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Laboratory Biosafety and Good Laboratory Practices

In order to ensure biosafety, comprehensive guidelines have been prepared by the National Institutes of Health (NIH) and the World Health Organization (WHO). Both the NIH and the WHO guidelines recommend classification of biological agents based on their potential to cause harm to humans, animals, and the environment. Four Biosafety Levels are recommended to handle organisms of increasing risk potential. Recommended for each level are standard microbiological practices as well as facilities for physical and biological containment of genetically modified organisms (microbes, plants, or animals). In order to harmonize toxicity testing and generation of mutually acceptable preclinical data that may be used for decisions regarding regulation including commercialization, several countries have adopted the principles of Good Laboratory Practices. These principles establish a framework and a minimum standard for the conduct of tests and documentation and analysis of data.

Risk comes from not knowing what you’re doing. Warren Buffett, American business magnate, investor, philanthropist.

Paul Berg opening a jar under a protective hood.

11.1. Introduction

Handling organisms including microorganisms under laboratory conditions is an essential part of biotechnology research and applications. Responsible and safe handling of microorganisms (potentially pathogenic) is necessary to ensure the health of laboratory personnel, the community, and the environment. This chapter reviews practices and protocols that have been established at the international and national level to ensure biosafety in institutions involved in biotechnology research and development.

In the early days of the development of recombinant DNA technology, the consensus in the scientific community was that due to the potential to generate new (potentially harmful) forms of organisms, mere good microbiological techniques (GMT) alone would not suffice to ensure safety of workers in this area of research. Consequently, in June 1976, shortly after the Asilomar Conference (see Chapter 9: Ensuring Safety in Biotechnology), the US National Institutes of Health (NIH) brought out the NIH Guidelines for Research Involving Recombinant Nucleic Acid Molecules (henceforth referred to as “ NIH Guidelines ”). (The guidelines have undergone several revisions, the most recent one being in April 2016.) The guidelines recognize six classes of experiments based on the risk involved in the research, which require sanction from different regulatory bodies (see Chapter 9: Ensuring Safety in Biotechnology, Box 9.2).

Recognizing that biological safety is an important international issue, the United Nations World Health Organization (WHO) in 1983 published the Laboratory Biosafety Manual (henceforth referred to as “ WHO manual ”) establishing basic concepts and practices in safe handling of pathogenic microorganisms. The document encouraged countries to develop national codes of practice for implementation within their geographic boundaries . The WHO manual has since been revised twice, in 1993 and again in 2004. The third edition incorporates biosecurity concepts in addition to making specific recommendations for biosafety in handling genetically modified organisms.

Adhering to international standards and incorporating biosafety practices in national policies is important not only to protect plant, animal or human life, and health of its citizens, but also in trade in biotech products. Exporting countries need to demonstrate that the measures it applies to its exports achieve the same level of health protection as in the importing countries in order to avoid barriers in trade. Providing oversight to global rules of trade between nations is the mandate of the World Trade Organization. This organization administers the General Agreement on Tariffs and Trade (GATT) (see Chapter 13: Relevance of Intellectual Property Rights in Biotechnology). Article 20 of the GATT allows governments to regulate trade to address biosafety of their citizens provided they do not discriminate or use this clause to disguise protectionism. Countries therefore have made efforts to develop guidelines and appropriate legal frameworks for biosafety regulation. Although the developed countries (e.g., the United States) and regions (e.g., European Union) as leaders in the development of modern biotechnology started to develop these frameworks in the mid-1970s and early 1980s, the developing nations generally started the development of national biosafety systems more recently. The WHO manual has served as an important resource document and is consequently reflected in national regulatory instruments for ensuring biosafety.

11.2. Risk Categories of Microorganisms

In both the NIH guidelines and the WHO manual, four categories of microorganisms used in laboratory work are recognized . The basis of the classification is the risk of infection to laboratory workers and, in the event of escape from the laboratory, to the community. Assigning a microorganism to a risk category is dependent on an initial risk assessment made by the investigator and is based on current knowledge of the:

• 1. Pathogenicity of the organism (all microorganisms do not cause diseases),
• 2. Host range and mode of transmission of the organism,
• 3. Local availability of effective measures to prevent a disease outbreak , and
• 4. Local availability of effective treatment .

The Appendix B of the NIH guidelines, Classification of Human Etiological Agents on the Basis of Hazard , as does Table 1 of the WHO manual, recognizes four Risk Groups of microorganisms:

• • Risk Group 1 : Microorganisms unlikely to cause human or animal diseases and thus pose little or no risk to individuals and to the community; sometimes designated as generally regarded as safe (GRAS) organisms (e.g., asporogenic Bacillus subtilis or Bacillus licheniformis , the K-12 strain of Escherichia coli )
• • Risk Group 2 : Microorganisms that are pathogenic, but unlikely to pose a serious hazard to laboratory workers, livestock, the community, or the environment as effective treatment and preventive measures to limit spread of infection are available. These organisms thus are of moderate risk to the individual and low risk to the community (e.g., bacterial agents— Aeromonas hydrophila , E. coli , Klebsiella spp., Salmonella spp.; fungal agents— Penicillium marneffei , Blastomyces dermatitidis ; parasitic agents— Ascaris spp., Trypanosoma spp.; viruses—adenoviruses, Coronaviruses, Papilloma viruses)
• • Risk Group 3 : Microorganisms that are pathogenic and can cause serious human or animal diseases, but are not contagious or have effective treatment and preventive measures. These organisms pose high risk to the individual, but low risk to the community (e.g., bacterial agents— Brucella spp., Francisella tularensis , Rickettsia spp.; fungal agents— Coccidiodes immitis, Histoplasma spp.; Viruses and prions—Togaviruses, Flaviviruses such as the Japanese encephalitis virus, West Nile virus, Pox viruses, prions such as the transmissible spongiform encephalopathies, retroviruses such as human immunodeficiency virus, rhabdovirus)
• • Risk Group 4 : Microorganisms that usually cause serious diseases in humans and animals and can be readily transmitted either directly or indirectly from one to the next individual. Effective treatment and preventive measures are usually unavailable . This class of organisms thus poses a high risk to individuals and to the community (e.g., viral agents such as the Lassa virus, Ebola virus, Marburg virus, Herpes virus simiae, Kayasanur Forest disease, Central European encephalitis, and as yet unidentified hemorrhagic fever agents).

The NIH guidelines recognize that this classification is dependent on current knowledge of pathogenicity, and with the development of better therapeutic and preventive measures, pathogens may be assigned to a lower risk category. Different countries may assign the same organism to different risk groups, possibly because the same organism is more virulent in certain parts of the world than others depending on climatic conditions and other factors. Also, any strain more virulent than the wild-type parent strain should be assigned to a higher risk group.

11.3. Biosafety Levels

Both the NIH guidelines and the WHO manual recommend four Biosafety levels (BLs) 1 to 4 for handling organisms corresponding to the four risk groups. Implementation of safety procedures in each level relies on:

• 1. Standard practices of GMT
• 2. Physical barriers provided by special procedures, equipment, and laboratory installations commensurate with the estimated biohazard.

Appendix G of the NIH guidelines describes four BLs of Physical Containment summarized in Table 11.1 for standard laboratory experiments. For large-scale (over 10 L) research or production, physical containment requirements are defined in Appendix K (see Chapter 12: Recombinant DNA Safety Considerations in Large-Scale Applications and Good Manufacturing Practice) (WHO Laboratory Biosafety Manual, 2004). The BL assigned for specific research work depends on the assessed risk group of the organisms handled as well as professional judgment of risk associated with the activity.

Relation of Risk Groups to Biosafety Levels, Practices, and Equipment

BSC , biological safety cabinet; GMT , good microbiological techniques.

11.3.1. Physical Containment

The first principle of physical containment is strict adherence to good microbial practices , hence, all personnel directly or indirectly working with recombinant or synthetic nucleic acids should be trained in GMT . Appendix G-II of the NIH guidelines describes four levels of physical containment BL1, BL2, BL3, and BL4 , representing facilities in which experiments ranging from low to high potential hazard may be conducted. For each BL, the guidelines specify the following:

• • Standard microbiological practices,
• • Special practices,
• • Containment equipment, and
• • Laboratory facilities.

Table 11.2 summarizes the facility requirements at the four BLs (for details, see Box 11.1 ).

Summary of Biosafety Level Requirements

Physical Containment for Standard Laboratory Experiments

Appendix G of the NIH guidelines identifies strict adherence to good microbiological practices as being the first principle of containment; hence, all personnel directly or indirectly associated with experiments involving recombinant or synthetic nucleic acid molecules should be trained in good microbiological techniques. The four levels of physical containment Biosafety Levels 1 through 4 as described in Appendix G are summarized below:

Biosafety Level 1:

• • Access to the laboratory is limited or restricted at the discretion of the Principal Investigator (PI).
• • Work surfaces are decontaminated once a day, all liquid and solid wastes are decontaminated before disposal.
• • Mouth pipetting is prohibited.
• • Eating, drinking, smoking, or storing food in the refrigerators is prohibited.
• • Procedures are performed carefully to prevent formation of aerosols.
• • Good hygiene including washing hands and wearing protective clothes is encouraged.
• • Contaminated materials to be decontaminated at a site away from the laboratory are transported in durable, leak-proof containers with closed lids.
• • An insect and rodent control program is required.
• • Generally, not required for BL1
• • The laboratory should be designed to be easily cleaned.
• • Benchtops should be resistant to water, acid/alkali/organic solvents and should have sinks for hand-washing.

Biosafety Level 2:

• • As described for BL1 and
• • Experiments of lesser biohazard can be conducted concurrently in demarcated areas of the laboratory.
• • PI limits access to the laboratory and establishes policies and procedures whereby persons entering the laboratory are aware of the hazard and meet any specific entry requirements (such as immunization).

Biohazard warning sign for laboratory doors.

• • Protective clothing used exclusively in the laboratory is required; gloves are to be used to prevent skin contamination with experimental organisms.
• • Only needle-locking hypodermic syringes are used, placed in puncture-proof containers after use, and decontaminated before disposal.
• • A biosafety manual is prepared and adopted for safety of personnel.
• • Baseline serum samples of all laboratory and at-risk personnel should be collected and stored in accordance with institutional policy.

Schematic representation of a Class II biological safety cabinet.

(A) Front opening; (B) sash; (C) exhaust HEPA filter; (D) rear plenum; (E) supply HEPA filter; (F) blower.

• • An autoclave required for decontamination.

Biosafety Level 3:

• • As described for BL2 and
• • Persons below 16 years of age are not permitted entry.
• • Laboratory doors are kept close when experiments are in progress.
• • Laboratory clothing that protects street clothes is to be worn in the laboratory, removed when exiting the laboratory, and decontaminated prior to laundry or disposal.
• • Molded surgical masks or respirators are worn in rooms containing experimental animals.
• • If animals housed with conventional caging system, personnel must wear protective devices that includes wrap-around gowns, head covers, gloves, shoe covers, and respirators; personnel shall shower on exit from areas where these devices are required.
• • Alternatively, laboratory animals shall be housed in partial-containment caging systems; no animals other than the experimental animals are allowed.
• • Vacuum lines are protected with high efficiency particulate air (HEPA) filters and liquid disinfectant traps.
• • Spills and accidents which result in potential exposure to modified organisms are immediately reported to the Biological Safety Officer, Institutional Biosafety Committee (IBSC) and to the NIH Office of Science Policy. Written records are to be maintained on appropriate medical evaluation, surveillance, and treatment provided.
• • Biological safety cabinets (class I, II, or III) or other appropriate personal protective devices (such as special protective clothing, masks, gloves, respirators, centrifuge safety cups, sealed centrifuge rotors, containment cages for animals) are used.
• • Laboratory to be separated from open areas within the building and accessed through two sets of doors; physical separation of high containment laboratory from other laboratories or activities, may be provided by a double-door clothes change room with showers, airlock, or other double-door access features.
• • Interior surfaces of walls, floors, and ceilings are water resistant for easy cleaning, should be capable of being sealed for decontaminating the area.
• • Access doors are self-closing.
• • The HEPA-filtered exhaust air from Class I or II biological cabinets is discharged directly to the outside or through the building exhaust system.

Biosafety Level 4:

• • As described for BL3
• • As described for BL3 and
• • Access to the facility is limited by means of secure locked doors; accessibility is restricted to authorized personnel and is supervised and managed by the PI, Biological Safety Officer, or person responsible for the physical security of the facility. A log of entry and exit of personnel is maintained. All personnel are advised of potential biohazards and are to comply with instructions on entry and exit procedure. Protocols for emergency situations are established.
• • Biological material to be removed in an intact state are to be sealed in a primary nonbreakable container, enclosed and sealed in a secondary nonbreakable container, and removed from the facility through a disinfectant dunk tank, fumigation chamber, or an airlock designed for the purpose.
• • Any other material to be removed from the facility are to be autoclaved or decontaminated before exiting the maximum containment laboratory.
• • Personnel enter and exit the facility only through clothing change and shower rooms; shower every time they exit the facility.
• • Street clothing is removed and kept in an outer changing room. Complete laboratory clothing (may be disposable) is provided and to be used by all personnel entering the facility. When exiting, the laboratory clothing is removed in an inner changing room before proceeding to the shower area. The clothing is decontaminated prior to laundering or disposal.
• • Supplies and material are brought into the facility through a double-door autoclave, fumigation chamber, or airlock.

Schematic representation of a Class III biological safety cabinet (glove box).

(A) glove ports for arm-length gloves; (B) sash; (C) double-exhaust HEPA filters; (D) supply HEPA filter; (E) double-ended autoclave or pass-through box; (F) chemical dunk tank. Connection of the cabinet exhaust to an independent building exhaust air system is required.

• • The maximum containment facility is to be housed in a separate building or a clearly demarcated and isolated zone within a building. Access to the facility requires outer and inner change rooms separated by showers for entry and exit of personnel, and double-door autoclave, fumigation chamber or airlock for passage of materials, supplies, and equipment.
• • Internal surfaces of walls, floors, and ceilings of the facility should be water, acid, and alkali resistant; the facility should be sealable for fumigation, animal and insect proof. Drains in the floor contain traps filled with suitable chemical disinfectant and are connected directly to the liquid-waste decontamination system. Sewer and other ventilation lines contain HEPA filters.
• • Benchtops have seamless surfaces impervious to acids, alkalis, organic solvents, and moderate heat; construction of the facility should have adequate space for accessibility for cleaning.
• • Access doors are self-closing and locking.
• • An individual supply and exhaust air ventilation system that maintains pressure differentials and directional airflow ensures that airflow inwards from areas outside the facility toward areas of highest potential risk within the facility. The supply and exhaust airflow is monitored by manometers to assure inward (or zero) airflow at all times.
• • Exhaust air from the facility is filtered through HEPA filters before discharge to the outside.
• • A specially designed suit area may be provided in the facility entry into which is through an airlock fitted with airtight doors. The air pressure within the suit area is maintained greater than that of adjacent areas. Personnel who enter this area shall wear a one-piece positive pressure suit ventilated by life-support system. A chemical shower is provided to decontaminate the surface of the suit before the worker exits the area.

11.3.2. Biological Containment

The growth and dissemination of organisms are naturally limited. For ensuring safety, biological containment takes advantage of these natural barriers such as:

• 1. The infectivity or host specificity of a vector or virus
• 2. Its spread and survival in the environment.

Appendix I of the NIH guidelines describes Biological containment strategies for recombinant or synthetic nucleic acid molecules. The vector (plasmid, organelle, or virus) for the recombinant or synthetic nucleic acid molecule and the host (bacterial, animal, or plant cell), in which the vector is propagated, are taken together as a Host–Vector system for consideration of biological containment. Selection of a Host–Vector system aims to minimize:

• 1. Survival of the vector in its host outside the laboratory and
• 2. Transmission of the vector from the propagation host to other nonlaboratory hosts.

Host–Vector 1 Systems provide moderate level of containment. The EK1 system has E. coli K-12 (or derivatives) as the host , and the vectors include nonconjugative plasmids (e.g., pSC101, Co1E1) and variants of bacteriophage lambda .

Host–Vector 2 Systems (EK2) provide a high level of biological containment with escape of the recombinant or synthetic nucleic acid molecule to other organisms under specified conditions being <1/10 8 .

11.4. Physical and Biological Containment for Research Involving Plants

The BLs 1 through 4 are applicable to microorganisms, but Appendix P of the NIH guidelines specifies physical and biological containment conditions for experiments involving recombinant or synthetic nucleic acids in plants, plant-associated microorganisms, and small animals . The plants include, but are not limited to, mosses, liverworts, macroscopic algae, and vascular plants including terrestrial crops, forest, and ornamental species. Plant-associated microorganisms include those that have a benign or beneficial effect as also those that cause diseases, and include viroids, virusoids, viruses, bacteria, fungi, protozoans, small algae, as well as microbes being modified for association to plants. Plant-associated small animals include arthropods and nematodes, tests on which require the use of plants. The purpose of the containment is to prevent unintentional transmission of recombinant or synthetic nucleic acid molecule containing plant genomes (nuclear or organellar DNA), or release of modified organisms associated with plants . Appendix P-II establishes four levels referred to as BL1-Plants (P), BL2-P, BL3-P, and BL4-P, which specify the use of plant tissue culture rooms, growth chambers within laboratory facilities, or experiments performed on open benches. Appendix P-III specifies Biological Containment Practices if botanical reproductive structures are produced that can potentially be released. For further details, see Box 11.2 .

Physical Containment for Experiments Involving Plants

Appendix P of the NIH guidelines supersedes Appendix G (Physical Containment) when the research plants are of a size, number, or have growth requirements that preclude use of the containment conditions outlined in Appendix G. The containment principles in Appendix P are based on the premise that the organisms pose no health threat to humans or higher animals and that the purpose of the containment is to minimize the possibility of unanticipated deleterious effects on organisms and the ecosystem. The physical containment levels describe greenhouse practices and special greenhouse facilities for physical containment.

Biosafety Level 1—Plants (BL1-P):

• – Limited or restricted, at the discretion of the Greenhouse director when experiments are in progress.
• – Personnel shall be required to follow standard greenhouse procedures.
• – Record shall be maintained of experiments in progress in the facility.
• – Experimental organisms shall be rendered biologically inactive by appropriate methods prior to disposal.
• – Appropriate methods shall be adopted to control undesired species of weeds, rodents, arthropod pests, and pathogens.
• – If macroorganisms are released in the greenhouse, precautions are to be taken to minimize escape from the greenhouse facility.
• – Provided the work is conducted in accordance with BL1-P practices, experiments involving other organisms that require containment level lower than BL1-P may be conducted.
• • The floor of the greenhouse may be of gravel or other porous materials, impervious (concrete) walkways are recommended.
• • The greenhouse may be vented with windows or other openings in walls or roof, screens are recommended as barriers to contain or exclude pollen, microorganisms, or small flying animals.

Biosafety Level 2—Plants (BL2-P):

• – As described for BL1-P
• – Personnel should be aware of and follow BL2-P practices and procedures.
• – As described for BL1-P and
• – The PI shall report any greenhouse accident involving inadvertent release or spill of microorganisms to the Greenhouse Director, Institutional Biosafety Committee, the NIH Office of Science Policy, and other appropriate authorities. Written records are to be maintained on any such accident.
• – Decontamination of run-off water is not generally required, although periodic cleaning to remove any organisms potentially entrapped by the gravel is to be done.
• – A sign shall be posted to indicate that a restricted experiment is in progress, shall indicate the name of the responsible person, the plants in use, and any special requirements for using the area.
• – Materials containing experimental organisms brought into or removed from the greenhouse facility in a viable state shall be transferred in a closed nonbreakable container.
• • As described for BL1-P.
• • An autoclave shall be available for treatment of contaminated greenhouse materials.

Biosafety Level 3—Plants (BL3-P):

• – As described for BL1-P.
• – Personnel should be aware of and follow BL3-P practices and procedures.
• – As described for BL2-P.
• – All experimental materials including water shall be sterilized in an autoclave or rendered biologically inactive by appropriate methods before disposal (except those that are to remain in a viable or intact state for experimental purposes).
• – Arthropods and other motile macroorganisms shall be housed in appropriate cages; when appropriate to the organism, experiments shall be conducted in the cages.
• – Involving organisms that require containment lower than BL3-P may be conducted concurrently provided BL3-P practices are followed.
• – As described for BL2-P and
• – If organisms used have a recognized potential for causing detrimental impacts on managed or natural ecosystems, their presence should be indicated on a sign posted on the greenhouse access door.
• – If there is a risk to human health, a sign with the universal biosafety symbol shall be posted.
• – A sealed nonbreakable secondary container shall be used for experimental material brought into or removed from the greenhouse facility in a viable state.
• – At the time of transfer, the surface of the secondary container shall be decontaminated by passage through a chemical disinfectant or fumigation chamber or any method found effective.
• – Disposable clothing (such as solid front or wrap around gowns, scrub suits, or other appropriate clothing) shall be worn if deemed necessary by the Greenhouse Director.
• – Such clothing shall be removed before exiting the facility and decontaminated before laundering or disposal.
• • The greenhouse floor shall be of concrete or other impervious material with provision to collect and decontaminate liquid run-off.
• • Windows shall be sealable, glazing shall be resistant to breakage; internal walls, ceilings, and floors shall be resistant to penetration by liquids to facilitate cleaning and decontamination; benchtops and other surfaces should be seamless, resistant to acids, alkali, organic solvents, and moderate heat; a foot, elbow, or automatically operated sink should be located near the exit for hand washing.
• • The greenhouse shall be a closed self-contained structure, separated from areas open to unrestricted flow of traffic; it shall be surrounded by a security fence or protected by security measures.
• • An autoclave (double door recommended) shall be available for decontaminating materials within the facility.
• • An individual supply and exhaust air ventilation shall be provided that maintains pressure differentials and directional airflow (assures inward, or zero, airflow from areas outside the greenhouse).
• • Exhaust air shall be filtered through HEPA filters prior to discharge.

Biosafety Level 4—Plants (BL4-P):

• – As described for BL3-P and
• – Personnel shall enter and exit the greenhouse facility only through the clothing change and shower rooms and shall shower each time they exit the facility; airlocks are used only for emergency exits; all reasonable efforts taken to ensure that viable propagules are not transported from the facility in an emergency.
• – Prior to entry, personnel should read and follow instructions on BL4-P procedures.
• – A record and time-log is kept of all people entering or exiting the facility.
• – Water that comes in contact with the experimental material (such as run-off water) shall be collected and decontaminated before disposal; all equipment and materials used will be decontaminated as in standard microbiological practices.
• – As described for BL3-P
• – Experiments involving organisms that require containment less than BL4-P may be conducted concurrently.
• – Supplies and materials shall be brought into the facility through a double-door autoclave, fumigation chamber, or airlock that is fumigated between uses.
• – Street clothing is removed and kept in an outer changing room. Complete laboratory clothing (may be disposable) is provided and to be used by all personnel entering the facility. When exiting, the laboratory clothing is removed in an inner changing room before proceeding to the shower area. The clothing is decontaminated prior to laundering or disposal.
• • The maximum containment greenhouse shall consist of a separate building or a clearly demarcated area; should be able to maintain negative pressure; surrounded by a security fence or similar security measures.
• • Outer and inner change rooms separated by a shower shall be provided for entry and exit of personnel; doors should be self-closing; windows closed and sealed; glazing shall be resistant to breakage; ceilings and floors shall be resistant to penetration by liquids to facilitate cleaning and decontamination; benchtops and other surfaces should be seamless, resistant to acids, alkali, organic solvents, and moderate heat.
• • A double-door autoclave, fumigation chamber, or ventilated airlock shall be provided for passage of materials, supplies, and equipment.

11.5. Physical and Biological Containment for Research Involving Animals

Appendix Q of the NIH guidelines deals with the requirements for containment and confinement for research involving whole animals. The guideline covers both animals whose genome has been altered by stable integration of recombinant or synthetic nucleic acid molecules into the germ line ( transgenic animals ), as well as modified microorganisms tested on whole animals . The animals covered in the guidelines include, but are not limited to, cattle, swine, goats, horses, sheep, and poultry. As in the case of plants, four levels of containment are established, referred to as BL1- Animals (N), BL2-N, Bl3-N, and BL4-N. For further details, see Box 11.3 .

Physical Containment for Experiments Involving Animals

Appendix Q of the NIH guidelines supersedes Appendix G (Physical Containment) when the animals are of a size or have growth requirements that preclude the use of the physical containment described in Appendix G. For experiments that require prior approval of the IBSC that utilize facilities described in Appendix Q, the IBSC shall include at least one scientist with expertise in animal containment principles. The institute shall establish a health surveillance program for personnel working with viable microorganisms carrying recombinant or synthetic DNA that require BL 3 or greater.

Biosafety Level 1—Animals (BL1-N):

• – The containment area shall be locked; access shall be limited or restricted when experiments are in progress; the area shall be patrolled/monitored at frequent intervals.
• – The containment area shall be in accordance with state and Federal laws and animal care requirements.
• – All genetically engineered neonates shall be permanently marked within 72 hours of birth (or if size does not permit, the containers shall be marked); transgenic animals should contain distinct and biochemically assayable DNA sequences that allow distinction between modified and nonmodified animals; a double barrier shall separate male and female animals unless reproductive studies are part of the study.
• • Animals shall be confined to securely fenced areas or enclosed animal rooms to minimize the possibility of theft or unintended release.

Biosafety Level 2—Animals (BL2-N):

• – As described for BL1-N and
• – The Animal Facility Director shall establish procedures to ensure personnel who enter are advised of potential hazards and meet specific requirements (such as vaccination); animals of the same or different species, not involved in the experiment, shall not be permitted.
• – Materials to be decontaminated elsewhere are to be placed in closed durable leak-proof containers, needles and syringes in puncture-proof containers to be autoclaved before disposal.
• – Warning signs incorporating the universal biosafety symbol to be posted on access doors containing details of special provisions (such as vaccinations) for entry, agents and animal species involved in the experiments, and details of the Animal Facility Director.
• – Protective coating to be worn in the animal area, to be removed in nonlaboratory areas, gloves to be worn and care to be taken to avoid skin contamination.
• – Any incident involving spills or inadvertent exposure or release of modified microorganisms shall be reported to the Animal Facility Director, Institutional Biosafety Committee, the NIH Office of Science Policy, and other appropriate authorities. Written records are to be maintained on any such accident, and if necessary, the area shall be decontaminated.
• – When appropriate, base line serum samples of animal care workers and at-risk personnel may be collected and stored.
• – Advance approval for transfer of material shall be obtained from the Animal Facility Director; biological material shall be transferred in a sealed nonbreakable primary container, sealed in a second nonbreakable container, both of which are to be disinfected before removal; unless inactivated, packages are to be opened in a facility having equivalent or higher physical containment.
• – Appropriate steps to be taken to prevent horizontal transmission or exposure of personnel; eating, drinking, smoking is not permitted in the work area.
• • As described for BL1-N and
• • Surfaces shall be impervious to water and resistant to acids, alkalis, organic solvents, moderate heat, easy to clean; windows that open shall be fitted with fly screens; special attention to be taken to prevent entry and exit of arthropods.

Biosafety Level 3—Animals (BL3-N):

• – As described for BL2-N
• – As described for BL2-N and
• – Special safety testing, decontamination procedures, and IBSC approval require for transfer of agents or tissue/organ specimens from a BL3-N to a facility of lower containment classification.
• – Liquid effluent from the facility shall be decontaminated by heat treatment prior to release to the sanitary system.
• – Full protective clothing shall be worn in the animal area; personnel are required to shower before exiting the BL3-N facility; protective clothing shall not be worn outside the containment area and will be decontaminated before laundering or disposal.
• – Appropriate respiratory protection shall be worn in the containment rooms.
• – A permanent record book shall maintain details of experimental animal use and disposal.
• • As described for BL2-N and
• • The animal containment area shall be separated from other areas; access doors shall be self-closing; passage through two sets of doors and clothes change room equipped with integral showers and airlock.
• • An exhaust air ventilation system shall be provided that creates a directional airflow; that draws air into the animal rooms vacuum lines shall be protected with HEPA filters; liquid effluent from containment rooms shall be decontaminated before discharge into the sanitary system.

Biosafety Level 4—Animals (BL4-N):

• – As described for BL3-N and
• – Individuals below 16 years of age shall not be permitted to enter the animal area.
• – Personnel shall enter and exit through the clothing change and shower rooms, and use the airlocks in case of an emergency.
• – All contaminated liquid and solid wastes and wastes from the animal rooms shall be decontaminated before disposal.
• – As described for BL3-N
• – Street clothes shall be removed and kept in the outer changing room; complete laboratory clothing (may be disposable) shall be provided for all personnel entering the animal facility, which is to be removed and placed in bins in the inner changing room while exiting the facility; clothing is decontaminated before laundering or disposal; personnel shall shower each time they exit the containment facility.
• – A ventilated head-hood or a one-piece positive pressure suit shall be worn by personnel entering rooms that contain experimental animals when appropriate.
• – A permanent record and time-log of entry and exit of personnel is to be maintained.
• – Supplies and materials needed in the animal facility shall be brought in by way of the double-door autoclave, fumigation chamber, or airlock appropriately decontaminated between use.
• – Animal-holding areas shall be cleaned at least once a day and decontaminated immediately if spilling of viable materials occurs.
• – An essential adjunct to the reporting, surveillance system is the availability of a facility for quarantine, isolation, and medical care of personnel with potential or known laboratory associated diseases.
• • As described for BL3-N and
• • The BL4-N shall have a double barrier to prevent release of recombinant or synthetic nucleic acid molecule containing microorganisms to the environment such that even if the barrier of the inner facility is breached, the outer barrier will prevent release into the environment; physical separation of the animal containment area is by double-door clothes change room equipped with showers and airlock.
• • All equipment and floor drains shall be equipped with minimally 5-in.-deep traps; ducted exhaust air ventilation shall be provided that is filtered through double HEPA filters and creates a directional airflow that draws air into the laboratory.

11.6. Good Laboratory Practice

By definition “ Good Laboratory Practice embodies a set of principles that provide a framework within which laboratory studies are planned, performed, monitored, recorded, reported, and archived ” ( Dolan, 2007 ). The primary purpose of GLP is to ensure uniformity, consistency, and reliability of safety tests (nonclinical) for pharmaceuticals, agrochemicals, aroma and color food/feed additives, cosmetics, detergents, novel foods, nutritional supplements for livestock, and other chemicals . These safety tests are used to generate data on various parameters from physicochemical properties to toxicity (nonclinical) for use of regulatory authorities in order to make risk/safety assessments. Originally, GLP regulations were intended for toxicity testing only and were reserved for laboratories undertaking animal studies for preclinical work. GLP is now followed in all laboratories where research or marketing studies are to be submitted to regulatory authorities such as the FDA. Establishment of GLP is mandatory to evaluate safety or toxicity of products intended to undergo clinical trials.

Historically, GLP was introduced in several countries (including the United States in 1978) in response to a scandal involving an American industrial product safety testing laboratory in Illinois, the Industrial Bio-Test (IBT) Laboratory. This laboratory performed more than one-third of all toxicology testing in the United States in the 1950s to 1970s, but was found guilty of extensive scientific misconduct, resulting in indictment and convictions of several of its staff in the early 1980s. As data generated by IBT had been used by regulatory authorities for marketing licenses, the United States Environmental Protection Agency was forced to pull several pesticides from the market pending reevaluation of its safety data.

The Organization for Economic Cooperation and Development Principles of Good Laboratory Practice (GLP) was first developed in 1978 by an Expert Group led by the United States with experts from Australia, Austria, Belgium, Canada, Denmark, France, the Federal Republic of Germany, Greece, Italy, Japan, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, the Commission of the European Communities, the WHO, and the International Organization for Standardization. The GLP was formally recommended for use in Member countries in 1981. A more comprehensive document specifying the Principles of GLP was brought out by the OECD in 1992 (revised in 1997) ( OECD, 1998 ) and has since been adopted by several countries and incorporated in national regulatory policies and documents.

Compliance with GLP requires that:

• 1. The tests should be conducted by qualified personnel .
• 2. Each study should have a Study Director responsible for the overall conduct of the tests.
• 3. The laboratory study and the accompanying data should be audited by a Quality Assurance Unit.
• 4. All laboratory activities must be performed in accordance with written and filed management-approved Standard Operating Procedures (SOPs) . SOPs should cover policies, administration, equipment operation, technical operation, and analytical methods.
• 5. All control and test articles and reagents must be identified, characterized, and labeled with information regarding source, purity, stability, concentration, storage conditions, and expiration date .
• 6. The equipment must be maintained, calibrated, and must be designed to meet analytical requirements .

Compliance with GLP has served to harmonize test methods across nations, facilitating generation of mutually acceptable data , thus avoiding duplication of tests, and saving time and resources.

Key Takeaways

The primary purpose of GLP is to ensure uniformity, consistency, and reliability of safety tests (nonclinical) for pharmaceuticals, agrochemicals, aroma and color food/feed additives, cosmetics, detergents, novel foods, nutritional supplements for livestock, and other chemicals. Establishment of GLP is mandatory to evaluate safety or toxicity of products intended to undergo clinical trials .

11.7. Summary

Crucial to the research and development of new applications of genetically modified organisms derived by the transfer of synthetic or recombinant nucleic acid molecules are measures to prevent hazards (to laboratory personnel as well as to other persons, animals, and the ecosystems) from being realized. Guidelines prepared by the NIH and the WHO have helped establish processes and systems that build on GMT in order to ensure biosafety. The guidelines form an integral part of normative policies and regulation of genetically modified organisms in countries using recombinant DNA technology. Both the NIH and the WHO guidelines recommend classification of biological agents based on their potential to cause harm to humans, animals, and the environment. Four BLs are recommended to handle organisms of increasing risk potential. Recommended for each level are standard microbiological practices as well as facilities for physical and biological containment of genetically modified organisms (microbes, plants, or animals). In order to harmonize toxicity testing and generation of mutually acceptable preclinical data that may be used for decisions regarding regulation including commercialization, several countries have adopted the principles of GLPs. These principles establish a framework and a minimum standard for the conduct of tests, and documentation and analysis of data.

• Dolan K. Laboratory animal law: Legal control of the use of animals in research. Blackwell Publishing Limited; Oxford: 2007. [ Google Scholar ]
• NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) retrieved from http://osp.od.nih.gov/sites/default/files/NIH_Guidelines_0.pdf .
• OECD . OECD series on principles of good laboratory practice and compliance monitoring number 1. Environment Directorate, Organisation for Economic Co-operation and Development; Paris: 1998. OECD principles on good laboratory practice (as revised in 1997) Retrieved from http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/mc/chem(98)17&doclanguage=en . [ Google Scholar ]
• WHO Laboratory Biosafety Manual 2004 Third edition, retrieved from http://www.who.int/csr/resources/publications/biosafety/en/Biosafety7.pdf .

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Good Laboratory Practice (GLP)

This course provides training on good laboratory practice for non-clinical laboratory studies that reflects regulations and best practices established by key regulatory agencies and guidelines.

About this Course

Good Laboratory Practice (GLP) describes how nonclinical laboratory studies should be planned, performed, monitored, recorded, reported, and archived as set forth by the U.S. Food and Drug Administration (FDA), Environmental Protection Agency (EPA), and U.S. Department of Agriculture (USDA), as well as the Organization for Economic Co-operation and Development (OECD) international guidelines.

It is intended for anyone involved or planning to be involved in nonclinical laboratory studies within industry, academia, government, or other testing facilities. It provides a working knowledge of GLP that supports and reinforces technical education and training.

This course was authored by Kathryn Hackett-Fields, RQAP-GLP of QualiStat, Inc. and peer-reviewed by experts.

Language Availability: English

Suggested Audiences: Nonclinical Researchers

Organizational Subscription Price: $675 per year/per site for government and non-profit organizations; $750 per year/per site for for-profit organizations Independent Learner Price: $220 per person

Course Content

History of the good laboratory practices: a breach of trust.

Discusses the need for GLP regulations including the historical events that led to their initial development. It identifies how the foundations of GLPs are translated into practical controls, guidelines, and standard procedures encountered by technical and other laboratory/research personnel.

Recommended Use: Required ID (Language): 16696 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc

Here & There: U.S. and Global Regulatory Agencies

Describes the scope and mission of the FDA, EPA, and OECD concerning nonclinical laboratory studies. It compares the typical types of study groups submitted to the FDA and EPA, and identifies the different methods used by these agencies to inspect a submitted study’s data, testing facility, and personnel for GLP compliance.

Recommended Use: Required ID (Language): 16697 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Let’s Be Clear: Words Matter in GLP

Identifies definitions from the FDA, EPA, and OECD GLP regulations. It is intended to help learners master specific GLP terms and differentiate key terms having a similar focus among the regulations.

Recommended Use: Required ID (Language): 16698 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Components of Compliance

Explains how the foundations of GLP are observed and expressed in nonclinical laboratory settings, and in FDA’s GLP regulations. It identifies general elements of a quality system, intersecting points between key study documents that establish study control and direction, and how to evaluate and improve SOPs used in a testing facility.

Recommended Use: Required ID (Language): 16701 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

GLP Requirements of Personnel

Identifies the regulatory requirements and responsibilities for personnel involved in all aspects of regulated studies including staff (technical and non-technical), study directors, management, QA personnel, and PIs.

Recommended Use: Required ID (Language): 16699 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

The Responsible Use of Laboratory Animals (LA) – Part 1

Introduces the GLP regulations pertinent to the use of animals in research and testing, as well as their intersection with the Animal Welfare Act. It identifies the appropriate methods of interaction between technicians responsible for nonclinical studies and personnel responsible for tasks related to animal care and vivarium operations.

Recommended Use: Required ID (Language): 16703 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

The Responsible Use of Laboratory Animals (LA) – Part 2

Identifies GLP requirements for study conduct and how they affect interactions between technical and animal care personnel. It describes the general process of an Animal and Plant Health Inspection Service (APHIS) inspection, and how to achieve regulatory compliance in end-of-study procedures such as collection of specimens, euthanasia, and necropsy.

Recommended Use: Required ID (Language): 16704 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Standard Operating Procedures (SOPs) and Equipment Operation

Identifies the importance that SOPs for common operations and equipment maintenance have on establishing a quality system. It discusses the GLP requirements for SOP preparation and differences in requirements for equipment found in research and testing facilities, and equipment that generates or measures data.

Recommended Use: Required ID (Language): 16702 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Understanding Raw Data and Reconstruction

Discusses the importance of raw data collection and analysis in nonclinical laboratory studies. It describes what constitutes raw data, the importance of raw data, how to collect and evaluate raw data, and how reconstruction of study data is accomplished to bridge gaps in a GLP-compliant manner.

Recommended Use: Required ID (Language): 16700 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Required Reading: Study Protocols

Describes the importance and role of the protocol in nonclinical laboratory studies. It discusses how the protocol is developed and used by the study director, technicians, QA personnel, and in regulatory enforcement, as well as the reasons for documentation and communication of protocol changes and deviations to all personnel involved in the study.

Recommended Use: Required ID (Language): 16705 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Archiving Study Data and Specimens

Presents the GLP requirements for a compliant study archive including the procedures that should be used to protect an archive from common hazards. It identifies the responsibilities of all personnel typically involved in archiving.

Recommended Use: Required ID (Language): 16708 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

The Quality Assurance Unit (QAU)

Describes the purpose and functions of the QAU. It discusses appropriate interactions with QA professionals during study or husbandry inspections, and the requirement for QA independence from study conduct.

Recommended Use: Required ID (Language): 16707 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Chemicals, Test Articles, and Solutions

This module identifies GLP requirements for the receipt, distribution, storage, and disposal of chemicals. It describes the role of laboratory personnel in ensuring security and integrity of test and control articles, and other commonly used substances. It also discusses the proper handling procedures for commercial products and test articles by using information provided on safety data sheets (SDSs) and SOPs.

Recommended Use: Required ID (Language): 16706 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

Reporting of Study Results and Regulatory Decisions on Study Disqualification

Discusses the requirements involved in creating a final report of study results intended for submission to the regulatory authorities. It identifies the conditions that may result in the disqualification of a study by FDA or EPA, and describes the role of a compliance statement in a final report. It also shows the ways in which data integrity and overall quality is directly related to the actions of study and supervisory personnel.

Recommended Use: Required ID (Language): 16709 (English) Author(s): Kathryn Hackett-Fields, RQAP-GLP - QualiStat, Inc.

CME/CEU Credits

To purchase CE credits and units, you need to be affiliated with an organization that subscribes to this course or buy it as an independent learner first. Learn more about CE/CME Credits.

What is the importance of GLP training?

GLP training ensures that nonclinical laboratory studies are planned, performed, monitored, recorded, reported, and archived as set forth by the U.S. Food and Drug Administration (FDA), Environmental Protection Agency (EPA), and Department of Agriculture (USDA), as well as the Organisation for Economic Co-operation and Development (OECD) international guidelines.

When should someone consider taking the GLP course?

This course is suitable for learners seeking an educational resource that helps ensure compliance with GLP regulations and guidelines. There is no uniform standard for how frequently GLP training should occur. For a retraining (refresher) cycle, organizations should designate the frequency for their learner groups. Unlike other CITI Program courses, there is no “refresher” version available at this time, but learners can retake the GLP course or complete whatever subset of modules their organization has selected for them.

How is this course structured?

It consists of 15 modules that provide a highly detailed training on GLP regulations and guidelines. The modules contain expert content, images, supplemental materials (such as, case studies), and a quiz. Learners may complete the modules at their own pace.

What regulations and topics does GLP cover?

GLP discusses FDA, EPA, and USDA regulations, and OECD international guidelines pertaining to GLP. It also covers a history of GLP, U.S. and international regulatory agencies, GLP definitions, compliance with GLP, personnel responsibilities, use of laboratory animals, SOPs and equipment operation, raw data and reconstruction, study protocols, archiving study data and specimens, quality assurance, chemicals and test articles, reporting study results, and study disqualification.

What are the recommendations for setting up a GLP learner group?

CITI Program allows organizations to customize their learner groups, which means they can choose the content modules their learners need to complete. We will work with your CITI Program designated admin to determine the learner groups that best fit your organizational needs.

The standard recommendation for GLP is to designate each module as required in a learner group. This helps to ensure a complete training for the learner. However, organizations may also elect to present certain modules as supplemental, particularly when the organizations provide specific training on the topic(s). The standard passing score for a GLP course is 80 percent.

What are the advantages of CITI Program's GLP training?

GLP was developed and reviewed by industry experts to provide organizations and individuals with an educational resource that will help ensure compliance with GLP regulations and guidelines. The author has over 28 years of experience in quality assurance and working with EPA, FDA, and OECD-compliant research and testing. Along with CITI Program's advantages, including our experience, customization options, cost effectiveness, and focus on organizational and learner needs, this makes it an excellent choice for GLP training.

Related Content

BSS offers courses that cover the principles of biosafety and biosecurity, including the safe use and containment of biohazardous agents.

This course covers the fundamental safety practices for working with hazardous chemicals in the laboratory.

IPS covers data protection principles, focusing on basic information security requirements and the educational records and data-related requirements of FERPA.

Covers various technologies and their associated ethical issues and governance approaches.

This role-based course covers supervision, delegation, management, reports, and communication for investigators.

Provides an overview of health disparities while raising awareness of this issue in research design and conduct.

GCP consists of basic and refresher courses that provide essential good clinical practice training for research teams involved in clinical trials.

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Good Laboratory Practice for Nonclinical Laboratory Studies

Under the proposed GLP Quality System, we intend to enhance the current quality system approach for nonclinical laboratory studies. The GLP Quality System will provide additional responsibilities for testing facility management and new responsibilities for maintaining SOPs. We propose modifications to the definition of a testing facility to be applicable to all nonclinical laboratory studies, whether they are conducted at a single facility or at multiple sites. We propose amending roles and functions consistent with the revised testing facility definition. We expect that a GLP Quality System will provide the appropriate framework for building quality into a nonclinical laboratory study and will result in more reliable data for us to consider when making regulatory decisions.

Costs estimates of the rule include annual costs from the additional reporting and recordkeeping responsibilities required under the proposed GLP Quality System. One-time costs include reading and understanding the rule, updating existing SOPs, writing new SOPs, and training. We estimate annualized costs, over a 10-year period, at a 7-percent discount rate would average $51.9 million, or $51.5 million with a 3- percent discount rate. We lack sufficient information to quantify the benefits of the proposed rule, but we anticipate that it would result in better quality and more reliable data to support applications and submissions to us.

Regulatory Impact Analysis

Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed Rule (PDF - 548KB)

Federal Register: Good Laboratory Practice for Nonclinical Laboratory Studies

Docket: FDA-2010-N-0548-0088

Good Laboratory Practices

Good Laboratory Practices (GLP) is an official regulation that was created by the FDA in 1978. Good Laboratory Practice (GLP) is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.

The purpose of GLP is to

• Ensure quality test data
• Ensure sound laboratory laboratory management
• Ensure robust conductance of laboratory testing
• Ensure accurate reporting of test findings
• Ensure safe archival of laboratory data

The GLP Principles basically encompasses following points

1. Test facility organization and personnel

• Test facility management should designate personnel to assume responsibility for the quality assurance programme, and these personnel should not be involved in the conduct of the regulatory work being assured.
• Test facility management should ensure that there is a quality assurance programme, with designated personnel, and assure that the quality assurance programme is being performed in accordance with the principles of GLP.
• Has the responsibility for the overall performance of the study and the final report.
• Approves the study plan and amendments and communicate them to the QA personnel.
• Ensures that SOPs, study plans and their amendments are available to study personnel.
• Ensures that the SOPs are followed, assess the impact of any deviations and takes appropriate corrective and preventive action.
• Ensures that raw data are documented and recorded.
• Computerized systems are validated.
• Sign and date the final report to indicate acceptance of responsibility.
• Knowledge of the GLP principals
• Access to the study plan and appropriate SOPs
• Comply with the instructions of the SOPs
• Record raw data
• Study personnel are responsible for the quality of their data
• Exercise health precautions to minimize risk
• Ensure the integrity of the study

2. Quality Assurance (QA) programme

• Quality control is the process, procedures and authority used to accept or reject all components, drug product containers, closures, in-process materials, packaging material, labeling and drug products and the authority to review production records to assure that no errors have occurred, that they have been fully investigated.
• The quality and reliability of test data count on the state and condition of the test system which is used in its production.
• The test facility should have a documented Quality Assurance Programme to guarantee that studies performed comply with these Principles of Good Laboratory Practice.
• The Quality Assurance Programme should be performed by an individual or by individuals designated by.
• The Quality Assurance personnel should be responsible of maintaining copies of all approved study plans and Standard Operating Procedures in use in the test facility and have access to an up-to-date copy of the master Schedule, verifying that the study plan contains the information required for compliance with these Principles of Good Laboratory Practice, conducting inspections to determine if all studies are conducted in accordance with these Principles of Good Laboratory Practice.
• Inspections should also determine that study plans and Standard Operating Procedures have been made available to study personnel and are being followed.
• Inspections are made in order to determine compliance of the study with GLP principles.
• Three types of inspection are basically carried out: Study-based inspections, Facility-based inspections, Process-based inspections.
• These inspections should involve those parts of a study that have particular importance for the validity of the data and the conclusions to be drawn from there, or where deviations from the rules of GLP would most heavily have a powerful effect on the integrity of the study.
• Quality Assurance thus has to find a balance in their inspectional activities, evaluating the study type and “critical phases”, in order to achieve a well supported view of the GLP compliance at the test facility and within the studies conducted.
• In the final reports it should be confirmed that the methods, procedures, and observations are accurately and completely described, and that the reported results accurately and completely reflect the raw data of the studies.
• Inspections of the final reports are done for accurate and full description.
• The audit of the final report, hence serves to ascertain the quality and integrity of the specific study with its detailed assessment of GLP compliance throughout the study and with its concomitant review of all relevant information, records and data.

3. Facilities

• GLP requires that test facilities be of appropriate size, construction and location to meet the requirements of the study and minimize disturbances that would interfere with the validity of the study.
• They should be designed to provide an adequate degree of separation between the various activities of the study.
• Separation renders the assurance that different functions or activities do not interfere with each other or affect the study.
• Physical separation: this can be achieved by walls, doors or filters, or by the use of isolators. In new buildings or those under transition or renovation, separation will be part of the design.
• Separation by organization, for example by the establishment of defined work areas within a laboratory carrying out different activities in the same area at different times, allowing for cleaning and preparation between operations or maintaining separation of staff, or by the establishment of defined work areas within a laboratory.
• Isolation of test systems and individual projects to protect from biological hazards.
• Suitable rooms for the diagnosis, treatment and control of diseases.
• Storage rooms for supplies and equipment.
• Separate areas for receipts and storage of the test and reference items.
• Separation of test items from test systems.
• Archive facilities for easy retrieval of study plans, raw data, final reports, samples of test items and specimens.
• Handling and disposal of waste in such a way not to jeopardize the integrity of the study.
• Documented inspection, cleaning, maintenance and calibration of apparatus.

4. Test systems

• Equipment, including validated computerized systems, used for the generation, storage and recovery of data, and for controlling environmental factors relevant to the study should be suitably located and of appropriate design and adequate capacity.
• Equipment records should include: name of the equipment and manufacturer, model or type for identification, serial number, and date equipment was received in the laboratory, copy of manufacturers operating instruction(s).
• Equipment used in a study should be periodically inspected, cleaned, maintained, and calibrated according to Standard Operating Procedures.
• Records of these activities should be maintained.
• Calibration should be traceable to national or international standards of measurement.
• Instrumentation validation is a process necessary for any analytical laboratory.
• Data produced by “faulty” instruments may give the appearance of valid data.
• The frequency for calibration, re-validation and testing depends on the instrument and extent of its use in the laboratory.
• Chemicals, reagents, and solutions should be labeled to indicate identity, expiry date and specific storage instructions.
• Information concerning source, preparation date and stability should be available.
• Appropriate design and adequate capacity of apparatus used for the generation of data.
• Integrity of physical/chemical test systems and biological test systems.
• Proper conditions for storage, housing, handling and care.
• Humanely destruction of inappropriate test systems.
• Records of source date of arrival and arrival conditions of test systems.
• Acclimatization of biological systems to the test environment.
• Proper identification of test systems in their housing or container or when removed.
• Cleaning and sanitization of housings or containers.

5.Test and reference items

• Records including test item and reference item characterization, date of receipt, expiry date, quantities received and used in studies should be maintained.
• Handling, sampling, and storage procedures should be identified in order that the homogeneity and stability are assured to the degree possible and contamination or mixup are precluded.
• Storage container(s) should carry identification information, expiry date, and specific storage instructions.
• Each test and reference item should be appropriately identified (e.g., code, Chemical Abstracts Service Registry Number [CAS number], name, biological parameters).
• For each study, the identity, including batch number, purity, composition, concentrations, or other characteristics to appropriately define each batch of the test or reference items should be known.
• In cases where the test item is supplied by the sponsor, there should be a mechanism, developed in co-operation between the sponsor and the test facility, to verify the identity of the test item subject to the study.
• The stability of test and reference items under storage and test conditions should be known for all studies.
• If the test item is administered or applied in a vehicle, the homogeneity, concentration and stability of the test item in that vehicle should be determined.
• For test items used in field studies (e.g., tank mixes), these may be determined through separate laboratory experiments.
• A sample for analytical purposes from each batch of test item should be retained for all studies except short-term studies.
• The register for all reference substances and reference materials should be maintained and contain the following information:
• a) the identification number of the substance or material
• b) a precise description of the substance or material
• c) the source
• d) the date of receipt
• e) the batch designation or other identification code
• f) the intended use of the substance
• g) the location of storage in the laboratory, and any special storage conditions
• h) expiry date or retest date
• i) certificate (batch validity statement) of a pharmacopoeial reference substance and a certified reference material which indicates its use, the assigned content, if applicable, and its status (validity)
• j) in the case of secondary reference substances prepared and supplied by the manufacturer, the certificate of analysis

6.Standard Operating Procedures (SOP’s)

• Standard Operating Procedures (SOPs) are intended to describe procedures that are routinely employed in the performance of test facility operations. Indeed they are defined as “documented procedures which describe how to perform tests or activities normally not specified in detail in study plans or test guidelines.”
• A test facility should have written Standard Operating Procedures approved by test facility management that are intended to ensure the quality and integrity of the data generated by that test facility.
• Revisions to Standard Operating Procedures should be approved by test facility management.
• Each separate test facility unit or area should have immediately available current Standard Operating Procedures relevant to the activities being performed therein.
• Published textbooks, analytical methods, articles and manuals may be used as supplements to these Standard Operating Procedures.
• Laboratory management must be sure that the SOPs used in the laboratory are useful in daily operations and they should be scientifically sound and also, they should always be updated as necessary and rewrites should be the part of the routine process.
• While writing SOP guidelines there must be some precautions such as avoiding restrictive language such as “vortex for exactly 1 minute” but include clear instructions such as “vortex until homogenized” if that satisfies the purpose. Unnecessary steps should not be added such as “consult the manual” unless personnel are required to follow this step.
• Study personnel should easily access the study plan and appropriate Standard Operating Procedures should be applicable to their involvement in the study.
• It is their responsibility to comply with the instructions given in these documents. Study personnel should exercise health precautions to minimize risk to themselves and to ensure the integrity of the study.
• Deviations from Standard Operating Procedures related to the study should be documented and should be acknowledged by the Study Director and the Principal Investigator(s), as applicable.

7. Performance of the study

• Performance of the Study should be monitored carefully.
• All the standards supplied by the GLP should be followed from the beginning of the study to the end by the final report.
• For each study, a written plan should exist prior to the initiation of the study.
• The study plan should contain the following information: Title, nature and purpose of the study, test item identity, reference item used etc.
• Information concerning the sponsor and facility, names and address (sponsor, test facility, study director), dates approval, dates of the study plan, estimated starting and completion dates etc.
• The study plan should be approved by a dated signature of the Study Director and verified for GLP compliance.
• Deviations from the study plan should be described, explained, recognized and dated in a timely fashion by the Study Director and/or Principal Investigator(s) and maintained with the study raw data.
• Computerized system design should always supply for the retention of full audit trails to show all changes to the data without obscuring the original data.
• It should be possible to associate all changes to data with the persons having made those changes. Reason for changes should be given.

8. Reporting of study results

• All studies generate raw data that are the original data gathered during the conduct of a
• Raw data refers to any laboratory worksheets, records, memoranda, notes, or exact copies that are the results of original observations and activities of a study.
• The term covers all data necessary for the reconstruction of the report of the study.
• Raw data may include handwritten notes, photographs, microfiche copies, computer print-outs, magnetic media, dictated observations, and electronically recorded data from automated instruments.
• They are essential for the reconstruction of studies and contribute to the traceability of the events of a study.
• Raw data are the results of the experiment upon which the conclusions of the study will be based.
• Some of the raw data may be used directly, and some of them will be treated statistically.
• The results and their interpretations provided by the scientist in the study report must be a true and accurate reflection of the raw data.
• A final report should be prepared for each study.
• The study report, like all the other scientific aspects of the study, is the responsibility of the Study Director. He/she must ensure that it describes the study accu Reports of Principal Investigators or scientists involved in the study should be signed and dated by them.
• The final report should be signed and dated by the Study Director to indicate acceptance of responsibility for the validity of the data.
• If necessary, corrections and additions to a final report should be in the form of amendments.
• Amendments should clearly specify the reason for the corrections or additions and should be signed and dated by the Study Director.
• The Study Director is responsible for the scientific interpretation included in the study report and is also responsible for declaring to what extent the study was conducted in compliance with the GLP Principles.
• The GLP Principles list the essential elements to be included in a final study report.
• The final report should include the following information: A descriptive title; identification of the test item by code or name, characterization of the test item including purity, stability and homogeneity.
• Information concerning the sponsor and the test facility should imply; name and address of the sponsor, any test facilities and test sites involved, the study Director, the Principal Investigator(s) and the phase(s) of the study, delegated and scientists having contributed reports to the final report, experimental starting and completion dates.
• A Quality Assurance Programme statement listing the types of inspections made and their dates, including the phase(s) inspected, and the dates any inspection results should be reported to management and to the Study Director and Principal Investigator(s).
• This statement should also serve to confirm that the final report reflects the raw data.
• It should contain the Description of Materials and Test
• A summary of results should be
• All information and data required by the study plan; A presentation of the results, including calculations and determinations of statistical significance; An evaluation and discussion of the results and, where appropriate, conclusions.
• It should imply the location(s) where the study plan, samples of test and reference items, specimens, raw data and the final report are to be stored.
• A computerized system to be used in a GLP area should include both the dating and timing of the original entry and the retention of a full audit trail.
• Such identification could be possible either by the use of personal passwords recognized by the computer or by digital
• Therefore GLP wants to ensure that data safety and integrity remains the same electronically as in manually recorded data, irrespective of how they were recorded, and that reconstruction of the way in which the final results and conclusions were obtained remains fully possible.
• The Study Director must sign and date the final report to indicate acceptance of responsibility for the validity of all the data.

Storage and retention of records and materials

The following should be retained in the archives for the period specified by the appropriate authorities:

• a) The study plan, raw data, samples of test and reference items, specimens, and the final report of each study;
• b) Records of all inspections performed by the Quality Assurance Programme, as well as master schedules;
• c) Records of qualifications, training, experience and job descriptions of personnel; d) Records and reports of the maintenance and calibration of apparatus;
• e) Validation documentation for computerised systems;
• f) The historical file of all Standard Operating Procedures;
• g) Environmental monitoring records.
• In the absence of a required retention period, the final disposition of any study materials should be documented.
• When samples of test and reference items and specimens are disposed of before the expiry of the required retention period for any reason, this should be justified and documented.
• Samples of test and reference items and specimens should be retained only as long as the quality of the preparation permits evaluation.
• Material retained in the archives should be indexed so as to facilitate orderly storage and retrieval.
• Only personnel authorized by management should have access to the archives.
• Movement of material in and out of the archives should be properly recorded.
• If a test facility or an archive contracting facility goes out of business and has no legal successor, the archive should be transferred to the archives of the sponsor(s) of the study(s).

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Home » Resources » Blogs » Good Laboratory Practices (GLP): Ensuring Quality and Reliability in Scientific Research

Good Laboratory Practices (GLP): Ensuring Quality and Reliability in Scientific Research

• Hovsep Kirikian
• June 14, 2023

Good Laboratory Practices (GLP) are the guidelines and standards that laboratories and researchers follow to help ensure the accuracy, reliability, and reproducibility of experimental results in scientific research. GLP encompasses the principles and practices of designing and conducting experiments and documenting and reporting the results. This blog delves into the fundamental aspects of GLP and how it helps life sciences organizations maintain scientific rigor.

Learn how to overcome challenges in the journey from R&D to commercialization. Watch USDM’s virtual event specifically for pre-commercial life science companies: Emerging Life Sciences on-demand webinar .

Defining Good Laboratory Practice

GLP is a set of internationally recognized quality assurance principles and guidelines that govern the conduct of non-clinical laboratory studies. These guidelines were established to help ensure that the data generated from these studies are reliable, accurate, and traceable. GLP applies to facilities, equipment, personnel, methodologies, data management, and reporting.

Key Principles of GLP

GLP is based on fundamental principles for maintaining quality and reliability in laboratory studies, including:

Standard Operating Procedures (SOPs) : SOPs provide detailed instructions on how to carry out specific tasks or procedures in the laboratory and help to ensure consistency and accuracy across experiments and researchers.

Read our case study: Fast DocuSign Validation and SOPs for Clinical-Stage Biopharma Needing GxP System Expertise .

Personnel Training: Training laboratory personnel to conduct experiments consistently is imperative. Training programs should cover experimental techniques, safety protocols, data management, and GLP regulations. See how USDM can help your organization with GxP training .

Facilities and Equipment: Laboratories must provide suitable facilities and maintain well-calibrated equipment to help ensure accurate and reliable results. Regular equipment maintenance, calibration, and validation are essential to minimize errors and deviations.

Quality Assurance: GLP helps organizations to implement quality assurance measures throughout the entire experimental process. This includes validating analytical methods, documenting experimental procedures, and conducting regular inspections and audits to identify and rectify any potential issues. Read how ZenQMS has partnered with USDM Life Sciences to simplify GxP quality assurance.  

Data Integrity and Management: Accurate and traceable data is the cornerstone of GLP . Laboratories must establish robust systems for data collection, storage, and archiving so that data can be retrieved and verified at any time. Proper data management minimizes the risk of data loss, manipulation, or unauthorized access.  

Reporting and Documentation: GLP requires comprehensive documentation of experimental procedures, observations, and results. This documentation should be clear, detailed, and organized to enable effective review, replication, and verification of the study. Transparency and traceability are vital to maintaining scientific integrity.

GLP in Various Research Fields

Good Laboratory Practices are relevant across research fields, including pharmaceuticals, chemicals, pesticides, biotechnology, and environmental sciences. GLP helps ensure that data generated from non-clinical studies–such as toxicology, environmental fate, and efficacy testing–are reliable and usable for regulatory submissions and risk assessment.  

GLP and Regulatory Compliance

In addition to maintaining scientific integrity, GLP is highly relevant to regulatory compliance. Regulatory authorities like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require that data from non-clinical studies that are submitted for product registration comply with GLP regulations. GLP is necessary for obtaining approval and market authorization for pharmaceuticals, chemicals, and other regulated products.

Challenges in Maintaining GLP

While GLP provides a robust framework for ensuring quality and reliability in scientific research, challenges still exist; for example, establishing laboratory SOPs, managing equipment and documentation, and providing necessary training. Some laboratories may face resource constraints, such as limited funding or outdated equipment, which can hinder their ability to maintain GLP.

How can USDM Life Sciences help with your GLP needs?

• Regulatory Strategy Operations  
• Regulatory and Clinical Strategy  
• Lifecycle Management  
• FDA/Agency Meeting Preparation  
• IND, NDA/BLA, ANDA, IDE, 510(K), PMA Preparation  
• Submissions & Publishing & eCTD  
• Drug & Device Labeling  
• Regulatory Affairs IT Systems  
• Process Improvement & Implementation  
• Lab Controls and Data Integrity  
• Data Integrity Remediation  
• Interim Subject Matter Experts & Staffing  
• Staff Training  
• Project Management  
• Quality Systems Design, Strategy, and Implementation  
• Quality Systems Development  
• Data Integrity  
• Risk Management  
• Design Controls  
• Support to Implement New/Revised Standards & Regulations  
• FDA/EMA/Health Authority Agency Intelligence  
• Coordination with Regulatory Counsel  
• Third-Party Support  
• Auditing and Assessments  
• Supplier Assessments

We’ve helped 200+ pre-commercial life science companies. Contact us to see how we can help you!  

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