Professional Documents
Culture Documents
Validation For GLP
Validation For GLP
Perspectives - Minireview
Practice Institutes
Validation specifies and coordinates all relevant activities to ensure compliance with good laboratory
practices (GLP) according to suitable international standards. This includes validation activities of
past, present and future for the best possible actions to ensure the integrity of non-clinical labora-
tory data. Recently, validation has become increasingly important, not only in good manufacturing
practice (GMP) institutions but also in GLP facilities. In accordance with the guideline for GLP regu-
lations, all equipments used to generate, measure, or assess data should undergo validation to
ensure that this equipment is of appropriate design and capacity and that it will consistently func-
tion as intended. Therefore, the implantation of validation processes is considered to be an essen-
tial step in a global institution. This review describes the procedures and documentations required
for validation of GLP. It introduces basic elements such as the validation master plan, risk assess-
ment, gap analysis, design qualification, installation qualification, operational qualification, perfor-
mance qualification, calibration, traceability, and revalidation.
Key words: Good laboratory practice, Validation, Qualification, Calibration
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2 K.-H. Cho et al.
792.81 OECD sections II 7.4 and II. and KFDA 7.5(2) surement criteria; (c) Computer systems validation veri-
state that facility inspection, cleaning, maintenance, fies the logic of computer programs as well as the
testing (validation), calibration, and standardization of secure management and storage of documents; (d)
equipment should occur and that appropriate remedial Cleaning validation is performed to prevent cross con-
action should be taken in the event of equipment fail- tamination; (e) Manufacture utilities system validation
ure or malfunction (EPA, 1989; OECD, 1997; US FDA, verifies the management system that controls air and
2003; KFDA, 2005; Weinberg, 2007; Yoshihito, 1985; water for injection, process management, monitoring,
Yu et al., 1999, 2000). According to the last revision of and common appliances; (f) Equipment validation ensures
Korea Good Laboratory Practice interpretation text, that equipment made by a manufacture is working
computer systems that contain measuring devices and according to its intended use and role (Gibson and
control the environment and disinfection of animal Powell-Evans, 1998; KPTA, 2000; EU 2003).
cages, racks, and accessories should be checked for Validation can also be classified by timing: (a) Pro-
integrity and reproducibility of results (KFDA, 2008). spective validation is the preliminary inspection of risk
Whereas validation is internationally required to ver- factors of a process with the percentage integrity of
ify the result of non-clinical laboratory study data, which each item to measure; (b) Concurrent validation deals
can influence people's health, validation execution of with a specific condition, such as process transfer or
GLP laboratory institutions are not sufficient in most of defined process; (c) Revalidation is gauged within state
Korea. In this review, the basic techniques for consis- interval or basic period, or quality deterioration of
tent, smooth validation are discussed. equipment; (d) Retrospective validation is demonstrated
after pharmaceutical product has reached the market;
APPROACH METHODOLOGY (e) Change control is performed to prevent machine
deterioration, part change that can affect results and
Classification and personnel. Validation is classi- measurements are changed if they deviate from nor-
fied according to the working process: (a) Process vali- mal (FDA, 1987; KPTA, 2000).
dation guarantees a reproducible process to follow a Generally, the facility for non-clinical laboratory stud-
pre-specified rule for suitable and documented results; ies has a validation structure similar to that shown in
(b) Method validation verifies that any errors (devia- Fig. 1. This structure includes the validation commit-
tions) in the analytical method for a given product (e.g., tee, validation manager, validation specialist (or valida-
a pharmaceutical product) do not exceed a set mea- tion study director), equipment, and the qualification
Fig. 1. The Team and Working Party Structure (Modified from Gibson and Powell-Evans, 1998).
Basic Principles of the Validation for Good Laboratory Practice Institutes 3
quality assurance unit, validation team, utility team, checked, errors are measured, and potential risk fac-
computational statistics teams) are defined in this plan tors are determined. Third, business risks are identi-
(LabComplience, 2004; Bridges, 2005). fied such as increase of repair charge, economic high
In addition, the following items are included in valida- possession and lack of data credit. Fourth, the
tion master plan: the floor plans for the building, the expected risks are assessed. Fifth, it is evaluated that
movement line for the building, the constitution for the the severity of a risk is influenced on regulatory compli-
utilities, local area network, air handling unit, water sup- ance and reputation. Sixth, the probability of detection
ply, sewage, validation overview, qualification content is assessed, including how to find risks more quickly
overview, set measure item, list of all equipment, evalu- and how to decrease their influence. For example, the
ation of characterization, development of user specifica- expectation and severity of risk impact can be used to
tion, equipment purchase system, vendor list, selection determine the level of danger. The assigned risk classi-
tool, risk analysis, gap analysis, documentation, rescue fication and probability of detection can be used to
of equipment, and references (WHO, 1996; Gibson and classify the magnitude of danger (Yu, 2004). After the
Powell-Evans, 1998; Haider, 2002a; LabComplience, strategy for risk reduction is set up according to the
2004; Bridges, 2005; KFDA, 2008). After the validation performance step of risk analysis, the validation study
master plan is reviewed and approved by the manage- director must apply this strategy to reduce risk.
ment or validation committee, a validation is carried out Gap analysis: The gap analysis contains a brief out-
under the direction of the validation study director. line, observes GLP regulatory requirements, and is con-
Risk analysis: The purpose of risk analysis is to venient for the process and validation strategy. It has the
find risk factors in advance and to reduce or eliminate management of qualification execution plan, and makes
the factors that may affect a test result. The goal of risk a lot of facility maintenance validity (Bridges, 2005).
analysis is to evaluate the factors on a scientific basis Gap analysis includes the role or responsibility of rel-
which include the requirements of regulatory adminis- evant personnel, feature of equipment to be evalu-
trations, integrity of the data, and GLP guidelines for ated, the model number, serial manufacture number,
beginning new studies, purchasing new equipment, serial asset number, using purpose, location, docu-
writing user requirement specifications, performing ven- ment or SOP, number, equipment logs, date of last cali-
dor audits, evaluating functional requirement specifica- bration, personnel training records, a validation certificate,
tions, and performing change control. Although the system controls, data storage methods, risk type, the
items to be tested are the same, if the object of analy- level of the responsible person, and validation special-
sis is different, it is a fundamental rule that the analy- ist (validation study director) (Bridges, 2005).
sis must be repeated for each object (Haider, 2002a; Gap analysis offers the easy and convenient informa-
Yu, 2004; Bridges, 2005; Brockmeyer, 2006). tion for the validation process. The validation study
The risk analysis documents describe the role and director needs to cooperate with the manufacture or
responsibility of staff or department and the methods to vendor, and to notify any peculiarity of the facility to
process. The process of risk analysis is as follows. them. The document for gap analysis is similar to
First, process identification is preformed, in which all those shown in Table 1.
systems are grouped by skill and equipment. Second, Design qualification: Design qualification is per-
all GLP risks are identified. The integrity of results is formed for design of equipment, evaluation of quality,
quality and confidence level of manufacturer, and using and processes follow design specification. The pro-
purpose of validation specialist (or validation study cess of installation qualification checks that the acquisi-
director) for compatibility decision and equipment selec- tion, equipment, and accessories follow the purchase
tion. The process of design qualification is as follows. specifications. The validation specialist must also check
First, simple specifications are documented prior to the the installation environmental conditions (e.g., clean
purchase of equipments. Second, the manufacturer or room requirements, temperature, and humidity) with the
vendor to supply equipments, which meet the user’s manufacture (Bedson and Sargent, 1996; Gibson and
specifications and functional requirements, should be Powell-Evans, 1998; EU, 2003; PIC/S, 2003; KFDA,
selected. Third, the user’s requirement specifications 2008).
are presented and checked (Bedson and Sargent, After the validation specialist receives equipment,
1996; Gibson and Powell-Evans, 1998; EU, 2003; PIC/ hardware, software, accessory and spare parts, he or
S, 2003; KDFA, 2008). she must check with the manufacture that they meet
Functional requirements, which the manufacturer or the purchase specifications. The validation specialist
vendor presents to the user, must be checked as will check the operational manual for equipment instal-
related contents: study object, facility manual, SOP, lation, maintenance, training, calibration, safety train-
technique for operation, training, total sample volume, ing, equipment operation, software installation, and
explanation of total sample volume, data acquisition, external damage of equipment by the validation spe-
service, utilities, expendable supply, environmental con- cialist and the manufacturer, and then develops the
ditions and ranges (e.g., humidity, temperature, vibra- draft SOP, which includes developing the calibration
tion, dust), equipment maintenance method, calibration SOP for each apparatus, preventative maintenance
cycle (including contract that has a calibration cycle), items, and cleaning schedules (Bedson and Sargent,
item and cost, certificate, maintenance, warranty period, 1996; Gibson and Powell-Evans, 1998; EU, 2003; PIC/
health, safety, and information about environmental S, 2003; KFDA, 2008).
issues. Operational qualification: Operational qualifica-
If a user has the same or similar equipment, it is tion is performed to pass design qualification and
possible to perform a supplementary test using previ- installation qualification. The test items of facility must
ous information. In order to confirm the details of the reproduce the perfect results in an installed environ-
record (e.g., source code, development record of the ment. First of all, a user must learn the technical infor-
equipment, method of using the equipment, calibration mation about the equipments such as operation
certification, test record, report of batch, certificate doc- process, maintenance, safety items, cleaning and steril-
umentation for hardware and software, and certificate ization (Bedson and Sargent, 1996; Gibson and Pow-
of qualification of the development-related engineer), it ell-Evans, 1998; EU, 2003; PIC/S, 2003; KFDA, 2008).
is necessary that the user visit the manufacturer’s The validation specialist develops a working SOP,
office or review the equipment document and the ven- checks that the facility follows the process of working
dor inspection sheet (e.g, vendor audit checklist), as SOP, and confirms that the equipment to check getting
well as the certification that was inspected as escrow. result indicating value of each alarms and interlock.
After confirming the details, a user integrates all opin- This result must fulfill the test item and acceptance cri-
ions and selects the manufacturer and intended equip- teria, which set up system requirement specifications.
ment. A user must obtain accurate design and speci- When a high technical skill is required for an opera-
fications, education, documents for quality manage- tional qualification of special equipment, the expert of
ment, quality assurance methods, all-embracing test manufacture should performs the qualification process
plan for each system, application of change control, (Bedson and Sargent, 1996; Gibson and Powell-Evans,
and automatic error control instrument and remedy 1998; EU, 2003; PIC/S, 2003; KFDA, 2008).
(Bedson and Sargent, 1996; Gibson and Powell-Evans, Performance qualification: Performance qualifica-
1998; EU, 2003; PIC/S, 2003; KFDA, 2008). tion is performed for an operating facility that already
Installation qualification: The installation qualifica- has undergone design qualification, installation qualifi-
tion must be performed before the validation specialist cation, and operational qualification. This qualification is
uses the facility for a study. The installation qualifica- performed to ensure that the test items are reproduc-
tion consists of equipment design features (e.g., materi- ible with meeting the acceptance criteria, and show an
als of construction, clean ability) and installation intended use. This process is performed by the valida-
conditions (e.g., wiring, utilities, functionality). The vali- tion specialist, who demonstrates operation according
dation specialist must also check that an equipment to the procedure for operation and the SOP. The pro-
6 K.-H. Cho et al.
cess corrects for a deviation factor from each proof ment, calibration cycle, form, and acceptance criteria.
item, and establishes an intended use (Bedson and After calibration, it is necessary to attach the notifica-
Sargent, 1996; Gibson and Powell-Evans, 1998; EU, tion label, which specifies the calibration date, operation
2003; PIC/S, 2003; KFDA, 2008). range, next calibration date, and calibration standard.
The validation specialist checks that the test results As a result, the validation study director of GLP facility
are reproducible following accepted criteria. He or she can check the calibration of the equipment in use (Bed-
checks the reproducibility of a test result more than son and Sargent, 1996, International Standard ISO/IEC
three times, and should set up a plan to maintain the 17025:2005, 2006).
integrity of the equipment. Also, it is useful to test the Revalidation: The facility or equipment, which
results of limit value, low and high values, and worst have already been validated, must be revalidated if
case of equipment. The validation specialist conforms the validation specialist or validation study director
the SOP from the installation and operational qualifica- changes the facility by intent (e.g., exceed the expire
tions (Bedson and Sargent, 1996; Gibson and Powell- date, removal of equipment environment, change main
Evans, 1998; EU, 2003; PIC/S, 2003; KFDA, 2008). part, change for function improvement, change of
The validation specialist combines the raw data, proto- goal) (Gibson and Powell-Evans, 1998; Haider, 2002a;
col, and report from each qualification, and prepares PIC/S, 2003; KFDA, 2008). The validation study direc-
the final report. As example, the records for perfor- tor should perform revalidation after important changes
mance qualification results are shown in Table 2. are carried out, because these changes affect meas-
Calibration and traceability: The sensitivity of the urement accuracy. If any parts of a facility are changed,
measuring instrument can affect the integrity of the the validation study director needs to make the docu-
equipment for producing data. Thus, ISO Guide 25, ments about the reason of the change, the distinguish-
ISO 9000 Standards, and GLP guidelines require users ing feature, and the advantages and disadvantages.
to follow national and international standards that allow The facility validation study director checks the veri-
traceability for inspection and calibration. This process fied document in the course of instrument develop-
reflects the consistency of the measurement. The mea- ment. If a software system is changed, the instrument
suring instrument, which has been installed in a GLP user must consider compatibility with the existing soft-
facility, or the recording (e.g., pressure gauge, flow meter, ware. If this is not done, the validation study director
thermometer, timer, balance, thermometer recorder, must upgrade the system verification to the manufac-
humidity recorder, wavelength, and controller system) turer. After revalidation is completed, the facility must
are used to calibrate the equipment. Calibration must receive the appropriate tests and inspections. If a test
follow the calibration equipment list and calibration and inspection needs to be re-verified, the validation
schedule, and be performed by a person who has study director compares a new result with an old
mastered the calibration technique of an equipment. In result, and records the differences in the equipment
particular, the calibration equipment list contains equip- log (Gibson and Powell-Evans, 1998; PIC/S, 2003;
Basic Principles of the Validation for Good Laboratory Practice Institutes 7
present status in Japan. Korean J. of Toxicology, 1, 31-41. Yu, I.J., Maeng, S.H., Lee, J.Y., Lee, Y.M. and Chung, H.K.
Yu, I.J., Chung, Y.H., Maeng, S.H., Song, K.S., Lee, Y.M., (2000). Designation of a GLP facility by the Korean minis-
Chung, H.K., Kim, H.J., Park, J.I., Lee, S.K., Lee, Y.H. try of environment GLP authority: The case of the center
and Chang, J.S. (1999). History of Korean GLPs and for occupational toxicology. Quality Assurance, 8, 11-17.
activities and perspectives of the Korean Society of GLP. Yu, J.H. (2004). Risk Assessment for Validation, IVS,
Quality Assurance, 7, 57-62. www.validation.co.kr.