Implementation of Good Laboratory

Practice in a University Research Unit

Xavier Abad1,*, Albert Bosch1 and Carme Navarro2
1

Enteric Virus Laboratory, Microbiology Department, School of Biology, University of Barcelona, Av.
Diagonal, 645, 08028 Barcelona, Spain
2
Quality Assurance Unit, Scientific-Technical Services, University of Barcelona, C. Josep Samitier, 1-5,
08028 Barcelona, Spain

Summary
This article describes our experience in the implementation of Good Laboratory
Practice (GLP) in a research group of the Department of Microbiology in the
University of Barcelona (UB). Some issues relating to quality assurance in a research
laboratory setting are reviewed, and several comments and suggestions arise from
our experience in setting up GLP. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: GLP; Good Laboratory Practice; enteric viruses; virus safety; virus removal; inactivation

Introduction
The Enteric Virus Laboratory (EVL) at the
University of Barcelona has been conducting
research on environmental virology since 1978,
with particular attention to hepatitis A virus,
rotaviruses and astroviruses, but also to other
enteric viruses. One of our research areas is the
study of viral inactivation and removal, and its
mechanisms, and how to eliminate viruses from
water, fomites, foods and other environments.
We are also pursuing several other research
areas, including molecular studies on hepatitis A
virus, molecular epidemiology of rotaviruses
and astroviruses, etc. All of these have been
performed by two professors, some technical
personnel and several PhD students; as a
consequence more than one hundred international publications and hundreds of communications to international congresses and
workshops have been produced. As our reputa*Correspondence to: F. X. Abad, Enteric Virus Laboratory, Microbiology Department, School of Biology,
University of Barcelona, Av. Diagonal, 645, 08028
Barcelona, Spain. E-mail: xavier.abad@ub.edu
Copyright r 2005 John Wiley & Sons, Ltd.

tion in the field of viral inactivation grew,

several private companies, forced by regulations
to certify the capability of their processes for the
inactivation or removal of viruses, contacted us
with requests to validate their methods for viral
elimination. The evaluations needed to be
conducted in compliance with Good Laboratory
Practice (GLP) principles.
This article describes our experience in
implementing GLP in our own Viral Validation
Unit (VVU) within the EVL. This implementation achieved GLP compliance certification in
2001. An historical outline of this implementation is shown in Table 1.

Objectives
Our goals were to provide reliable, high quality
analytical data to support the research and
development efforts of our industrial sponsors.
GLP are the recognized rules governing the
conduct of non-clinical safety studies. They
ensure the quality, integrity and reliability of
the study data; they reduce the likelihood that
Qual Assur J 2005; 9, 304311.
DOI: 10.1002/qaj.352

Implementation of GLP in a University Research Unit

Table 1. History of GLP Implementation in

the EVL
Year

Activity

1996

Writing SOPs for the most frequent

experimental procedures and apparatus
Implementation of study inspections from
the QAU
First Facilities Inspection from the QAU
Move to facilities in a new research building
Settlement of final EVL personnel
organizational chart and decision flow
diagram
Achievement of GLP certification
Most recent renewal of GLP compliance

1998
1998
2000
2000

2001
2003

our industrial sponsors will need to spend

money on repeating any stage of these experiments and they provide the basis for a good
working relationship with our sponsors. We also
recognized that achieving GLP status, regardless
of its workload, would be of benefit to our own
research, for example developing standard
operating procedures (SOPs), development of
standard controls, and instrument calibration.

Organization
All organizations have their own natural
quality systems, though often they are informal
systems which do not follow a specific standard
(e.g. GLP). As such, some of the road has
already been traveled in any organization prior
to any decision to implement GLP. To benefit
from the collective experience in the EVL, our
first activity was to identify and formalize the
elements of our expertise and then to focus on
how best they could be used to meet the goals of
our industrial sponsors.
Research is a continuously evolving process
aimed at discovering new facts. By its own
nature, the research work of PhD students is
subjected to changes in direction in response to
new and often unexpected results. In fact, the
end-result of research may be unrelated to the
initial aims of a research project. Moreover, in
our field, short-term contracts are common
practice leading to high staff turnover. Whilst
this can bring vigor to a research group, it can
Copyright r 2005 John Wiley & Sons, Ltd.

305

also detract from establishing the mechanisms

that ensure consistency and reliability of data
over the long term.
For these reasons, and because quality assurance (QA) can be more readily implemented in
research and development than in basic research
[1], we decided to create a VVU, within the
EVL, specialized in methods and techniques for
external sponsors, eventually leading to a
routine research activity, in our case virus
validation studies with its own regulations to
become GLP compliant [26]. The advantage of
designating a separate study unit is that it could
respond to the demands of our industrial
sponsors, and at the same time not detract from
the atmosphere of flexibility and freedom in
other areas of basic research in our laboratory.
The organization of the VVU within the EVL
is described in Figure 1. Firstly, a Head of
Laboratory (HL) (the vertex of the pyramid) was
appointed, who would be ultimately responsible
for implementation of GLP. Secondly, two Study
Directors (SD) were appointed, contracted as
full-time university staff, and highly skilled in
virology. At the initiation of each study, a SD is
assigned and this person takes responsibility for
GLP compliance, being the point of contact for
VVU staff on that study and for the external
collaborator. The usual tasks of a SD are:
*

Generate a study protocol in response to a

request from an outside sponsor.
Assume responsibility for the overall conduct
of the study, particularly all decisions that
may affect the integrity of the study.
Generate the final report that is sent to the
study sponsor.

In addition to these normal duties, one SD was

also designated by the HL as the GLP coordinator, to be responsible for implementing the
principles of GLP and for compliance within
VVU. The tasks of this GLP coordinator are:
*

Generate accurate job descriptions, and a

clear delineation of the decision flow path.
Write SOPs concerning the use of apparatus,
sub culturing of cell lines, production of viral
stocks, etc.
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X Abad et al.

306

QUALITY ASSURANCE
UNIT (QAU)

HEAD OF LABORATORY

Head of QAU
and other personnel
Function: to audit viral
validation studies and
control compliance of GLP
principles

VIRAL VALIDATION UNIT

RESEARCHS UNITS
Research staff, Pre- and
Post-doctoral students
Function: Basic research and
development of techniques

Study directors
Other personnel
Function: to develop and
conduct GLP-compliant viral
validation studies

TECHNICAL STAFF
Function: supply media and reagents for research units and for
viral validation unit.

Figure 1. Organizational chart of the EVL

Create data systems to record the arrival,

maintenance, use and destruction of cell lines
and viral strains.

We also needed a system for independent

evaluation of all activities within the VVU. This
was achieved by setting up a QAU that serves
the entire University, and is located within the
Scientific Technical Services. The QAU personnel are highly experienced in implementing GLP
and ISO standards, are not funded by our group,
and operate under a different hierarchical chain.
The QAU personnel carry out the following
activities:
*

Verify protocols in order to assure their

compliance with GLP principles.
Conduct inspections of facilities and studies,
and report their results to the SD and HL.
Audit final reports, prepare and sign a quality
assurance statement.

In addition to day-to-day training given by SDs,

all staff within the EVL (whether associated
with the VVU or not) receive at least one day a
year of GLP training given by the QAU.
Copyright r 2005 John Wiley & Sons, Ltd.

Training records for all personnel are maintained by QAU.

Facilities
The test facilities occupy nearly 40 square
meters. Additionally, an independent room for
performing validation experiments is available
when complex procedures or special environmental conditions (temperature) require a second area. Samples are received and processed in
a clean area well-segregated from the validation
room. This area is provided with several airflow
cabinets and a biohazard cabinet. Separate areas
have been designated for the maintenance of
uninfected cell lines used to test and grow the
viruses, and for the viruses themselves with
infected cell lines (virus/cells couple, also called
experimental systems). All of these precautions
ensure a proper degree of separation of the
different activities in each study and help
prevent contamination and mix-ups upon receipt, testing and storage of materials. A
transient archive facility has been set up within
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Implementation of GLP in a University Research Unit

the EVL for the safe storage and retrieval of

study protocols, raw data notebooks, sponsor
and SD communications, and final reports. The
ultimate destination of these records is the
storage facilities in the QAU. Waste collection,
storage and disposal have been designed in such
a way as not to jeopardize the integrity of the
studies nor the health and safety of other staff in
the Department of Microbiology. All biological
systems, infected or not, are autoclaved at the
appropriate temperature and time period.

Apparatus, Material, and Reagents

The apparatus used in the studies are periodically inspected, cleaned, maintained, and calibrated according to internal SOPs. Records of
all these activities are maintained and transferred after each test facility inspection to QAU.
All chemicals, reagents and solutions (PBS,
trypsin solutions, etc.) are labeled to indicate
identity (with concentration if appropriate),
expiration date and specific storage instructions.
Additional information is available for each
reagent and solution as a separate written record
describing the source (suppliers, batch identification), preparation date, person in charge and
stability.

Biological Experimental Systems (also

called test systems in the OECD GLP
Principles [7])
For some authors [8] GLP standards define the
test system as any animal, plant, microorganism, or subparts thereof to which the test or
control item is administered or added for study.
By this definition, some authors [9] consider the
best technical analogy to label as test system the
scaled-down manufacturing process and the
product intermediate as the test article. Our
aim is to measure the efficacy of viral elimination or decay in a manufacturing process. We
have defined the test item as both the intermediate from a manufacturing process, and/or
the actual step, scaled down from the manufacturing process, that is intended to remove
Copyright r 2005 John Wiley & Sons, Ltd.

307

viruses. The test system is the couple virus plus

cell line that responds to the test item with a
change in viral titer (Figures 2(a) and 2(b)).
By its very nature, the use of a binomial test
system with two biological components is
potentially subject to high variability from study
to study. Therefore, we perform robustness
assays for each experimental (test) system to
ensure that changes in post-infection media
composition, adsorption time, age of host cells,
or differences in cells passage number have not
affected final viral titer. Records of source, date
and condition of arrival of experimental test
systems (viral strains and cell lines) have been
maintained since 1994.
All information needed to properly identify
the test systems appears on their container
(usually plastic micro plate or flasks): cell line
name, growth medium, date of subculture,
and operator are noted for non-infected cell
lines. Infected cell lines are additionally
noted with virus strain, sample code, assayed
dilutions, protocol code, and operator. Containers are of single-use, consequently when data
(virus titers) are recorded all these materials
(both infected and non-infected) are destroyed
by autoclaving at appropriate temperature and
time period.

Test and Reference Items

Upon receipt of the test item, records are started
which note the sample characteristics, date of
receipt, expiration date, recipient, and quantities. A sample is taken to verify that sample
characteristics match those reported to us; and
appropriate records are kept (date of extraction,
quantity withdrawn, remaining weight, study
code, and responsible person) each time a
sample is withdrawn. Storage containers carry
identification information, expiration date, and
specific storage instructions. According to GLP
regulations (No. 1 Series OECD [7]), each test
item has to be properly identified with code
number, chemical abstracts service registry
number, name, and biological parameters. In
many viral validation studies, however, this
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308

X Abad et al.

Figure 2. (a) Typical relationship between test system and test item; and (b) relationship
between test system and test item in viral validation studies. If characteristics of product
intermediate or critical parameters of manufacturing steps are changed, the viral persistence
could change, too. So, new validation studies should be performed. *The viral suspension
alone cannot be the test system since we need a cell line for replication of the virus in order
to evaluate its infectious titer. It is the combination of virus strain and susceptible cell line
that form the test system (or experimental system). Moreover, results differ using same virus
strain and several susceptible cell lines, or using quite similar viral strain and the same
susceptible cell line.

detailed characterization is impossible, as we

work with intermediates produced from industrial processes with only a few biologically or
chemically defined parameters. Moreover, not
only the intermediate, but also the inactivation
step itself can be considered as test items, if we
take into account than we are evaluating the
Copyright r 2005 John Wiley & Sons, Ltd.

response of an experimental system to a defined

inactivation treatment, when diluted in a matrix
(intermediate) (Figures 2(a) and 2(b)). We
require sponsors to provide the identity, batch
number, composition data, concentrations, and
other defined characteristics appropriate to
define each batch of test item.
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Implementation of GLP in a University Research Unit

Standard Operating Procedures

SOPs provide documentation of all routine
experiments. Strict adherence to the SOPs
ensures the quality and integrity of data
generated, and allows comparison of results
from different experiments. In our test facilities
more than one hundred SOPs (from use of
apparatus to experimental processes) have been
written and subsequently approved by the Head
of Laboratory. SOPs are reviewed once every
two years, with up to two revisions, or a period
no longer than six years before a new SOP must
be generated and approved. QAU personnel
coordinate all revisions, distribute copies, and
retain originals. All original operation manuals
that may be used as supplements to SOPs are
filed in a single place inside the laboratory to
make consultation easy. Any deviation from an
SOP is documented in each study notebook and
acknowledged by the SD, who evaluates the
necessity and impact of these deviations in
relation to the whole study. Our SOPs cover
the following main areas:
1.

2.

3.

4.

5.

Test items, reference items and starting

materials: Receipt, identification, labeling,
handling, and storage.
Apparatus, materials and reagents: Use,
maintenance, cleaning and calibration of
apparatus; and preparation and labeling of
reagents and solutions.
Record keeping: Reports, storage and
retrieval, coding of studies, data collection,
indexing systems, and handling of data.
Experimental test system (cell lines and viral
strains): Procedures for receipt, proper
placement, characterization, identification,
care, preparation for a study, and handling
of infected systems during the study.
SOPs in groups 14 were written and
reviewed by EVL personnel and approved
by HL. In addition we comply with SOPs
written and approved by QAA personnel
detailing.
Quality assurance procedures: Planning,
scheduling, performing, documenting and
reporting inspections by QAU personnel.

Copyright r 2005 John Wiley & Sons, Ltd.

309

All SOPs are distributed by the head of the QAU.

Performance of the Study

The study protocol is the key document of a
GLP study [10] since it describes the study that
is to take place. For each study, the SD prepares
a draft protocol and sends it to the study
sponsor for comments. On return, the protocol
is revised and sent to QAU for verification of
GLP compliance. The final version of the
protocol is approved, by dated signature by the
SD and HL, verified for GLP compliance and
signed by QAU personnel, and accepted by
sponsor. Standard study protocol format is
followed, according to GLP regulations [7] and
the EURACHEM CITAC guide [11], and a final
addendum of scientific and technical references
and SOPs is included. After signing the protocol,
any amendments are justified and approved by
the SD, HL and study sponsors, and signed and
dated by the SD. Deviations from the protocol
during a study are described, explained, acknowledged and dated by the SD whose
responsibility it is to evaluate the impact of the
change on the integrity of the study. All
deviations are also noted in the study raw data
notebook and included in the final report.
Besides the protocol, a strictly defined plan is
distributed to QAU, HL and sponsor, indicating
dates and hours of each experiment, with special
attention to the critical steps of the process.
We tend to receive two types of study
proposals relating the evaluation of efficacy of
particular steps in removal or inactivation of
viruses from an industrial manufacturing process, or to ascertain the antiviral capacity of a
defined formulation:
1.

The sponsor who is interested in evaluation

of virucidal capability of a step in the
production process, performs test runs of
their manufacturing process using their
own personnel, materials and apparatus.
In this case, since the sponsor personnel
performs the whole scale down industrial
process, only sample analysis is within the
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X Abad et al.

310

2.

framework of the GLP compliant facilities

at EVL.
The sponsor requests a study of the antiviral capacity of a defined formulation, and
the inactivation assays as well as the
analyses are performed by EVL personnel.
In which case, all processes are under GLP
compliance at the EVL.

Reporting of study results

The SD prepares a final report containing the
results and interpretation of raw data from the
study notebooks. A draft report is sent to the
sponsor for comments. After the addition of any
relevant comments, a final draft is sent to QAU
for auditing along with all other records and
study notebooks. The final version of the report
includes the statement of GLP compliance from
the SD and the QAU statement, which list the
inspections performed and their dates.

Archive of documentation
The archive is located in the QAU facilities; it
contains all the original documents relating to
the studies performed by EVL under GLP
principles, including study notebooks and other
raw data. Access to the archive is restricted to
personnel authorized by the HL, and documents
cannot be taken out the archive without the
permission of the sponsor.

Discussion and Conclusions

Setting up a GLP system implies long-term
commitment, not only by management, but also
(and more importantly) by every staff member in
the laboratory. A process that starts with the
main goal of obtaining a compliance declaration
or certification, rather than achieving real
quality improvement, will be poorly accepted
and certainly misunderstood by technical and
scientific staff [10]. In our case, we feel that our
GLP implementation has been successful for
several reasons: probably the most important
was that the system was developed bottomup
Copyright r 2005 John Wiley & Sons, Ltd.

involving staff at all levels, rather than the top

down approach of managerial imposition [12].
Secondly, it is the good science and technical
competence of staff within the EVL and QAU,
hand-in-hand with GLP principles, which
brought us to achieve compliance [10,13]. GLP
principles mainly apply to the formal aspects of
a study (planning, performance and record
keeping) and do not evaluate the technical
competence of the study staff [10]. In fact, it
was this technical competence that led our study
sponsors to contact the EVL in the first place,
and this remained the defining quality as we
sought to apply GLP in the laboratory. This
same principle was elegantly stated by Dent
[13]; application of basic common sense and
good science can bring us to find that we
achieved compliance.
A third factor in our favor was the small size
of our group and well-defined management
structure that allowed us to overcome some of
the GLP implementation challenges that can
prevail in universities [1,14].
Some challenges remain. Now that we have
established GLP to comply with the requirements of our sponsors, we find that the
principles of GLP are bringing benefit to other
areas of research in the laboratory. Our most
important challenge now is how to enhance our
non-GLP activities with the best of the GLP
principles. An obvious benefit that we have seen
is that common experimental controls have been
established, and laboratory instruments are
maintained to a high working standard. A
second benefit is that the GLP-compliant SOPs
allow us to perform all research activities (GLP
and non-GLP) under their scope in the same
way. This brings us closer to ensuring reproducibility within our laboratory, and they have
become an excellent training tool for laboratory
workers. A third benefit that we have begun to
see is that the principle of rigorous documentation in a more formalized manner results in good
record keeping amongst all the students in the
laboratory. Notebook keeping is so often at the
whim of the individual and lacks uniformity, but
this benefit of the GLP principles is seen by
everybody.
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Implementation of GLP in a University Research Unit

Our next challenge is to develop a wider and

deeper quality assurance system that will take
into account good scientific and technical performance. This is not an unrealistic desire, but
almost an obligation. In the same way as
productive and service industries and public
authorities take the principle of total quality
management seriously, subcontractors such as
university laboratories should also follow these
principles. Although it is widely accepted that
excellence in research is mostly located in
universities and research institutes, in our opinion
excellence can no longer be simply based on
reputation and promises, but on a well defined
quality system, preferably certified or accredited.
This system needs to be simple and flexible, to
provide added value to the organization, and its
implementation should not be considered as an
end, but as a means to achieve higher technical
standards within the setting of the laboratory
research. In the near future, there may be no
other alternative than to adopt some kind of
quality assessment system, mainly due to external
pressures from industrial contractors or public
authorities. GLP principles are probably the most
useful way to begin to fulfill this requirement.

311

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CPMP/ICH/295/95.

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Evaluation of Biotechnology Products Derived
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6. EMEA. CPMP/QWP/848/96. Note for Guidance on
Process Validation. London, 2001.
7. OECD. OECD Principles of Good Laboratory Practice.
OECD Environmental Health and Safety Publications: Series on Principles of GLP and Compliance
Monitoring. No. 1. OECD: Paris, 1998.
8. Korneyeva M, Rothensal S, Trukawinski S, Li H, Hotta
J, Remington K, Franks L, Pifat D, Petteway Jr SR,
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