GLP TOPICS
GLP Organization
and Personnel
BBS UNITED, ALEX HAYDEN/GETTY IMAGES
Cindy Green
“GLP Topics” addresses topics associated with good laboratory practice requirements.
We intend this column to be a useful resource for daily work applications. The key
objective for the column: Useful information.
Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Suggestions for future discussion topics or questions to be addressed are requested. Manuscripts or case studies submitted by readers illustrating
compliance strategy and planning are also most welcome. Please send your comments
and suggestions to column coordinator Cindy Green at [email protected] or to
coordinating editor Susan Haigney at [email protected].
ORGANIZATION OF THE TEST FACILITY
Management of test facilities engaged in the conduct of studies regulated under
good laboratory practice (GLP) (21 CFR 58) is required to clearly define the
organizational structure and responsibilities of the assigned personnel (1,
2). This includes, but is not limited to, the requirement to designate a study
director, establish a quality assurance unit (QAU), and ensure study personnel are knowledgeable and trained prior to initiating the GLP study. The use
of a current organization chart and job descriptions provides an immediate
mechanism for describing the test facility operations. Compliance history has
demonstrated that “without full management commitment and the formal
involvement of personnel, GLP systems lack credibility and will not function
as they should. Management and organizational systems therefore are a critical
element of setting up GLP in a laboratory (1).” Further details on the roles and
responsibilities of these individuals are provided in this article. The role of the
sponsor is also described.
PERSONNEL RESPONSIBILITIES
The following sections detail the GLP responsibilities of personnel.
Test Facility Management
Test facility management has the overall responsibility for implementation
of both good science and good organization, including compliance with
GLP. Good science can be defined as the accurate and complete definition of
experimental design and acceptance criteria, basing studies on sound scientific
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procedures, controlling and documenting experimental
variables, thorough evaluation of study results, and accurate conclusions based on scientific fact. Good organization can be defined as providing for adequate physical
facilities and qualified staff, appropriate identification and
assignment of staff, clear definition of the responsibilities
for study personnel, good recordkeeping, and compliance with GLP (1, 2).
During a US Food and Drug Administration audit,
FDA expects to see that the organizational structure
is appropriate to ensure that studies are conducted in
compliance with GLP regulations, and that management, study directors, study personnel, and sponsors
are satisfying their assigned responsibilities. In addition,
FDA expects to see objective evidence of involvement of
testing facility management in the operations at the testing facility (2) and adequate oversight by sponsors.
When the testing facility contracts work to other facilities, the oversight of those assigned responsibilities must
be clearly defined and evident on the organization chart.
Procedures should be in place describing the selection of
a study director. When selecting a study director, it is the
responsibility of testing facility management to be aware
of that person’s workload for both current and planned
studies. Using the master schedule, resource loading can
be effectively managed.
Test facility management should assure that the test
facility is compliant with applicable GLP regulations by
ensuring that the following are performed:
• Assignment of individuals to the study is documented
• A study director is assigned prior to initiating a study
• When required, a study director is replaced during the conduct of a study and the replacement is
documented
• A QAU is established, supported, and operates in
compliance with applicable regulations
• For multi-site studies, a principle investigator, if
necessary, is designated, qualified, properly trained,
and experienced to fulfill his responsibilities for the
assigned study and there are clear communication
lines between all study participants
• Standard operating procedures (SOPs) are established describing responsibilities and operation of
the test facility
• New and revised SOPs are adequately reviewed and
approved by testing facility management prior to
implementation, and historical versions are maintained by a designated individual
• The study protocols are reviewed and approved by
testing facility management and the study director;
the approval of the study protocol is documented;
and the study protocol is available to the QAU
• A master schedule is maintained and workloads
managed appropriately; the master schedule must
list all nonclinical studies conducted on FDA-regulated products intended to support an application for
a research or marketing permit
• Personnel, facilities, equipment, supplies, etc. are
available for timely execution of scheduled studies
• Facilities, equipment, and supplies meet requirements and are appropriate for their intended use
• There is a sufficient number of personnel assigned to
the study
• Appropriate technical training is provided
• Personnel are properly educated and trained for
study participation, including documented evidence that personnel understand the functions that
they have been asked to perform (i.e., evidence of
competency is required) and are made aware of any
special test and control article handling and storage
requirements
• Records of personnel qualifications, job descriptions,
training, and education are maintained
• Control and test articles are appropriately tested for
identity, strength, purity, stability, and uniformity
• Computerized systems are validated to demonstrate
they are suitable for their designated purpose and
are operated according to their validated use
• Deviations from GLP regulations are promptly communicated to the study director
• Corrective and preventive actions are taken when
and if deviations occur (2, 3).
Study Director
The study director plays a significant role in the conduct of GLP studies. The study director has the overall
responsibility for the conduct of the study and its final
report. The study director assumes full responsibility for
GLP compliance of all activities that take place during the
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GLP TOPICS
study and for activities that support the study including
the adequacy of the study protocol (4). At the end of the
study, the study director must evaluate the conduct of
the study and sign and date the statement that the study
was conducted in compliance with GLP regulations.
Therefore, the study director must be fully aware of the
activities that could potentially influence the quality and
integrity of the data, to evaluate their potential impact,
and determine appropriate corrective and preventive
actions (1, 5).
Some of the responsibilities assigned to the study director can be delegated; however, the ultimate responsibility remains with the study director. As the single point
of contact, the scientific, administrative, and regulatory
aspects of the study must be effectively overseen by the
study director (5).
During an FDA inspection, FDA will assess the extent
of the actual involvement and participation by the study
director. If the study director is physically at a different
location, communication files between the testing facility,
the QAU, and the study director must be available. Objective evidence must be available that demonstrates that
the study director is kept informed of any and all events
that may potentially impact the quality and integrity of
the data (2, 5).
The study director must ensure that procedures are in
place that assure the following:
• Protocol and amendments (if any) are reviewed and
approved with a dated signature
• The responsibilities of the principal investigator,
test facilities, and test sites for a multi-site study are
defined and documented
• Testing facility management has committed adequate resources to conduct the study and that test
materials and test systems are available
• Delegation of tasks to competent staff members is
documented
• Contract facilities are qualified and suitable for
conducting the parts of the GLP study contracted to
them
• The QAU has a copy of the study protocol and
amendments in a timely manner
• Communication between the study director and
the QAU are effective throughout the conduct of the
study
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• Study personnel have access to the protocol, amendments, and applicable SOPs
• All raw data generated are fully documented and
recorded
• Data are accurately recorded and verified
• Data are collected as specified by the protocol and
amendments and associated SOPs
• Computerized systems are suitable for their intended
use, validated, and are fit for use
• Personnel are familiar with and adhere to the study
protocol (and amendments) and applicable SOPs
• Unexpected events that may potentially impact
the quality and integrity of data are documented,
investigated, evaluated, and corrective/preventive
action assigned
• The final report is signed and dated indicating
responsibility for the validity of the data and the level
of compliance with GLPs
• Study protocol, raw data, related material, and final
report are archived at the close of the study with reference to the location for storage of documentation,
samples, and specimens
• If an acting or deputy study director is assigned
study responsibility, that study records identify the
individual assigned to this temporary role (2, 3, 5, 6).
Study Personnel
Each study must have an adequate number of qualified
personnel assigned to assure the study is conducted in
a timely and efficient manner. Study personnel include
specialists, such as pathologists, statisticians, etc. The
assignment of these individuals must be documented
in the final study report. Each individual assigned to
the study must have sufficient education, training, and
experience (or the combination thereof) to enable that
individual to perform their assigned tasks (6).
Study personnel must take the necessary precautions to minimize the potential of contaminating test
and control articles. In addition, personnel must
take steps to ensure their own sanitation and health
including precautions to minimize potential exposure to themselves or their co-workers to unforeseen
hazards (7).
Study personnel must dress appropriately including
the use of protective garments such as lab coats, gloves,
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and masks. The garments must be changed as necessary to minimize the potential risk of contamination of
test/control articles or personnel exposure to adverse
conditions or agents.
If an individual becomes aware of a health condition
that may potentially impact the quality or integrity of
the study, the individual has the responsibility to notify
the area supervisor and relieve him or herself from the
assigned responsibilities (3, 7).
Study personnel are responsible for the following:
• Being knowledgeable in GLPs that are applicable to
their assigned tasks
• Complying with the applicable GLPs, study protocol, applicable SOPs, and instructions from the study
director
• Reporting deviations from the study protocol and
associated SOPs to the study director
• Recording raw data promptly and accurately
• Recording data using established good documentation practices
• Taking necessary steps to minimize the potential of
contamination or mix-up of test and control articles
• Taking necessary precautions to minimize personal
health risk, risk to co-workers, and risk to the quality and integrity of study data (2, 3, 7).
Quality Assurance Unit
The QAU must be a separate function (i.e., independent
witness) from the study director and the studies that they
are assigned to audit (7). Top management must provide
support to the QAU and assure that the QAU has full access to all applicable documents and procedures. A QAU
individual may participate in a GLP study; however, that
same individual cannot perform QAU functions on the
study in which they participated (2, 6).
The individuals assigned to the QAU are not required
to be technical personnel; however, must be able to
clearly understand their assigned responsibilities. For
example, the QAU is not expected to perform a technical
review of study results; however, the QAU is expected to
ensure that GLPs, SOPs, and protocols are being followed
as approved and that the study results accurately reflect
the work completed (i.e., comparison between study results and raw data) (7). The QAU must review all phases
of the study.
The QAU is required to maintain copies of all protocols and amendments as well as all SOPs applicable to
QAU operations. In summary, the QAU is responsible
for the following:
• Protocol review for GLP compliance, clarity, and
completeness
• Maintaining copies of all protocols for which the
QAU is responsible
• SOP review to assure compliance with GLP, clarity,
and consistence with other SOPs
• Maintaining a copy of the master schedule of all
nonclinical studies indexed by test article and
identifying the test system, nature of the study, study
initiation date, current status, sponsor, and study
director
• Maintaining the QAU inspection and audit schedule
• Conducting inspections and audits (e.g., studybased, facility/system-based, process-based, and
audits of contractors and suppliers) at appropriate
intervals to assure study integrity and to assure that
the study is being conducted consistent with the
approved protocol and applicable SOPs
• Maintaining records of the inspections performed
including the date of the inspection, study inspected,
phase of the study inspected, findings, action recommended and taken to resolve issues, and scheduled
date for re-inspection, if required
• Notifying the study director of any findings during
an inspection that may potentially impact the quality
or integrity of the study
• Periodically submitting a study status report to management and the study director noting any problems
observed
• Reviewing the final study report to assure that the
report accurately reflects the methods and materials
used and the study conducted; and that the conclusions are supported by the raw data and the reported
results of the study
• Preparing a QAU statement for inclusion in the final
study report that states that the QAU conducted inspections during the study and includes the interval
or point of the inspection, the date(s) conducted, and
the results of the inspection
• Assuring that SOPs describe the roles and responsibilities of the QAU (2, 3, 4, 6, 7).
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GLP TOPICS
The inspections that are conducted for study-based
audits are pre-planned and performed at key points
during the study. To assure that the study-based audit
is effective, it is important for the QAU to communicate
with study personnel. Prior to the inspection, the assigned individual must become familiar with the study
protocol as well as the applicable SOPs. Familiarity
with the SOPs is especially important to assure that
all relevant policies are followed with respect to entry
to the area, gowning practices, and safety regulations.
The individual conducting the inspection must not
negatively impact the study for the sake of conducting
the inspection. Sufficient time must be allowed for the
inspection to ensure that the inspection is complete and
covers the key steps identified for the inspection. At the
completion of the inspection, the assigned individual
is responsible for preparing and issuing a factual report
of the findings. The process used for the conduct of
the inspection and preparation of the report must be
described in SOPs (3, 4).
The inspections that are conducted for system or
facility-based audits are performed independently of any
particular study. These audits are conducted for the test
facility management rather than the study director. The
following areas are typically covered during a system or
facility-based audit:
• Study personnel qualification and training
• Recordkeeping
• Receipt and handling of test systems
• Facility cleaning
• Waste handling and waste flow
• Personnel hygiene, gowning, and flow
• Equipment maintenance and calibration
• Animal food handling
• Purchasing controls
• Computerized systems
• Test and control article identification and storage
• Controlled drug receipt, handling, and disposition
• Material receipt, handling, and labeling
• SOP initiation, revision, and control
• Archiving of records, test/control articles, and
specimens (1, 4).
Process-based inspections are also conducted independent of a specific study and are intended to review
procedures or processes that are repeated frequently by
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the testing facility. For example, process-based inspections may be assigned for the following:
• Receipt of test and control articles
• Controlled drug accountability
• Archiving of records
• Personnel training records
• Equipment calibration (1).
The QAU is also responsible for conducting audits
of contractors and suppliers. Typically, these audits are
performed at external test facilities such as those used
for specialized testing of specimens, metrology laboratories, etc. Major suppliers should also be audited such as
the suppliers of animals and feed (1, 4).
Sponsor
A sponsor is defined in 21 CFR 58.3 as “A person
who initiates and supports, by provision of financial
or other resources, a nonclinical laboratory study;
person who submits a nonclinical study to the Food
and Drug Administration in support of an application
for a research or marketing permit; or testing facility, if
it both initiates and actually conducts that study (8).”
A sponsor typically is the party that initiates the GLP
study and submits the result of the study to the regulatory authorities. Based on these activities, the sponsor assumes the responsibility for confirming that all
nonclinical studies were conducted in compliance with
GLP. Therefore, it is the responsibility of the sponsor
to assure there is adequate oversight of the GLP study
including the identification, selection, qualification,
and monitoring of the testing facility operations. This
responsibility includes the validity of raw data and
conclusions summarized in the test report prepared by
the contract facility (8).
The responsibilities of the sponsor are to assure the
following:
• Understanding of GLP and those sections applicable to the test facility operations, by the assigned
study director and designated study personnel
• The test facility selected is qualified and capable of
conducting the study in compliance with GLP
• Prompt and complete disclosure of any known or
potential hazards (e.g., environmental, human, or
animal health) associated with the test article
• Adequate characterization of test articles
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• The content of the study protocol is compliant with
GLP requirements
• Review and approval of the study protocol
• The content of the test report is compliant with GLP
requirements and accurately reflects the conclusions
from the raw data
• Review and approval of the test report
• Submission of the study results to the regulatory
authorities
• Storage and retention of study records and material
when it is necessary for the testing facility to transfer
these materials (8).
Personnel Training
A training program must be in place to assure that there
is documentation of training in all aspects of the GLP
study. This training program must also assure that the
study director is adequately trained and has a thorough
understanding in all aspects of the planned study, including the scientific and regulatory aspects. A current summary of training, experience, and job description must
be on file for all personnel. Personnel assigned to the
study must have a thorough understanding of GLP, applicable regulatory requirements, and the study protocol,
as well as all applicable SOPs (1).
A record of all training applicable to GLP studies
should be maintained in documented training records,
including but not limited to the following:
• Work experience under the supervision of senior staff
• Scientific and technical meetings
• In-house training sessions
• External conferences, seminars, courses, etc.
• Membership in professional societies
• On-line training
• Webinars
• Self-taught training (e.g., reading to understand GLP
topics) (6).
Personal development should be continuously monitored. Additional training or retraining may be necessary, for example, when policies and procedures change
or if deviations to the protocol occur.
Documentation of the training program, training
conducted or completed, and effectiveness of the training should be available for all personnel assigned to the
study (1).
REFERENCES
1. UNDP/World Bank/WHO Special Programme for Research and
Training in Tropical Diseases (TDR), Handbook on Good Laboratory
Practice (GLP), based on proceedings 1999-2000.
2. Compliance Program Guidance Manual, Good Laboratory Practice
(Nonclinical Laboratories), CPGM 7348.808, implemented February 21, 2001.
3. 21 CFR 58.29, 58.31, 58.33, 58.35.
4. Organization for Economic Co-Operation and Development
(OECD), OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring: Number 4, “Quality Assurance and GLP,”
ENV/JM/MONO(99)20, October 26, 1999.
5. OECD, OECD Series on Principles of Good Laboratory Practice
and Compliance Monitoring: Number 8 (Revised), “The Role and
Responsibilities of the Study Director in GLP Studies,” ENV/JM/
MONO(99)24, September 15, 1999.
6. FDA, Good Laboratory Practice Regulations, GLP Questions and
Answers, 1981.
7. OECD, OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring: Number 1, “OECD Principles on Good
Laboratory Practice (as revised in 1997),” ENV/MC/CHEM(98)17,
January 26, 1998.
8. OECD, OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring: Number 11, “Advisory Document on the
Panel on Good Laboratory Practice. The Role and Responsibilities of the Sponsor in the Application of the Principles of GLP,”
ENV/MC/CHEM(98)16; January 22, 1998. GXP
ARTICLE ACRONYM LISTING
FDA
GLP
QAU
SOPs
US Food and Drug Administration
Good Laboratory Practice
Quality Assurance Unit
Standard Operating Procedures
ABOUT THE AUTHOR
Cindy Green, RAC, has been working with regulated industry for
nearly 35 years holding senior positions in regulatory, quality assurance, and quality control for several biotechnology and medical device
companies. She has been president of her own consulting company
for the past 16 years. Cindy can be reached by e-mail at cindynwrs@
seanet.com.
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