used to
generate the curve is a GLP regulatory requirement. How raw
data are recorded and retained is fundamental. Students near
graduation and looking for employment in the pharmaceutical
2013 American Chemical Society and
Division of Chemical Education, Inc.

RAW DATA
All raw data must be recorded and retained as part of the study.
The GLP regulations dene raw data as any laboratory
worksheets, records, memoranda, notes, or exact copies thereof,
that are the result of original observations and activities of
a non-clinical laboratory study and are necessary for the
reconstruction and evaluation of the report of that study.2
Raw data may include photographs, microlm or microtch
copies, computer printouts, magnetic media, including dictated
observations, and recorded data from automated instruments.2
It is obvious that the regulation was written to anticipate the
role that technology does and will play in the future of recording
and retrieving raw data.
It is important to distinguish between raw data and the media
used to record it. For example, the laboratory may use an
analytical balance that has both an LED display and a paper
printout of the result of a measurement so that the analyst may
choose to read the LED display and hand write the displayed
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computer systems and laboratory information management

systems in general, must meet the same requirements as ink-onpaper systems. To demonstrate to the FDA that the electronic
record is trustworthy, reliable and generally equivalent to
paper records,4 the laboratory must comply with the
regulations set forth in Title 21, Code of Federal Regulations,
Part 11, which, among other things, dictate the level of control
that the lab must have over the electronic record and the extent
that the computer system generating this record must be
validated. This subject is left for a later time in a future
publication.
Furthermore, information, in addition to results, from measurements will typically be required to reconstruct the study.
Examples include instrument conditions and parameters, records
of instrument performance issues, and investigations into suspect
data. Although some of these records are also stored in other
places, for example, quality assurance keeps all audit reports, it is
important to tie all records to their specic study so that they are
an integral part and to make them readily retrievable. The ability
to retrieve all study data in a timely fashion is important and helps
to show compliance with GLP regulations, which is especially
important when the lab is being audited by the FDA.

value into their laboratory notebook or get an ink-on-paper

printout from the balance printer. The raw data is the same, a
recorded weight, though the media used to record it are
dierent and will be treated dierently. If the LED display is
dened as the raw data, then the measurements must be
directly recorded into workbooks or notebooks. However, if the
lab denes the ink-on-paper printout to be the raw data from
the balance, the analyst should immediately paste it into his or
her workbook or notebook. However, this piece of paper could
be altered or removed and replaced. As such, it is typical to
write the date and the name or initials of the analyst across the
seam of the print out and the page, thereby further integrating
the printout and workbook or notebook. Furthermore, the analyst
will write on the printout sample identication information. In
his book, Professor Wilson3 illuminates the importance of such
good documentation practices by contrasting them with the
practices of astronomer Le Monnier, who missed out on the
discovery of Uranus as a result of writing his observations down
on a paper bag.
Data must be entered in its unaltered raw form. For example,
the concentration of a standard solution may be calculated from
the ratio of the observed weight of reference material dissolved
in the observed volume of solution (or solvent). The concentration is a calculated value and not raw data. It is expected that
both the raw data, which is the weight of the standard and the
volume of solution or solvent, and the calculated value both
be recorded and that an example of the calculation (including
appropriate units and considering the signicant gures
convention) be shown in the workbook or notebook. Similarly,
it must be recognized that results from smoothing data and
other data transformations, although perhaps necessary and
useful, cannot take the place of contemporaneously recorded
raw data.

GOOD DOCUMENTATION PRACTICES

An old industry joke is that GLP stands for generate lots
of paper. It originates from the importance placed on
documenting a study from beginning to end. A 1990 estimate
of the amount of documentation provided in a typical new drug
application is given as 2 to 15 volumes of summary material
generated during the safety and ecacy investigations as well as
proposed manufacturing and analytical testing along with 10 to
100 volumes of raw data to support the summary.5 This
magnitude should serve the reader as a benchmark. All of this
information must be properly documented for a drug to be
approved by the FDA.
Therefore, the Good Documentation Practices have been
developed. A short selection is given in Box 1. Many of these
practices have grown out of the research lab and are familiar to
chemists and even students, with some practices specically
prompted by the need to support (in court) patent claims on
products and processes.6 Because it is required that raw data
be readily retrievable and that the study itself be easy to
reconstruct from the record, it is clear that a device such as a
workbook or lab notebook along with the requirement that the
analyst make entries directly to the workbook or notebook at
the time of observation is helpful. It is expected that raw data be
attributable, legible, contemporaneous, original, and accurate.
By attributable is meant that the data are linked to their
source, including the person making the observation and the
record and the study, test article, instrument, and analytical run.
It is a GLP requirement that the person making the data entry
shall sign (or initial) the entry on the date it was recorded.
Similarly, in automated data collection systems, the person
responsible for direct data input shall be identied at the time
of data input. By contemporaneous is meant that data are
recorded at the time the observation is made. By original is
meant the rst recording of the data, which is assumed to be
the most accurate and reliable recording of the data. Following
good documentation practices helps to instill these quality
attributes. Changes can be made to data entries but they must
not obscure the original entry and they must, at the time the
change is made, be signed (or initialed) and dated by the
person making the change, who must also record the reason for

DATA STORAGE AND RETREIVAL

Before modern computing technology became an integral a
part of scientic research, following proper GLP guidelines for
data recording and retention was simpler: write down everything exactly as it happened, do not change what was recorded,
and keep all documentation. However, with the increased
presence of technology in scientic research, the requirements
of the GLPs are more complicated. A simple example illustrates
nuances involved in data storage and retrieval under the
GLP requirements. If the analytical balance is not capable of
electronically storing the result, then the procedure to verify
that the balance printout and the LED display are the same is
easy to perform and document (typically in the instrument
logbook). If, instead, the balance is capable of retaining in
electronic memory (for printing at a later date) the old weight
while generating a new weight, then the question arises: What
protects against confusing old with new data, altering or
deleting data, or losing data when power to the balance fails?
In this case, the procedure for verifying that the lab has control
over the raw data may become involved. And it may include
some sort of disaster recovery to protect against the power
failure or to mitigate its impact on studies. Furthermore, lab
personnel other than those working on the study will typically
have access to the balance and the data stored in its memory
so that some sort of logon with password control may be
required.
The same principles of data storage and retrieval under GLP
apply, whether the media used for storage is ink-on-paper or
not. Systems that store data in electronic form, for example,
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Box 1. Examples of Good Documentation Practices

Box 2. Examples of Information Required in Workbooks

and Notebooks To Document the Study and Analysis

1. Record all data and observations legibly in indelible ink

(except those generated by automatic data collection
systems).7
2. Enter all data directly into laboratory workbooks,
logbooks, or notebooks at the time of observation. Do
not record any data on scraps of paper that can be lost.7
3. Date and sign or initial all entries in workbooks,
logbooks, or notebooks.7
4. Changes in data entries should not obscure the original
entry. Instead, strike out the original entry with a single
line. Initial and date changes and document the reasons
for change, perhaps with an error code.7
5. Shared workbooks or notebooks must clearly identify
which analyst (student) performed what portion of the
work.
6. Exact copies of originals can be included such as exact
copies dilution schemes or instrumental conditions. Exact
copies should be marked as such and signed and dated.
Exact copy printouts from automatic data collection
systems must contain all the information that is in the
electronic record such that the experiment can be
reconstructed. This includes a record of all changes
made to the electronic le.

the change. To facilitate this, many laboratories create error

codes (that are dened in a standard operating procedure) and
simply write the error code alongside the change rather than
use a full sentence to give the justication. For example, MD
might be used for Misdated.

Analyst Name
Date
Document Control Number
Method or Protocol Number
Study Number
Test specications or ranges
Objective or Purpose
Sample Information (sample ID #, lot #, description of
the sample and sample container or closure system)
Reference Standard Information (name, manufacturer,
lot #, grade or purity, expiration date)
Reagents List (manufacturer, lot #, grade or purity,
expiration date)
Instrument List (instrument ID #, date of last
calibration, next calibration due date)
Preparation of diluent ad mobile phases (lot #,
manufacturer, expiration date of each reagent used)
Reporting Results (include units and round to the
proper number of signicant gures)
Instrument Setup and Parameters
Preparation of Stock and Working Standards
Preparation of Samples (including weights, volumes,
dilution factors, and nal concentrations)
Calculations (with units)

information is supplied in Box 2. Including such information

in laboratory workbooks and notebooks facilitate both the
peer-review and the quality assurance inspection of the work.
Although building prompts into the workbooks for the analyst
greatly increases analyst eciency, such prompts are not meant
to take the place of thinking. Workbooks and notebooks will
typically contain a lot of data that is not common across all
analyses, but is important and needs to be included nonetheless

WORKBOOKS AND NOTEBOOKS

To facilitate the orderly recording of raw data, most laboratories use a workbook or notebook. The notebook is a research
notebook, issued to the analyst and tracked by a notebook
number assigned by the document control unit. The document
control unit tracks all ocial documents, including reports and
lab workbooks or notebooks, using unique document numbers.
The notebook consists of many bound, prenumbered, blank
pages and a space for the analyst and witness to sign and date
each page. The notebook is usually not specic to the analysis
or the study and the analyst is expected to keep it until it is
lled. How data are organized in the notebook is left up to
the analyst and will dier from analyst to analyst. This format,
though it works well for some laboratories, has many shortcomings when compared with workbooks, particularly in a
contract research organization, where the analyst may be
expected to work on a variety of studies supporting a number
of dierent sponsors all of whom want their studies to be
condential. The workbook is also a preprinted with a document
control number that is issued and controlled by the document
control unit. The workbook template is created by the lab with a
specic analysis in mind. Revision to the workbook template
goes through a change control program that tracks all changes to
laboratory operating procedures. Therefore, workbook template
revisions must be justied from both a scientic and a
compliance viewpoint (i.e., the revision simplies the analysis
and increase GLP compliance).
Regardless of whether an analyst uses a workbook or a notebook format to record data, certain information is important to
include in both media. A list of examples of such requisite

LOGBOOKS
Not only is tracking data for a study important for GLP
compliance, but tracking how the laboratory runs is also
important. Much of this information is easily captured in a
logbook and is helpful in reconstructing a study. Common
examples include the instrument logbook and the sample
logbook. Logbooks contain information supporting multiple
GLP studies, making the ability to easily associate certain data
or information with a certain study important in reconstructing
study conduct.
Not only do logbooks make tracking certain information
easy, such as instrument use, but using instrument logbooks in
particular also fullls a GLP requirement. It is required that
written records shall be maintained of all inspection,
maintenance, testing, calibrating and/or standardization operations performed on equipment and instrumentation used in
the generation, measurement, or assessment of data and equipment used for facility environmental control.8 The instrument
logbook serves this purpose. Data are recorded into logbooks
following good documentation practices and the logbooks
themselves are under document control. A list of typical
information included in instrument logbooks is included in
Box 3. The instrument logbook is commonly the single source
of information on the history of the instrument including its
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10 years. Although this may seem tedious, especially for

academic laboratories, it is a signicant requirement of the GLP
regulations as it aords the ability to more completely reconstruct
how a study was conducted in the context of laboratory operations.

Box 3. Examples of Information Included in Instrument

Logbooks

Instrument Identication Number

Date of Installation Qualication
Details of the Performance Qualication
Instrument Type or Description
Qualication (calibration) Status
Identication of the SOP Followed for the Performance
Qualication
Manufacturer
Date of the Last Calibration
Details of the Preventative Maintenance
Model
Date when Next Calibration Is Due
Identication of the SOP Followed for the Preventative
Maintenance
Serial Number
Details of the Installation Qualication
Log of Instrument Failure
Instrument Custodian
Identication of the SOP Followed for the Installation
Qualication
Details of Instrument Repairs and Remedial Actions
Table of Contents: Running List in Chronological
Order of All Instrument Events
Identication of the SOP Followed for the Operational
Qualication
Instrument Location
Details of the Operational Qualication

CONCLUSION
Critical to performing laboratory work in compliance with the
GLP regulations are the implementation of good documentation practices and the proper identication of what must be
documented in addition to the raw data and data analyses.
When this is done, it is possible to reconstruct the experimental
study at a later date from archived study records. The examples
provided of the standardized laboratory workbook and the
instrument logbook should oer a fairly clear picture of the
practical side of the subject. It is hoped that the reader, whether
they go on to work in the GLP-regulated analytical or
pharmaceutical analysis laboratory or the nonregulated R&D
lab, will nd this introduction highly useful.

AUTHOR INFORMATION

Corresponding Author

*E-mail: rwedlich@nsf.org.
Notes

The authors declare no competing nancial interest.

REFERENCES

(1) Quote attributed to Mark Twain.

(2) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.3(k), Title 21, 1978.
(3) Wilson, E. B., Jr. An Introduction to Scientic Research; Dover
Publications, Inc.: New York, NY, 1990; p 130.
(4) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 11.1, Title 21, 1978.
(5) Hutt, P. B., Merrill, R. A. Food and Drug Law: Cases and Materials,
2nd ed.; Foundation Press: New York, NY, 1991; pp 519520.
(6) Wilson, E. B., Jr. An Introduction to Scientic Research; Dover
Publications, Inc.: New York, NY, 1990; p 132.
(7) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.130 (e), Title 21, 1978.
(8) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.63, Title 21, 1978.
(9) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.195 (c), Title 21, 1978.

qualication and calibration. These activities ensure that the

instrument is t for its intended use. Instrument logbooks
should not be confused with instrument use logs. The latter
create a record (including when the instrument was used, by
whom, for what study and test article) that can be very valuable
in the event of an investigation into the validity of data
generated on the instrument.

THE ARCHIVES
It is a regulatory requirement that all study materials required
for the reconstruction of the study be archived. In deciding
what to archive, one must consider the obvious, for example, all
the study raw data, study protocol and report, and so forth and
also the not so obvious, for example, those things required to
prove that the study was conducted in compliance with GLP.
For example, calibration and maintenance records for instruments generated by metrology, records showing how the test
and control articles as well as reference standards were stored
during the course of the study, and so forth. Samples of the test
and control articles, reference standards, and wet specimens
shall, if required, be archived for a time period dictated by their
chemical stability, that is, as long as the quality of the
preparation aords evaluation.9 The physical archives must
protect documents and materials in general against theft, re,
water damage, pests, mold, and all other forms of deterioration.
A system for archiving study materials that does all of this and
at the same time ensures that materials can be rapidly retrieved
at any time, that materials cannot be lost, cannot be replaced
without proper prior approval, and that sponsor-condential
materials cannot be viewed by unauthorized persons must be in
place. Study materials are typically archived for not fewer than
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pubs.acs.org/jchemeduc

Good Laboratory Practice. Part 3. Implementing Good Laboratory

Practice in the Analytical Lab
Richard C. Wedlich,* Amanda Pires, Lisa Fazzino, and Joseph M. Fransen
NSF Pharmalytica. Part of NSF Health Sciences, 719 Middle Street, Bristol, Connecticut 06010, United States
ABSTRACT: Laboratories submitting experimental results to the Food and
Drug Administration (FDA) or the Environmental Protection Agency (EPA)
in support of Good Laboratory Practice (GLP) nonclinical laboratory
studies must conduct such work in compliance with the GLP regulations.
To consistently meet these requirements, lab managers employ a divide and
conquer strategy: they break up the laboratory operation into key unit
functions. Next they consider the regulatory requirements that must be met by
each key unit function. This is called the quality system approach for
implementing GLP in the analytical laboratory and it is embraced by nearly
every laboratory endeavoring to perform this kind of work.

KEYWORDS: Upper-Division Undergraduate, Graduate/Research, Analytical Chemistry, Problem Solving/Decision Making,

Laboratory Management, Drugs/Pharmaceuticals

to the metrology system; requirement (e) gives rise to a

laboratory information management system, for example,
laboratory notebooks and workbooks, logbooks, electronic
information management systems, and the archiving system;
and requirement (g) gives rise to the document control unit
(DCU). In short, quality systems help management control the
laboratory environment and ensure the proper resources
(type and amount) are made available for the design, conduct,
and maintenance of all GLP studies in compliance with the
regulations. Aiding in resource allocation decisions is the master
schedule,7 which is a listing of all GLP studies planned for the
lab along with (among other things) a description of the nature
of each.

his article is intended to provide the chemistry student

considering a career in a pharmaceutical analysis laboratory an understanding of the key elements that go into the
organization and management of the Good Laboratory Practice
(GLP) -compliant laboratory. The specic organizational units
are the quality systems or programs, such as the metrology
program, the training program, and others that the lab puts
into place to ensure that all GLP studies are conducted in
compliance with GLP regulations.

LABORATORY MANAGEMENT
The focus of the GLP approach to ensure valid data are
reported is on the process by which the testing laboratory carries
out and documents activities, more so than on the product
being tested (i.e., test article) or the test results. Companies in
this regulated industry adopted a laboratory management program to ensure that (a) facilities are adequate;1 (b) equipment
and instrumentation are qualied and well-maintained;2 (c)
written procedures are in place;3 (d) personnel are adequately
trained to do their jobs, which are well-dened; (e) data are
properly recorded, retained, and readily retrievable;4 (f)
samples, reagents, and reference standards are properly labeled,
handled, and stored;5 and (g) GLP documents are living and
controlled, meaning that a record of its birth is kept, a
record of any and all changes made to it is maintained, and a
record of when it is retired and archived is made.6 A controlled
document cannot be lost or destroyed.
Management puts this laboratory management program into
place using a divide and conquer strategy. Each of the above
requirements (ag) gives rise to a corresponding quality
system in the program. For example, requirement (b) gives rise
2013 American Chemical Society and
Division of Chemical Education, Inc.

FDA INSPECTIONS OF THE LABORATORY

Historically (and still true today), the design and intention of
GLP was (is) to provide a platform on which to conduct the
study that facilitates its inspection. Quality system designs have
workings that are transparent and it is desired that they
have built-in mechanisms for traceability and accountability
(as desired for any good management system). The main tool
used by the U.S. Food and Drug Administration (FDA) to
enforce GLP is the inspection of laboratories by FDA eld
investigators. The number of FDA eld investigators employed
at any given time as well as the size of the agency has
historically been highly dependent on the politics of regulation
and deregulation.8 It is generally believed that there are not
enough investigators for the workload, hence the FDAs
expectation is that the quality assurance unit (QAU) of the
Published: June 3, 2013
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on each must indicate identity, titer or concentration, storage

requirements (e.g., store at room temperature and keep away
from light), and expiration date.

company will stand in (advocate) for the FDA and that

companies are to be self-inspecting and self-correcting.
The FDA will typically perform a facility audit of a contract
research laboratory that is providing analytical or bioanalytical
support to GLP studies under contract with a sponsor, every
two years. All such GLP laboratory inspections by the FDA will
include at least (i) an inspection of the QAU and (ii) inspection
of one other quality system. Included in this audit, the FDA will
inspect specic studies in the lab as needed. The FDA
investigators typically conduct their inspection of the laboratory
during normal business hours and without giving notice prior
to their arrival. Most detrimental to the labs success in an FDA
inspection is failure to demonstrate a clear understanding of the
GLP regulations as evidenced in the design of the quality
programs. This is followed closely by failure to actually
implement the programs. It should be noted that the FDA
does not certify laboratories. Rather, the FDA will make
public the results of all ndings (in the Establishment
Inspection Report) including all noncompliances found.
Those laboratories that are not in good-standing with the
FDA will receive a Warning Letter. Those that fail to remove
the deciencies cited in the warning letter will be disqualied.
Hence, the FDA cannot qualify the lab, but can disqualif y it.
Similarly, the FDA may disqualify a study.

THE METROLOGY PROGRAM

In reconstructing the GLP study, one must know what
instrumentation and equipment were used to generate study
data or to serve as environmental chambers to store test and
control articles and reference standards, the condition of all
such instrumentation and equipment during the study, and
their qualication status during the study. To facilitate this, each
instrument or piece of equipment is tagged with a unique
identication number and a record (called a master equipment
list) is made of them. A template for an instrument and equipment tag is the following: the name of the instrument
custodian, the room number of the lab where the instrument
is located, the date of the last qualication, and the date when
the next qualication is due. The term qualication and
standardization are used interchangeably and include the
more specic case of calibration. Instrumentation and
equipment in the lab that are not intended to be used to
support any GLP study, or those are not qualied for regulated
use or out of order, must be identied as such with a marker
in clear view for the user and inspector. Additionally, a logbook
is created for each instrument and kept under document
control, meaning that each page is numbered, the creation of
the logbook is recorded against a document control number
assigned it by the document control unit (DCU), and
eventually, the logbook is archived. The instrument logbook
holds the history on the instrument including when it was
qualied, cleaned, inspected, and repaired. It is expected that all
GLP instrumentation and equipment will be placed on a
calibration schedule that includes dates for inspection and
routine maintenance and that all qualications shall be
performed following an approved standard operating procedure
(SOP) that details the steps to be taken, identies the person
who is responsible for carrying out the procedure (i.e., the
instrument custodian), and has clearly dened acceptance
criteria for deciding on a pass or fail assignment to conclude
the qualication procedure.
Many laboratories will have in place an instrument use log
that is controlled by the DCU and captures the name of the
person using the instrument, date of use, study number for the
study being worked on at the time of use and the workbook
number associated with the use.11 At times these greatly
facilitate instrument trouble shooting, for example, by helping
the lab to identify analysts or analytical methods that may be
causing an instrument problem and they can provide valuable
information in the event that the instrument becomes involved
in an investigation (see below), particularly as they help the lab
to identify all studies that may have been impacted by the
instrument problem.
The lab will usually have one metrology SOP for each type
of instrument (equipment) and this SOP must be in place prior
to starting the qualication activities on the instrument (equipment).
Likewise, a signicant eort goes into the metrology program
and it is customary to employ a dedicated metrologist to
administer the program and develop an overall master plan for
maintaining compliance. This person will likely perform all the
instrument qualications. With a good program in place, it is a
relatively simple task to collect at any time, all qualication data
generated on all instruments and equipment used for generating data or otherwise critically supporting the GLP study.

THE TRAINING PROGRAM

Persons working on a GLP study must be qualied to do so.9
Qualication may come via a combination of education, prior
job experience, in-house training, outside professional training,
and other forms of training. Training may be general, such as
training on the GLP regulations or highly specic, such as
training on the HPLC technique or even a specic HPLC
analytical method. Each individual engaged in the conduct of
(or responsible for supervision of) a nonclinical laboratory
study must be able to perform his or her assigned functions and
there must exist documented evidence of this. Personnel
assignments are provided on company job descriptions, which
are kept in the employees training le along with their
curriculum vita. Employee qualications are documented in the
employee training le as they develop. Training is the most
important means to achieving the goal of good science
conducted under GLP.

TEST ARTICLES, REAGENTS, AND SOLUTIONS

It is required that an area in the laboratory be designated and
clearly marked-o for the receipt of GLP samples (test articles
and control articles).10 Having this GLP-sample receiving area
reduces the chance that such samples will be confused with
other materials such as those past their expiration dates to be
disposed. Samples are typically logged in, using an assigned
laboratory sample identication number and inspected to
ensure that the sample meets the sample description (provided
on the chain-of-custody paperwork sent along with the sample)
and that the sample container is not damaged or awed. Entries
are made into the sample log indicating the date of receipt and
the proper storage conditions for the sample. Other
information such as the laboratory study identication number
(that connects this particular sample to a particular study), lot
number, and quantity of material received should be logged at
this time. Finally, the sample is placed into the proper storage
condition and made available to the analyst for testing.
For reagents and solutions, the regulations are clear: the label
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CHANGE CONTROL
Changes that may impact the quality and integrity of the GLP
program must be controlled in order for the company to
remain in compliance with the regulations. What this means is
that a proposed change should go through a review and
approval process, typically through lab management and the
QAU. The process will ensure that the change is desirable and
specically, that it either raises or leaves unaltered the level of
compliance.
Regarding the critical area of document change control, the
document revision must capture the justication for the
revision: for example, when an SOP is revised, the new version
is assigned a new document control number and an entry is
made on the change control page of the SOP that gives the
justication for the change. In this way, a history of changes
made to the document is recorded. The new version must
receive the same level of review and approval as the original.

The reader can obtain further understanding of the metrology

function simply by reviewing the titles to some of the key SOPs
that go into creating the program: these are given in Box 1.
Box 1. Key SOPs for a Lab Metrology Program
1. Master Plan for Instrument or Equipment Qualication
2. The Master Instrument or Equipment List
3. Use of Instrument or Equipment Numbers, Instrument
Labels, and Instrument Owners (Responsible Persons)
4. Creation and Use of Instrument or Equipment Logbooks
5. Installation Qualication of Instruments or Equipment
6. Instrument of Equipment Calibration, Maintenance,
Inspection, Cleaning, and Repair
7. Creation and Use of the Calibration Schedule
8. Calibration and Maintenance of Analytical Balances
9. Calibration and Maintenance of Temperature and
Humidity Sensors
10. Operational and Performance Qualication and Preventative Maintenance of Temperature-controlled Storage Areas
11. Instrument Change Control
12. Metrology Investigations
13. Calibration and Preventative Maintenance of Instrument
or Equipment by a Vendor
14. Calibration and Preventative Maintenance of Laboratory
Automatic Dishwashers
15. Calibration and Preventative Maintenance of Laboratory
Fume Hoods and Bio-Safety Cabinets

INVESTIGATIONS
It is the responsibility of the study director to ensure that
unforeseen circumstances that may aect the quality and
integrity of the non-clinical laboratory study are noted when
they occur, and corrective action is taken and documented13
and that all good laboratory practice regulations are
followed.14 Study directors and study director management
are informed of such circumstances through the QAU.15
Study director management will typically have a formal
procedure in place, described in an SOP that denes the
following: when to investigate, how to investigate, how to
document the investigation, getting proper approval of the
steps taken, and what to do with the results of the investigation.
Investigations are documented in the study raw data and this
is often done by making reference to the investigation report
(via its document control number). The investigation report is
a controlled-document, having a unique document number
assigned it by the QAU and containing a detailed summary of
how the investigation was conducted along with the results and
conclusions of the investigation, including any impact upon
other studies and it will reference the raw data (often simply by
referencing the document numbers of the lab workbooks and
lab notebooks involved). The following criteria are used to
judge the quality of the investigation: (i) Was it a scientic
investigation starting with a provable hypothesis and ending
with conclusions supported by the data? (ii) Do the results
from the investigation either justify invalidating previously
generated raw data or else, keeping the raw data as they
stand? (iii) Was the investigation documented well enough
that an independent, objective scientist can review it (years
later) and come to the same conclusions?

Equipment used for the generation, measurement, or assessment of data will be adequately qualied. An SOP should be
written on each instrument and piece of equipment in the GLP
program that provides the procedures for qualication,
maintenance (nonroutine, routine, and preventative), cleaning,
and inspection. Such an SOP may or may not include a
procedure for the use of the instrument or piece of equipment.
What professor Wilson said many years ago is still true today,
The whole purpose of all these recording systems is to
preserve values. They should be carefully thought out to t the
conditions of each laboratory and should be adequate but not
over elaborate. If too much is demanded of human nature, the
system will break down.12

DEVIATIONS
Once written procedures are in place, it is inevitable that
personnel will from time-to-time deviate from them. Such
deviations may or may not impact upon the quality and
integrity of the study. When they do, they are major and require
an investigation into what happened, the impact on the
quality and integrity of the study, and the consequences
(if any) to other studies. Investigations must be documented
in the raw data (i.e., the workbook or logbook at the
locations in the book indicative of the when the deviation
occurred) and reported to and approved by the study
director. The QAU will typically review and approve
deviation investigation reports. Requiring the QAU to
review and approve these reports aids them in logging,
tracking, and trending deviations so that the companys
continuous improvement plans can target the specic areas
drawing larger numbers or more severe deviations.

CORRECTIVE AND PREVENTATIVE ACTIONS

In the quality systems approach to lab management, it is
important to have a platform on which to stand where the lab
manager can view compliance issues and productivity issues,
separate from the individual studies and personnel that
generate them. From this viewpoint, trends come to light as
do the root causes for many of the issues. Although it is true
that each study director must deal with the issues of their own
studies, the lab manager must identify problem spots and
allocate resources to remediate these as well as issues that
extend across multiple studies. To facilitate this, the corrective
and preventative action (CAPA) quality system is created and
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used. The lab manager is responsible for logging and tracking

all issues requiring corrective and preventative action, for
assigning personnel the task of completing such actions, for
allocating appropriate resources for the completion of each on
an as needed basis, and for following each action to
completion. It is common to assign a number to each issue
and to use this number in the CAPA log. It is also common for
the QAU to assign these CAPA identication numbers, because
most of the CAPA issues are ndings that the QAU have
reported to management as part of their audit of either a GLP
study or a quality system. The CAPA log can be created in
such a way as to make it possible to sort or search the log
using key search parameters such as the study number, the
name of the analyst or study director, the nature of the issue,
for example, protocol deviation or instrument failure, the date
the issue was detected, and others. The QAU will perform
trending analysis using the CAPA log and report back to
management.

Article

REFERENCES

(1) Good Laboratory Practice (GLP) for Nonclinical Laboratory

Studies. Code of Federal Regulations, Part 58.41, Title 21, 1978.
(2) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.63, Title 21, 1978.
(3) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.81, Title 21, 1978.
(4) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.195, Title 21, 1978.
(5) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.83, Title 21, 1978.
(6) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.190, Title 21, 1978.
(7) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.35 (b), Title 21, 1978.
(8) Hilts, P. J. Protecting Americas Health; Alfred A. Knopf: New
York, NY, 2003; pp 210223.
(9) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.29, Title 21, 1978.
(10) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.47 (a), Title 21, 1978.
(11) Wilson, E. B., Jr. An Introduction to Scientic Research; Dover
Publications, Inc.: New York, NY, 1990; p 133.
(12) Wilson, E. B., Jr. An Introduction to Scientic Research; Dover
Publications, Inc.: New York, NY, 1990; p 134.
(13) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.33 (c), Title 21, 1978.
(14) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.33 (e), Title 21, 1978.
(15) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.35 (b), Title 21, 1978.
(16) Good Laboratory Practice (GLP) for Nonclinical Laboratory
Studies. Code of Federal Regulations, Part 58.35, Title 21, 1978.
(17) Warchut, Anthony C. Food and Drug Administration, personal
communication, Sept. 25, 2002.

THE DOCUMENT CONTROL UNIT

Controlling documents is necessary to ensure that proper
written instructions are transmitted to the laboratory as well as
for positioning the company such that it can accurately and
completely reconstruct any study for the sake of an audit. The
responsibility for achieving this level of compliance and
maintaining this quality system falls on the DCU.

THE QUALITY ASSURANCE UNIT

Management puts into place an independent quality assurance
unit (QAU), having responsibility for monitoring each and
every GLP study being conducted by the laboratory and for
reporting back to upper management and the study director
any and all ndings of noncompliances.16

CONCLUSION
A GLP study is one conducted in compliance with the GLP
regulations. It is an honest, complete, and well-documented
representation of experimental work that was designed to meet
a clear, specic purpose. The study is conducted by qualied
persons using qualied equipment and instrumentation
following veried or validated analytical methods and written
procedures included as part of a well thought out study
protocol. The study is conclusive, and if not conclusive or if the
study is invalidated, the reasons why are properly documented
and supported by the evidence. The GLP-compliant lab will
have those management mechanisms in place (such as a
document control system, a change control system, a metrology
program, and a quality assurance unit) that ensure all studies
can be done in compliance and that the lab does not, over time,
fall out of compliance. Such mechanisms will be constantly
monitored by an independent quality assurance unit to ensure
that each is functioning as intended. The single largest
challenge for the lab is in implementing those standard
operating procedures developed by the lab: as one FDA
investigator put it, that is where the rubber meets the road.17

AUTHOR INFORMATION

Corresponding Author

*E-mail: rwedlich@nsf.org.
Notes

The authors declare no competing nancial interest.

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dx.doi.org/10.1021/ed300256a | J. Chem. Educ. 2013, 90, 862865